APOBEC3-Related Editing and Non-Editing Determinants of HIV-1 and HTLV-1 Restriction

Abstract

The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3/A3) family of cytosine deaminases serves as a key innate immune barrier against invading retroviruses and endogenous retroelements. The A3 family’s restriction activity against these parasites primarily arises from their ability to catalyze cytosine-to-uracil conversions, resulting in genome editing and the accumulation of lethal mutations in viral genomes. Additionally, non-editing mechanisms, including deaminase-independent pathways, such as blocking viral reverse transcription, have been proposed as antiviral strategies employed by A3 family proteins. Although viral factors can influence infection progression, the determinants that govern A3-mediated restriction are critical in shaping retroviral infection outcomes. This review examines the interactions between retroviruses, specifically human immunodeficiency virus type 1 and human T-cell leukemia virus type 1, and A3 proteins to better understand how editing and non-editing activities contribute to the trajectory of these retroviral infections.

1. Introduction

Restriction factors (RFs) are intracellular host proteins that inhibit viral replication, providing intrinsic immunity against viral infections (reviewed in [1,2,3,4,5]). RFs are either constitutively expressed or induced by mediators of the innate immune response to counteract specific steps of the viral life cycle (reviewed in [1,3,4,5,6]). The first discovered RF was Friend virus susceptibility-1 (Fv1), which restricts murine leukemia virus infection [7,8]. Afterward, multiple RFs were identified as inhibitors of human immunodeficiency virus type 1 (HIV-1) infection, which they achieve by blocking various stages of the virus’ life cycle (reviewed in [1,2,3,4,5,6]). However, viruses have evolved strategies to evade RF activity, enhancing viral infection, fitness, and spread (reviewed in [1,2,3,4]). Although viruses can escape RF-mediated restriction, rendering these factors ineffective in controlling replication in natural hosts, RFs often exhibit strong antiviral activity against viruses from other species, creating species-specific barriers to infection (reviewed in [1,5,9,10]). This dynamic interplay involves RFs targeting viral proteins to inhibit their functions and viral proteins counteracting RFs to promote replication (reviewed in [1,4,11]), ultimately shaping viral pathogenesis and infection outcomes.

The human apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3/A3) family of proteins is a critical group of RFs that defend against viral infections and suppress endogenous retroelement activity (reviewed in [1,2,12,13,14,15,16,17]). In humans, the A3 family comprises seven members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (Figure 1) (reviewed in [2,18,19,20]). The genes of this family are arranged as a tandem cluster between the flanking genes CBX6 and CBX7 on chromosome 22 (reviewed in [20,21,22]). A3 enzymes catalyze cytosine (C) deamination to uracil (U) in single-stranded DNA (ssDNA) substrates (reviewed in [2,18,19,21]). The deamination mechanism relies on a conserved zinc-binding domain (Z domain) and occurs via zinc-mediated hydrolysis, where a zinc-stabilized hydroxide ion interacts with the four-position of C, replacing the amine group (NH₂) with a carbonyl group (reviewed in [22,23]). A3 proteins possess either one (A3A, A3C, and A3H) or two (A3B, A3D, A3F, and A3G) conserved Z domains, categorized into three distinct groups: Z1, Z2, and Z3 (Figure 2) (reviewed in [2,19,20,24,25]). These structural differences underpin the functional diversity of A3 proteins.

Most functional insights into A3 proteins as RFs come from studies on retroviruses, particularly HIV-1 (reviewed in [1,2,18,22]). A3G was the first A3 protein identified to restrict the infectivity of viral infectivity factor (Vif)-deficient HIV-1 [26], binding viral and cellular RNA, packaging into nascent virions from virus-producing cells (Figure 1), and inducing lethal C-to-U mutations in viral cDNA (reviewed in [1,2,18,22]). Other A3 proteins, including A3C-I188, A3D, A3F, and stable haplotypes of A3H, also restrict HIV-1 infection in CD4⁺ T lymphocytes [27,28,29,30,31,32,33]. Additionally, A3 proteins employ deaminase-independent mechanisms to exert antiviral activity (Figure 1) [34,35,36,37,38,39,40,41]. To counteract A3 protein activity, HIV-1 has evolved a Vif-mediated proteasomal degradation pathway that prevents A3 proteins from being packaged into viral particles (reviewed in [1,2,18,22,42]).

Human T-cell leukemia virus type 1 (HTLV-1), another retrovirus, is also targeted by A3 proteins. Although HIV-1 and HTLV-1 share similar replication cycles, HTLV-1 spreads primarily through the clonal expansion of infected cells rather than via the production and release of new virions, thereby reducing exposure to A3-mediated antiviral effects (Figure 3) (reviewed in [43,44,45]). Consequently, the selective pressure exerted by A3 proteins on HTLV-1 differs markedly from that on HIV-1. This review explores the mechanisms through which A3 proteins antagonize HIV-1 and HTLV-1, along with the countermeasures these viruses employ to evade A3 protein activity, ultimately shaping infection outcomes.

In addition to retroviruses, many reports have demonstrated an interaction between A3 family proteins and non-retroviruses as A3-induced mutational signatures were detected in the genomes of ssDNA virus (transfusion-transmitted virus [46]), double-stranded DNA viruses (human herpes viruses [47,48], human papillomavirus [49,50], human polyomaviruses [50,51], human orthopoxvirus [52,53,54,55]), hepadnavirus (hepatitis B virus [50,56,57,58,59]), and single-stranded RNA (ssRNA) viruses (human coronaviruses [50,60,61,62,63,64]). Furthermore, the antiviral activity of A3 family proteins is also extended to parvovirus [65,66], herpes simplex virus 1 [47], Epstein-Barr virus [48], hepatitis B virus [67,68], and human coronavirus NL63 [69]. Although A3 family proteins have been reported to contribute to the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [50,60,61,62,63,64], these proteins may support SARS-CoV-2 replication [63,70].

2. Physiological Functions of APOBEC Family Proteins

The A3 proteins form part of the broader APOBEC family, which has been identified in most vertebrates [71,72,73,74,75]. The first member discovered was APOBEC1 (A1) [76,77], which is abundantly expressed in the small intestine, where it plays a role in lipid metabolism by targeting the apolipoprotein B (apoB) mRNA substrate (reviewed in [78,79,80]). Subsequently, several A1 proteins from various nonhuman species were found to deaminate ssDNA [81,82,83] and exhibit restriction potential against retroviruses and endogenous retroelements in cell line models [82,83,84,85,86,87,88,89]. In mice and rabbits, A1 mRNA is also expressed in immune cells along with the small intestine and liver [82,90]. These findings suggest an innate immune function for A1 protein in combating retroviruses and mobile elements in some nonhuman species [75]. The second identified APOBEC family member was activation-induced cytosine deaminase (AID), which mainly catalyzes the deamination of immunoglobulin (Ig) genes [91]. AID protein initiates somatic hypermutation and recombination events that drive antibody class switching (reviewed in [80,92,93]). Although this protein can also bind RNA, it exhibits no catalytic activity in this context [94]. Other APOBEC family members include APOBEC2 (A2) and APOBEC4 (A4) proteins. A2 protein is expressed in cardiac and skeletal muscles and is crucial for muscle development, as demonstrated by the development of myopathy in A2-knockout animal models [95,96]. A4, a less-characterized protein, is primarily expressed in mammalian testes and may contribute to promoter modulation or antiviral responses in birds [97,98]. Importantly, with the exception of A3D, A2, and A4 proteins, other APOBEC family proteins can edit epigenetic codes (reviewed in [99,100]) by deaminating 5-methylcytosine (5mC) to thymine (T). This process produces T-to-guanine (G) mismatches, followed by error-free DNA repair [101,102].

3. Factors Regulating the Catalytic Activity of A3 Family Proteins

The catalytic activity of A3 proteins is largely influenced by their biochemical and structural characteristics, as well as interactions with various cellular factors that determine the net outcome of A3-mediated deamination and retrovirus restriction capabilities (Figure 2) (reviewed in [15,19,22,103,104,105]). Understanding these factors is essential to evaluating the efficiency of A3-mediated catalytic activity. This section highlights the regulatory factors influencing A3 family proteins’ catalytic activity, which are key determinants of their restriction effectiveness against retrovirus infections (Figure 2).

3.1. Structural Characteristics of A3 Family Proteins

The protein organization of A3 family proteins markedly affects their activity (Figure 2). The catalytic domains of different A3 proteins have evolved distinctly around their conserved Z domains (Figure 2) (reviewed in [2,9,15,20]). Variations in the length, composition, and spatial arrangement of conserved secondary structural features near the catalytic site influence substrate selection and regulation of deamination, resulting in variable activity (Figure 1) (reviewed in [15,103,106,107]).

Interactions between A3 family proteins and nucleic acids occur through a shallow substrate-binding groove defined by four loops around the active site (loops 1, 3, and 7, with minor contributions from loop 5). High-resolution structural analyses of A3 proteins have revealed substantial plasticity and sequence variability within these loops (reviewed in [2,107]). Differences in the amino acid composition, length, and spatial confirmation of loops 1, 3, and 7 contribute to functional variations in substrate recognition and deamination activity (Figure 1) (reviewed in [15,107]). Studies using chimeric proteins, where putative DNA-binding loop regions of A3G protein were replaced with those from A3A protein, showed that replacing loop 3 enhanced A3G catalytic activity without altering its preferred dinucleotide substrate (5′-CC, where the underlined C is the target C). Conversely, replacing loop 7 altered A3G’s dinucleotide preference, mimicking A3A’s substrate preference (5′-TC). Notably, the simultaneous replacement of loops 3 and 7 produced a hyperactive A3G mutant [108].

Deamination target selection varies among A3 proteins, with intrinsic preferences for specific motif sequences and substrate structures (Figure 2). For example, A3G protein targets C preceded by another C (5′-CC), whereas A1 and other A3 proteins target C preceded by T (5′-TC) [30,31,85,86,108,109,110,111]. However, targeting specific dinucleotide sites alone does not guarantee deamination. Some TC dinucleotide sites are not targeted by A3G protein, whereas others (known as hotspots) are preferentially deaminated [112,113]. This suggests that A3 proteins exhibit preferences beyond dinucleotide contexts that remain to be fully elucidated [114].

Both catalytically active domains [present in all single-domain A3 proteins and the C-terminal domains (CTDs) of double-domain A3 proteins] and catalytically inactive domains [found in N-terminal domains (NTDs) of double-domain A3 proteins] interact with nucleic acid substrates (Figure 2) (reviewed in [103,115,116]). The noncatalytic NTDs, despite lacking deaminase activity, regulate catalytic activity by guiding the proteins to active sites, promoting oligomerization, and enhancing ssDNA binding affinity (Figure 2) (reviewed in [116]). For instance, positively charged patches on the noncatalytic domains of A3B, A3F, and A3G proteins enhance deamination [117]. In contrast, RNA binding competitively regulates A3 proteins by rendering them catalytically inactive [118,119]. Cellular RNA and substrate ssDNA bind to the same A3G tryptic peptides; thereby, competition between ssDNA substrate and ssRNA to bind A3G limits its deamination capacity, as it was shown that RNA binding to A3G inhibits its further binding to ssDNA substrates as well as promotes A3G multimer dissociation from substrates [118,119]. Similarly, RNA binding alters the structure of A3H protein (via loops 1 and 7), reducing its deamination capacity [120]. It also attenuates the deamination rate of native A3B protein and diminishes its ability to induce double-stranded DNA breaks [121].

3.2. Cellular Factors Regulating the Enzymatic Activity of A3 Family Proteins

The enzymatic activity of A3 family proteins is regulated through interactions with various cellular RNAs and proteins (Figure 2). These interactions are mediated by their RNA-binding ability, leading to incorporation into large ribonucleoprotein complexes. Multiple reports have shown that A3 family proteins (at least A3C, A3F, A3G, and stable A3H, but not A3A) can form high molecular mass (HMM) complexes consisting of A3-binding RNAs, A3-binding proteins, and various RNA-binding proteins [117,122,123,124,125,126,127,128,129,130,131,132,133]. Notably, the enzymatic activity of cellular A3B, A3G, and A3H proteins is inactivated in HMM complexes but can be restored following RNase treatment [48,117,120,126]. For example, a study reported that virion-incorporated A3G is enzymatically inactivated by association with viral RNA, and degradation of viral RNA causes A3G-mediated hypermutation against viral cDNA intermediates [126]. Another study demonstrated that HIV-1 preferentially infects phytohemagglutinin (PHA)/interleukin-2 (IL-2)-activated CD4+ T cells due to promoting HMM A3G formation [127]. Additionally, a study showed that heat-shock protein (HSP) 70 stabilizes A3G protein [129]. HSP90 enhances the deamination activity of A3B, A3C, and A3G proteins during coexpression in human HepG2 liver cells and increases A3G’s C mutation efficiency in hepatitis B virus DNA [134]. Another cellular protein, ubiquitin-specific protease 49, stabilizes the A3G protein by removing the HIV-1 Vif ubiquitination mark, thereby enhancing its activity [135]. Furthermore, the depletion of exosome component 9, a component of the RNA exosome, results in reduced A3G mRNA expression levels in a cancer cell model [136].

The subcellular localization of A3 proteins is also influenced by cellular factors (Figure 2). Each A3 protein typically localizes to the cytoplasm, nucleus, or both (reviewed in [21,137]). A3A and A3C proteins exhibit cell-wide distributions [30,48,125,138,139,140], whereas A3B protein is primarily nuclear [30,48,120,138,139,140,141,142,143]. Notably, endogenous A3A protein localizes to the cytoplasm in primary CD14⁺ cells and interferon (IFN)-stimulated THP-1 cells, in contrast to overexpressed A3A protein in HEK293 and HeLa cells [30,125,139,144]. This difference in subcellular localization between endogenous and overexpressed A3A proteins suggests a regulatory mechanism governing its enzymatic activity. A3D, A3F, and A3G proteins are predominately cytoplasmic [30,120,125,130,139,140,142], whereas A3H protein shows variable localization patterns depending on its haplotype, with haplotype I (hapI) distributed throughout the cell and haplotype II (hapII) localized to the cytoplasm and nucleolus [120,140,145,146].

4. Restriction Activity of A3 Family Proteins Against HIV-1

Acquired immunodeficiency syndrome (AIDS) was first identified in 1981, and its causative agent, HIV-1, was confirmed in 1983. HIV-1 infection triggers the expression of host RFs and upregulates IFN-stimulated genes, including the A3 proteins (reviewed in [104,105,147]). A3 protein expression confers innate immune responses by inducing hypermutation of the viral genome, causing potentially lethal changes to the virus and further restricting infection. However, HIV-1 has developed a mechanism to evade this defense: the Vif protein recruits host cofactors to ubiquitinate A3 proteins for degradation, neutralizing this defense mechanism (reviewed in [2,18,23,34,42]). Although structural characteristics and cellular factors regulate the enzymatic activity of A3 proteins (refer to Section 3), this section discusses the interaction of A3 proteins with HIV-1, which determines HIV-1 infection outcomes.

4.1. Editing and Non-Editing Mechanisms for HIV-1 Restriction

HIV-1 is a well-documented target of A3 proteins (reviewed in [1,2,18,22]). Among these proteins, the A3G protein was the first found to inhibit viral replication in Vif-deficient HIV-1 (Figure 1) [26]. The HIV-1 restriction mechanisms employed by A3 proteins (mainly A3C I188, A3D, A3F, A3G, and A3H stable haplotypes) involve packaging into nascent virions from virus-producing cells, where they induce lethal C-to-U mutations in HIV-1 minus-strand cDNA intermediates in target cells (reviewed in [1,2,18,22]). Notably, A3 proteins are highly expressed in diverse immune cells and cell lines [29,34,132,141,148,149,150,151,152,153].

The antiviral activity of A3 proteins is also mediated through multiple deaminase-independent mechanisms (Figure 1) (reviewed in [2,17,22,154]). The roadblock model, a well-known deaminase-independent mechanism, involves A3G protein physically blocking viral reverse transcription and reducing the accumulation of reverse transcription products [34,35,36,37,39,40,66]. The direct interaction of A3G protein with HIV-1 reverse transcriptase also blocks reverse transcription [155,156]. Notably, the antiviral activity of A3F and A3H protein mainly arises in a deaminase-independent manner [120,157,158,159]. Importantly, A3G and A3F proteins interfere with viral genome integration by disrupting the structural integrity of the HIV-1 preintegration complex to inhibit proviral DNA integration into the host genome and by directly interacting with HIV-1 integrase to inhibit provirus formation [160,161] or compromising viral integration efficiency by affecting the processing of long extremities for viral long terminal repeats (LTRs) [162]. Additional non-editing activities of A3 proteins include the A3F protein, and, to a lesser extent, the A3G protein, remaining associated with the viral preintegration complex as it traffics into the host nucleus [163], altering proviral DNA integration site selection to avoid gene coding sequences and/or favoring integration into short interspersed nuclear elements, oncogenes, or transcription-silencing non-B DNA [160], potentially promoting more latent HIV-1 expression profiles (Figure 1).

Although A3G protein has been demonstrated to deaminate ssDNA, A3G-mediated deamination has not been observed in HIV-1 RNA or synthetic RNA oligonucleotides, ruling out RNA editing functions for A3G protein [85,87,164,165]. However, A3 proteins may mediate host modifications that facilitate cellular antiviral responses by editing host RNA. For instance, the A3A protein reportedly mediates widespread site-specific C-to-U RNA editing of cellular transcripts and host mRNA involved in proinflammatory (M1 phenotype) polarization of macrophages and in monocytes exposed to hypoxia and/or IFNs [166,167]. Additionally, transiently overexpressed A3G protein results in the editing of various host mRNAs in a HEK293T cell model [168,169]. A3G site specifically edits hundreds of genes [169], including those involved in HIV-1 replication, assembly, transcription, and infectivity, such as charged multivesicular body protein 4B [170], N-myristoyltransferase 1 [171], and RNA-binding motif protein 14 [172]. Further investigation is needed to determine the indirect effects of A3-mediated RNA editing on HIV-1 infection.

4.2. Counter-Defense Mechanisms Employed by Vif to Evade HIV-1 Restriction Activity by A3 Family Proteins

HIV-1 expresses the accessory protein Vif to counteract the antiviral activity of A3 proteins. Vif efficiently degrades A3 proteins in virus-producing cells and inhibits their packaging into nascent virions (reviewed in [2,18,23,34,42]). The primary function of HIV-1 Vif is to target A3 proteins for ubiquitination and proteasomal degradation by recruiting an E3 ubiquitin ligase complex composed of cullin 5 (CUL5), elongin B/C (ELOB/C), RING-box protein 2 (RBX2), transcription factor core-binding factor β (CBF-β), and Ariadne homolog 2 (ARIH2) (Figure 1) [34,173,174,175,176,177,178,179,180,181]. Structural studies have faced challenges in clarifying the costructures of Vif with full-length A3 proteins. However, a cryo-electron microscopy study revealed the structure of full-length human A3G protein bound to the HIV-1 Vif, CBF-β, ELOB, and ELOC (VCBC) complex, with RNA acting as a “molecular glue” for the A3G–Vif interaction, enabling Vif to repress the antiviral activity of A3G protein [176]. Other important Vif motifs are PPLP and its short downstream α-helix, α6. A recent study found that PPLP and α6 are critical to forming the functional VCBC complex in maintaining Vif-A3 interaction and are crucial for degrading A3 proteins [182].

HIV-1 Vif also mediates degradation-independent inhibition of A3 protein. For example, Vif inhibits A3G transcription by competing with Runt-related transcription factor (RUNX) and hijacking CBF-β, affecting A3 gene expression, the regulatory domains of which are associated with RUNX [183,184]. Similarly, HIV-1 Vif induces translational inhibition of A3G mRNA via ribosome stalling at the 5′-untranslated region or shuttling A3G mRNA to ribonucleoprotein granules, thereby delaying or preventing translation [185,186]. Notably, HIV-1 Vif also induces G2/M cell cycle arrest, which potentiates HIV-1 replication in multiple cell lines [187,188,189,190,191,192,193]. Vif remodels the host phosphoproteome, efficiently depleting members of the PPP2R5 family of protein phosphatase 2A regulators, which are involved in G2/M progression regulation [191,193,194,195,196,197].

4.3. Natural Variations of A3 Family Proteins

In primary CD4⁺ T lymphocytes, up to five A3 proteins contribute to HIV-1 restriction (reviewed in [1,2,18,22]). HIV-1 Vif neutralizes this antiviral activity by targeting A3 proteins, a mechanism evolved to counteract the proteins’ effects (reviewed in [1,2,18,22]). However, A3 proteins exhibit genetic variations (Figure 2) that influence their antiviral activity against HIV-1 (reviewed in [198]). These variants may not necessarily correlate with Vif’s selective pressure but can impact the efficiency of A3 proteins in suppressing HIV replication. Moreover, a recent study showed that A3-induced mutations in the env and gag-pol region were correlating with vif diversity, suggesting that tolerance to such changes may benefit HIV-1 evolution [199].

A3C protein exhibits weak restriction activity against Vif-deficient HIV-1 [27,30,32,200], but the HIV-1 Vif targets A3C protein for proteasomal degradation [201,202], limiting its antiviral effects. A common A3C variant, characterized by a serine-to-isoleucine substitution at position 188, occurs frequently in African populations (around 10% prevalence) but globally at <2% [32,203]. This variant enhances A3C’s anti-HIV-1 activity in vitro [27,32]. Another rare variant, A3C S61P (<1% global frequency), also improves inhibition of Vif-deficient HIV-1 replication [200,204]. Structural analyses suggest that this variant exhibits improved interactions with ssDNA [200,204]. Despite these enhancements, A3C variants have limited mutagenic activity compared with other A3 family members [27,32,200,204], implying that they contribute to HIV-1 diversification through a lower mutation rate [204].

A3D protein displays superior antiviral activity compared with A3C protein, although its deaminase activity remains limited relative to that of A3F, A3G, and stable A3H haplotypes [30,203,205]. In a humanized mouse model, A3D protein is believed to play a role in HIV-1 diversification [206]. A3D variants, such as R97C and R238K, are more frequently observed in HIV-1-infected individuals compared to the general African population, with minor allele frequencies of 4.7% and 11.6%, respectively [203,207]. These variants exhibit markedly lower antiviral activity against Vif-deficient HIV-1 [203] but are highly sensitive to HIV-1 Vif degradation [203]. Although these common variants are less effective at restricting HIV-1 or HIV-2 compared with wild-type A3D protein [203,208], they share similar sensitivity to Vif.

A3F protein inhibits HIV-1 through deaminase-dependent and deaminase-independent mechanisms (Figure 1), with evidence suggesting that the latter is the predominant mode of inhibition [34,157,159,160]. A3F protein shows less mutagenicity compared to A3G protein but can drive HIV-1 evolution and confer drug resistance [206,209]. Common A3F variants include A108S, V231I, and Y307C [153,203,207,210]. The A3F Y307C variant is present at a low frequency in African and European populations (minor allele frequency < 5%) and absent in Asian populations [153,203,207]. This variant exhibits reduced antiviral activity and increased sensitivity to HIV-1 Vif [153,211]. The most frequent A3F polymorphisms are 108S/231I and 108A/231V [203,210]. These two single nucleotide polymorphisms (SNPs) show strong linkage disequilibrium in European and Asian populations but weaker linkage disequilibrium in mixed American and African populations [210]. Position 231 in the A3F protein contributes markedly to antiviral activity, with the A3F 231V variant being more stable and efficiently encapsidated into HIV-1 virions compared to the A3F 231I variant [210]. Interestingly, two A3F splice variants. A3FΔ2 and A3FΔ2–4, lack exon 2 and exons 2–4, respectively [212], and show lower expression levels and antiviral activity compared with wild-type A3F protein [212]. Notably, A3FΔ2 is resistant to Vif-mediated degradation, whereas A3FΔ2–4 is highly sensitive to Vif [212].

A3G, a potent antiviral protein, has been extensively investigated (reviewed in [1,2,18,22]). Among its many SNPs, the A3G H186R variant is particularly well-studied [203,213,214,215,216]. This variant is common in African American and African populations but rare in American European and European populations [203,213,215,216,217,218,219]. The H186R mutation is especially prevalent in the Zimbabwean population compared with the black South African (30%) and African American (37%) populations [219]. However, the antiviral activity of the A3G H186R variant is debated [203,214,215,216]. Another A3G variant, Q275E was found to be more common in a cohort of HIV-1-infected patients from Northern South Africa compared with African populations in the 1000 Genomes Project [207]. Duggal et al. showed that A3G H186R and Q275E variants exhibit antiviral activity similar to that of wild-type A3G protein, including in a dose-dependent manner [203].

A3H protein exists in two prominent haplotypes: stable and unstable [29,33,220,221]. These haplotypes are determined by four SNPs (positions 18, 105, 121, and 178) and one indel (position 15) in the A3H gene [29,33,220,221]. Classification of A3H haplotypes into stable and unstable is concluded by overexpression and pulse-chase experiments showing that 3 haplotypes yield proteins with relatively long half-lives (recognized as stable form), 1 haplotype produces a protein with weak stability, and further 3 haplotypes produce completely unstable proteins. A3H proteins produced from stable haplotypes are folded properly, resistant to degradation, and capable of HIV-1 restriction [220,221,222]. A3H haplotypes are further divided into four splice variants, namely SV154, SV182, SV183, and SV200, with SV200 being found only in stable haplotypes [33,223]. Interestingly, A3H hapI SV154 lacks deaminase activity, whereas other variants show strong activity, with slightly lower activity observed in A3H hap I SV200 [224]. According to the 1000 Genomes Project, 13 distinct A3H haplotypes exist [33]. The stable A3H hapII is predominant in African populations, whereas hapI is more common in other regions, including Europe and Asia [29,33]. Regardless of haplotype, all A3H mRNAs are detectable [29]. However, A3H unstable haplotypes are either difficult to detect (hapI) or undetectable, whereas stable haplotypes are easily detectable [28,29,33,220,221,225,226,227]. These A3H phenotypes align with their antiviral activity (Figure 2), where stable A3H haplotypes exhibit potent antiviral effects against HIV-1, whereas unstable haplotypes show reduced activity [28,29,33,220,221,225,226,227].

4.4. RNA Binding Capacity of A3 Family Proteins

During virion assembly, viral RNAs and host cell RNA polymerase III (pol III)–derived RNAs are packaged into virions (reviewed in [228,229]). RNA pol III–derived RNAs are noncoding RNAs essential for cellular functions (reviewed in [230,231]). The RNA pol III–derived RNAs commonly packaged into HIV-1 include 7SL RNA and Y RNA [123,232,233,234,235,236], with 7SL being a component of the signal recognition particle ribonucleoprotein complex and Y RNA being part of the Ro ribonucleoprotein complex (reviewed in [230,231]). These findings highlight the selective packaging of 7SL RNA and Y RNA by HIV-1 and suggest potential roles in viral assembly and replication.

The NTD of the A3G protein binds viral and cellular RNAs [35,36,37,38], whereas the A3F protein uses both its NTD and CTD for packaging [237]. These domains enable the incorporation of A3F and A3G proteins into virions, where they exert their antiviral activity (reviewed in [238]). Several studies have shown that 7SL RNA is highly enriched in HIV-1 virions, with A3F and A3G proteins preferentially binding 7SL RNA over Y RNA [232,233,239]. Notably, 7SL RNA is pivotal for the efficient incorporation of A3F and A3G proteins into virions [232,233,234,235]. Furthermore, the mutants A3F W126A and A3G W127A showed reduced 7SL RNA binding, exhibited poor RNA packaging, and thereby impaired antiviral activity [232,233], highlighting the relevance of 7SL RNA-mediated A3 packaging to their antiviral function. However, it has been indicated that 7SL RNA is not essential for the packaging of A3F and A3G proteins into virions [234]. Hence, further extensive studies will need to conclude whether 7SL RNA-mediated A3 packaging is important for their antiviral function.

A3F and A3G proteins share similar packaging mechanisms through interaction with the nucleocapsid (NC) domain [38,235,240,241,242,243,244,245,246,247]. Studies have shown that A3G’s interaction with the NC domain is RNA-dependent [240,243,246,248], whereas others have proposed that the interaction is direct [241,247]. Both A3F and A3G proteins associate with viral RNA sequences enriched in G and/or adenine (A), which are not scanned by ribosomes during translation [235]. They recognize unpaired 5′-AA motifs and, to a lesser extent, 5′-GA motifs [242]. A3 proteins also mimic the RNA-binding specificity of the NC domain [235], with binding to this domain ensuring A3G’s concentration in the viral core of mature HIV-1, near the reverse transcription complex. A3F and A3G proteins bind 3′-AA/GA motifs through an aromatic/hydrophobic pocket in the noncatalytic domain and 5′-AA/GA motifs via an aromatic/hydrophobic groove between the noncatalytic and catalytic domains [242,249].

RNA binding markedly increases the likelihood of A3 proteins being packaged into virions, indirectly supporting their antiviral activity. Cryo-electron microscopy studies have revealed that RNA acts as a “molecular glue” in the Vif–A3G interaction [176,180]. This is due to the negative electrostatic potentials on the Vif binding patches of A3G protein, whereas the RNA binding site is positively charged [181]. When RNA binds, the A3G–RNA complex displays an expanded region with negative electrostatic potentials [181], facilitating interactions with the positively charged Vif surfaces [181]. Thus, RNA binding enhances electrostatic complementarity between A3G and Vif, promoting their assembly [181]. This highlights the role of RNA binding in benefiting Vif.

4.5. Post-Translational Modulation of A3 Family Proteins

Phosphorylation regulates the antiviral activity of A3 proteins (Figure 2) [128]. For instance, phosphorylation at the A3G Thr32 residue reduces its degradation by diminishing its affinity for HIV-1 Vif [128]. This modulation allows A3 proteins to bind distinct nucleic acid substrates and specific motifs, influencing their catalytic activity [112,113]. Cellular mechanisms also regulate A3 protein expression (Figure 2). Proinflammatory cytokines, such as IFN-α/β, tumor necrosis factor (TNF)-α, IL-6, and IL-1β, are known to enhance A3 expression (reviewed in [147,250]). IFNs, for example, increase A3A and A3G mRNA levels along with their protein expression in myeloid cells, such as monocyte-derived macrophages and dendritic cells [144,148,251,252,253,254]. In HIV-1-infected monocyte-derived macrophages, IFN-α treatment boosts A3A protein expression and activity, marked by increased G-to-A editing and reduced viral DNA accumulation [254]. Additionally, cytokines that regulate macrophage polarization toward the M1 (IFN-γ and TNF-α) or M2 (IL-4) phenotypes modulate A3A and A3G protein expression [255]. Alternative splicing also influences A3 function through isoform generation; this is exemplified in the A3H protein, where isoforms exhibit nonfunctional, maintained, and enhanced antiviral activity [33,223].

4.6. Impact of A3 Family Proteins on AIDS Progression

Naturally occurring A3 variants not only influence antiviral activity but also correlate with AIDS progression [28,213,216,256,257,258]. The A3F 231V allele, for example, is associated with lower viral loads and slower AIDS progression [257]. Additionally, the A3G H186R variant has been linked to a decline in CD4⁺ T-cell counts [213,216] and accelerated AIDS progression [216,256]. However, other studies suggest that the A3G H186R variant does not markedly affect these parameters [217,259], possibly due to population genetic diversity. Furthermore, HIV-1-infected individuals with stable A3H haplotypes show slower AIDS progression [28,258]. Although the genetic variations of A3 family proteins are among the factors that affect AIDS progression, the genetic diversity of other host and virus factors associated with the antiviral activity of A3 family proteins should also be considered.

Several factors impact the mutagenic activity of A3 proteins against HIV-1 (reviewed in [22,260,261,262]). Lethal HIV mutagenesis is counter-selected, whereas moderate A3-induced mutations generate sublethal changes that enhance viral diversity and immune evasion [206,263,264,265,266,267,268,269,270,271,272]. This has been confirmed by constructing phylogenies of A3-induced hypermutated proviruses of HIV-1-infected individuals on antiretroviral therapy (ART), showing hypermutated viruses can persist for decades and may follow different evolutionary dynamics compared to intact proviruses [273]. Mutations in A3-preferred motifs often occur in HIV-1 epitopes targeted by cytotoxic T lymphocytes, promoting immune escape and reducing CD8⁺ T-cell responses [270,272]. Boichard et al. suggested that overexpression of the programmed cell-death ligand is correlated with A3 proteins and may contribute to immune exhaustion, potentially leading to AIDS [274]. Recently, it has been demonstrated that HIV-1 selectively packages intact genomic RNA despite A3G-induced hypermutation in cDNA, revealing a decoupling of G-to-A hypermutation from viral infectivity [275]. This may highlight a mechanism of HIV-1 for maintaining functional genomes under antiviral pressure and conserved replication.

Of note, A3-mediated HIV-1 proviral hypermutation not only produces defective proviruses but also involves positions scored for drug resistance and are referred to as APOBEC-context drug resistance mutations (AC-DRMs) [276]. Defective pol sequences are shown to harbor most of the AC DRMs. However, they are not associated with HIV-1 DNA levels in infected individuals, and their impact on clinical settings is not confirmed [277].

5. A3-Related Determinants of HTLV-1 Infection

Infection with the Deltaretrovirus HTLV-1 generally results in lifelong asymptomatic carriers in the majority of infected individuals, whereas approximately 5% of cases progress to develop adult T-cell leukemia/lymphoma (ATL) or HTLV-1-associated myopathy (HAM) (reviewed in [44,278,279]). However, the mechanisms driving progression toward either of these pathologies remain poorly understood. HTLV-1 evolved from the simian retrovirus simian T-cell leukemia virus type 1 through cross-species transmission to humans approximately 20,000–50,000 years ago (reviewed in [278,280,281,282]). Despite primarily targeting CD4⁺ T lymphocytes, HTLV-1 can also infect other immune cells, including CD8⁺ T cells and myeloid cells, especially dendritic cells, which can become productively infected and transmit the virus to CD4⁺ T cells (reviewed in [283]). Once integrated into the host genome, HTLV-1 maintains chronic infection through clonal expansion of infected CD4⁺ T cells, limiting genetic variability (as reverse transcription is not involved) and reducing exposure to antiviral factors [284]. However, low-level viral spread via cell-to-cell transmission, including through viral synapses, protrusions, and tunneling nanotubes, has also been reported (Figure 3) [285]. Unlike HIV-1 infection of CD4⁺ T cells, which results in the massive release of new viral particles and cell death, HTLV-1 infection induces rapid cessation of viral particle production and promotes CD4⁺ T-cell proliferation, transformation, and immortalization (reviewed in [286,287]). Therefore, both clonal expansion and cell-to-cell transmission suggest that host factors play an intrinsic role in restricting HTLV-1 infection (reviewed in [288]).

The 9-kb HTLV-1 genome encodes for Gag, Pol, Env, p12, p13, Rex, Tax, and HTLV-1 bZIB factor (HBZ) genes. These are transcribed from the 5′-LTR, except for HBZ, which is encoded on the proviral minus strand and transcribed from the 3′-LTR (reviewed in [44,45,283]). Two oncogenic genes, Tax and HBZ, produce viral regulatory proteins that mediate the pathogenicity of HTLV-1 infection (reviewed in [43,44,45]). Tax protein promotes viral transcription and is closely associated with immune dysregulation in patients with HAM, inducing diverse cellular gene expressions through activation of the nuclear factor kappa B (NF-κB) and cAMP response element binding protein/activating transcription factor (CREB/ATF) pathways, driving neoplastic transformation (reviewed in [45]). As Tax is a major target for cytotoxic T lymphocytes, its expression is tightly controlled to ensure the survival of HTLV-1-infected cells and evade the host immune response [289]. HBZ mRNA is ubiquitously expressed in HTLV-1-infected cells, including in peripheral blood mononuclear cells from infected individuals and ATL cells, where it promotes the growth and survival of leukemic cells [290]. HBZ has also been shown to interact with the CREB/ATF pathway, selectively inhibit the NF-κB pathway, and suppress Tax-mediated viral transcription (reviewed in [45,291]).

5.1. A3–HTLV-1 Interplay: Restriction Versus Resistance

HTLV-1 preferentially targets CD4⁺ T cells, which express several A3 family proteins [29,141,148,149,151,153]. However, the antiviral activity of A3 proteins against HTLV-1 remains controversial. Overexpression studies have shown that multiple A3 proteins (A3A, A3B, and A3H hapII) can restrict HTLV-1 infectivity through deaminase-dependent and -independent mechanisms [292,293,294]. Additionally, it has been proposed that nonsense mutations in the HTLV-1 genome, induced by the A3G protein in asymptomatic carriers and patients with ATL, could allow the virus to evade the host immune response [295]. A3-mediated editing of the HTLV-1 genome during viral reverse transcription has been confirmed (Figure 3), where A3-targeted motifs are underrepresented (depleted) in the HBZ gene, with similar findings in Gag, Pol, and Tax, indicating corresponding A3 editing activity [50]. HTLV-1 is particularly susceptible to A3G-mediated deamination during reverse transcription, as demonstrated by a study analyzing HTLV-1 provirus sequences from asymptomatic carriers and patients with ATL, which revealed A3G-preferred G-to-A mutations in around 50% of cases [295]. A comparative study of HTLV-1-infected asymptomatic carriers and HTLV-2-infected individuals showed that the A3G protein frequently generates G-to-A mutations in the HTLV-1 provirus, whereas these mutations are rare in the HTLV-2 provirus [296]. Deep sequencing of full HTLV-1 proviruses from asymptomatic carriers indicated that G-to-A mutations represented 73% of all detected mutations, with 87.1% of these being GG-to-AG mutations, which are a preferred target for A3G protein [296].

Notably, HTLV-1 appears to be relatively resistant or poorly susceptible to A3 proteins (Figure 3), as demonstrated via experiments showing that HTLV-1 is not efficiently restricted by A3D, A3F, or A3G proteins [38,292,294,297]. Unlike HIV-1, HTLV-1 does not encode a viral product, such as Vif, to mediate A3 antagonism, and it is apparently unable to degrade A3 proteins in cell cultures [298]. Consistent with this finding, hyper-edited HTLV-1 sequences are rare, with estimated frequencies of 0.1–5.0% in vitro [38,292]. However, despite increased A3G expression in patients with HTLV-1, this was not correlated with clinical status or proviral load [299]. The resistance of HTLV-1 to A3-mediated restriction is believed to be due to lower levels of A3G encapsidation [297]. A direct resistance mechanism to A3G protein has been described in HTLV-1, functioning via a cis-acting exclusion mechanism, which involves an acidic region in the C-terminus of the HTLV-1 NC domain. This mechanism leads to reduced A3G packaging efficiency in HTLV-1 particles compared with HIV-1 Vif-deficient virus-like particles and is not attributed to a viral accessory protein [297].

5.2. Factors Determining A3–HTLV-1 Interaction Outcomes

The viral replication strategy plays a major role in determining the effectiveness of A3-mediated restriction on HTLV-1 infection. HTLV-1 exhibits low-level replication and relies on the clonal expansion of infected cells, resulting in a reduced rate of de novo infection as well as cell-to-cell viral spread (reviewed in [43,44,45]). This infrequent replication, combined with reverse transcription in HTLV-1, substantially decreases the opportunities for A3 proteins to edit the viral genome [297]. Additionally, the genetic diversity of HTLV-1 is lower than that of HIV-1, particularly in the context of their respective env genes, which further suggests that HTLV-1 is more resistant to the antiviral activity of A3 proteins [300,301].

The HTLV-1 genome is notably GC-rich compared with the HIV-1 genome [302]. Despite this, the relatively low occurrence of G-to-A mutations in the HTLV-1 genome indicates that HTLV-1 is less susceptible to the mutagenic activity of A3 proteins. Although the HTLV-1 genome does not encode Vif or a Vif-like protein, it can still resist the antiviral activity of A3 proteins (particularly A3G), at least in vitro [297]. Moreover, although endogenous and overexpressed A3G proteins can be packaged into HTLV-1 virions produced in HEK293 and MT-2 cells, the frequency of G-to-A mutations remains low [292]. Derse et al. demonstrated that HTLV-1 diminishes A3 protein packaging (Figure 3) through a peptide motif in the C-terminal domain of the NC [297]. Nevertheless, A3-mediated mutations in HTLV-1 may be influenced by the genetic variability of A3 proteins. For example, higher frequencies of G-to-A mutations were observed in a small group of HTLV-1-associated disease cases harboring two rare A3G variants relative to the remaining study population lacking these rare variants [303].

6. Conclusions

The contribution of A3 family proteins to retrovirus restriction underscores their essential role as key host RFs in humans. These proteins mediate antiviral activity by inducing lethal mutations, leading to virus restriction. However, the overall restriction activity of A3 family proteins is governed by multiple factors, including structural elements, substrate selection, and cellular regulators, all of which markedly influence their editing and non-editing functions. HIV-1 counteracts A3-mediated restriction primarily through Vif, which triggers proteasomal degradation of A3 proteins. In contrast, HTLV-1 employs a unique dissemination strategy that minimizes exposure to A3 proteins by avoiding the production and release of new viral particles. Nevertheless, A3-mediated restriction is not completely circumvented, as evidenced by the presence of A3 protein footprints on HIV-1 and HTLV-1 genomes in infected individuals. Therefore, understanding the determinants of retroviral infection mediated by A3 proteins is essential for determining the outcomes of infection and for exploring A3 proteins as potential therapeutic tools via the manipulation of their mutagenic activity.

Author Contributions

S.L.: Conceptualization, Investigation, Writing-original draft, Writing—review and editing. H.N.: Conceptualization, Investigation, Writing—original draft, Writing-review and editing. T.I.: Conceptualization, Funding, acquisition, Investigation, Supervision, Writing—original draft, Writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Acknowledgments

We would like to thank all Ikeda lab members for providing much support.

Conflicts of Interest

Authors declare the absence of any commercial or financial relationships that could produce a potential conflict of interest as related to this research.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Figures

Figure 1. Mechanisms underlying A3-mediated restriction of HIV-1 infection. The A3-mediated restriction of Vif-deficient HIV-1 infection involves the binding of A3 proteins to viral RNA (red), which is then packaged into nascent virions during viral assembly in the producer cells. In target cells, A3 proteins perform deamination-dependent editing on the viral single-stranded cDNA intermediates (brown), introducing potentially lethal G-to-A mutations (highlighted in orange). Additionally, A3 proteins exert a deaminase-independent, non-editing restriction by physically hindering viral reverse transcription and altering the selection of proviral DNA integration sites, favoring transcriptionally silent regions of host DNA. To counteract A3-meditated restriction, HIV-1 employs its accessory protein Vif, which ubiquitinates A3 proteins, targeting them for proteasomal degradation. Consequently, A3 proteins are poorly incorporated into nascent virions, and the cDNA intermediates experience few or no sublethal G-to-A mutations, resulting in a reduced restriction of HIV-1 replication. Each A3 Z domains are colored, respectively, light green: Z2 domains, dark green: Z1 domain, and blue: Z3 domain. A3: apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3/APOBEC3, ARIH2: Ariadne homolog 2, CBF-β: Core-binding factor β, Cul-5: Cullin 5, ELOB: Elongin B, ELOC: Elongin C, Env: Envelope, Gag: Group-specific antigen, RBX2: RING-box protein 2, RT: Reverse transcriptase, Ub: Ubiquitin, Vif: Viral infectivity factor.

Figure 2. Structural, cellular, and substrate-based regulation of A3 family protein activity. The activity of A3 family proteins is influenced by various factors, including their protein properties, domain organization, amino acid composition, and conserved secondary structural features near the catalytic site, which affect substrate selection and regulate deamination enzymatic activity. Genetic variants of individual A3 proteins can lead to variable deamination activity. The presence of preferred nucleotides in the substrates enhances the deamination activity of specific A3 proteins. Cellular factors, such as protein localization, phosphorylation status, and the influence of cellular cofactors (e.g., HSP90) or upstream regulators (e.g., IFNs), further modulate the activity of A3 proteins, influencing both their editing and non-editing functions.

Figure 3. Controversial outcome of the A3–HTLV-1 interaction. During HTLV-1 reverse transcription, A3 proteins can induce editing activity (left) via A3-mediated deamination. A3G, for instance, induces G-to-A mutations in the proviruses of HTLV-1 carriers and patients with ATL. Overexpression studies also suggest that A3A, A3B, and A3H stable haplotypes can restrict HTLV-1 infection. However, HTLV-1 appears to be relatively resistant to A3 protein activity due to its distinct replicative strategy and transmission methods (right). The integrated HTLV-1 genome drives the clonal expansion of infected CD4+ T cells (top right), promoting viral dissemination without the production of large numbers of viral particles. HTLV-1 uses cell-based transmission mechanisms (middle right), including viral synapses, tunneling nanotubes, and cellular protrusions, minimizing exposure to A3 proteins. Finally, the HTLV-1 NC protein (bottom right) impairs A3G packaging into HTLV-1 virions, further contributing to the virus’ resistance to A3-mediated restriction.

References

1. Simon, V.; Bloch, N.; Landau, N.R. Intrinsic host restrictions to HIV-1 and mechanisms of viral escape. Nat. Immunol.; 2015; 16, pp. 546-553. [DOI: https://dx.doi.org/10.1038/ni.3156] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25988886]

2. Harris, R.S.; Dudley, J.P. APOBECs and virus restriction. Virology; 2015; 479–480, pp. 131-145. [DOI: https://dx.doi.org/10.1016/j.virol.2015.03.012] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25818029]

3. Zotova, A.A.; Atemasova, A.A.; Filatov, A.V.; Mazurov, D.V. HIV Restriction Factors and Their Ambiguous Role during Infection. Mol. Biol.; 2019; 53, pp. 240-255. [DOI: https://dx.doi.org/10.1134/S0026893319020171]

4. Boso, G.; Kozak, C.A. Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations. Microorganisms; 2020; 8, 1965. [DOI: https://dx.doi.org/10.3390/microorganisms8121965] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33322320]

5. Malim, M.H.; Bieniasz, P.D. HIV Restriction Factors and Mechanisms of Evasion. Cold Spring Harb. Perspect. Med.; 2012; 2, a006940. [DOI: https://dx.doi.org/10.1101/cshperspect.a006940]

6. Harris, R.S.; Hultquist, J.F.; Evans, D.T. The restriction factors of human immunodeficiency virus. J. Biol. Chem.; 2012; 287, pp. 40875-40883. [DOI: https://dx.doi.org/10.1074/jbc.R112.416925]

7. Lilly, F. Fv-2: Identification and location of a second gene governing the spleen focus response to Friend leukemia virus in mice. J. Natl. Cancer Inst.; 1970; 45, pp. 163-169.

8. Pincus, T.; Hartley, J.W.; Rowe, W.P. A major genetic locus affecting resistance to infection with murine leukemia viruses. I. Tissue culture studies of naturally occurring viruses. J. Exp. Med.; 1971; 133, pp. 1219-1233. [DOI: https://dx.doi.org/10.1084/jem.133.6.1219]

9. Uriu, K.; Kosugi, Y.; Ito, J.; Sato, K. The Battle between Retroviruses and APOBEC3 Genes: Its Past and Present. Viruses; 2021; 13, 124. [DOI: https://dx.doi.org/10.3390/v13010124]

10. Sauter, D.; Kirchhoff, F. Key Viral Adaptations Preceding the AIDS Pandemic. Cell Host Microbe; 2019; 25, pp. 27-38. [DOI: https://dx.doi.org/10.1016/j.chom.2018.12.002]

11. Rashid, F.; Zaongo, S.D.; Iqbal, H.; Harypursat, V.; Song, F.; Chen, Y. Interactions between HIV proteins and host restriction factors: Implications for potential therapeutic intervention in HIV infection. Front. Immunol.; 2024; 15, 1390650. [DOI: https://dx.doi.org/10.3389/fimmu.2024.1390650] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39221250]

12. Koito, A.; Ikeda, T. Intrinsic immunity against retrotransposons by APOBEC cytidine deaminases. Front. Microbiol.; 2013; 4, 28. [DOI: https://dx.doi.org/10.3389/fmicb.2013.00028] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23431045]

13. Koito, A.; Ikeda, T. Intrinsic restriction activity by AID/APOBEC family of enzymes against the mobility of retroelements. Mob. Genet. Elem.; 2011; 1, pp. 197-202. [DOI: https://dx.doi.org/10.4161/mge.1.3.17430] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22479686]

14. Refsland, E.W.; Harris, R.S. The APOBEC3 family of retroelement restriction factors. Curr. Top. Microbiol. Immunol.; 2013; 371, pp. 1-27. [DOI: https://dx.doi.org/10.1007/978-3-642-37765-5_1]

15. Salter, J.D.; Bennett, R.P.; Smith, H.C. The APOBEC Protein Family: United by Structure, Divergent in Function. Trends Biochem. Sci.; 2016; 41, pp. 578-594. [DOI: https://dx.doi.org/10.1016/j.tibs.2016.05.001]

16. Knisbacher, B.A.; Levanon, E.Y. DNA and RNA editing of retrotransposons accelerate mammalian genome evolution. Ann. N. Y. Acad. Sci.; 2015; 1341, pp. 115-125. [DOI: https://dx.doi.org/10.1111/nyas.12713]

17. Holmes, R.K.; Malim, M.H.; Bishop, K.N. APOBEC-mediated viral restriction: Not simply editing?. Trends Biochem. Sci.; 2007; 32, pp. 118-128. [DOI: https://dx.doi.org/10.1016/j.tibs.2007.01.004]

18. Desimmie, B.A.; Delviks-Frankenberrry, K.A.; Burdick, R.C.; Qi, D.; Izumi, T.; Pathak, V.K. Multiple APOBEC3 restriction factors for HIV-1 and one Vif to rule them all. J. Mol. Biol.; 2014; 426, pp. 1220-1245. [DOI: https://dx.doi.org/10.1016/j.jmb.2013.10.033]

19. Ikeda, T.; Yue, Y.; Shimizu, R.; Nasser, H. Potential Utilization of APOBEC3-Mediated Mutagenesis for an HIV-1 Functional Cure. Front. Microbiol.; 2021; 12, 686357. [DOI: https://dx.doi.org/10.3389/fmicb.2021.686357]

20. Nakano, Y.; Aso, H.; Soper, A.; Yamada, E.; Moriwaki, M.; Juarez-Fernandez, G.; Koyanagi, Y.; Sato, K. A conflict of interest: The evolutionary arms race between mammalian APOBEC3 and lentiviral Vif. Retrovirology; 2017; 14, 31. [DOI: https://dx.doi.org/10.1186/s12977-017-0355-4]

21. Cheng, A.Z.; Moraes, S.N.; Shaban, N.M.; Fanunza, E.; Bierle, C.J.; Southern, P.J.; Bresnahan, W.A.; Rice, S.A.; Harris, R.S. APOBECs and herpesviruses. Viruses; 2021; 13, 390. [DOI: https://dx.doi.org/10.3390/v13030390] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33671095]

22. Jonathan, M.; Ikeda, T. APOBEC3 family proteins as drivers of virus evolution. Front. Virol.; 2023; 3, 1332010. [DOI: https://dx.doi.org/10.3389/fviro.2023.1332010]

23. Harris, R.S.; Liddament, M.T. Retroviral restriction by APOBEC proteins. Nat. Rev. Immunol.; 2004; 4, pp. 868-877. [DOI: https://dx.doi.org/10.1038/nri1489] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15516966]

24. Kitamura, S.; Ode, H.; Iwatani, Y. Structural Features of Antiviral APOBEC3 Proteins are Linked to Their Functional Activities. Front. Microbiol.; 2011; 2, 258. [DOI: https://dx.doi.org/10.3389/fmicb.2011.00258]

25. Hayward, J.A.; Tachedjian, M.; Cui, J.; Cheng, A.Z.; Johnson, A.; Baker, M.L.; Harris, R.S.; Wang, L.F.; Tachedjian, G. Differential Evolution of Antiretroviral Restriction Factors in Pteropid Bats as Revealed by APOBEC3 Gene Complexity. Mol. Biol. Evol.; 2018; 35, pp. 1626-1637. [DOI: https://dx.doi.org/10.1093/molbev/msy048]

26. Sheehy, A.M.; Gaddis, N.C.; Choi, J.D.; Malim, M.H. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature; 2002; 418, pp. 646-650. [DOI: https://dx.doi.org/10.1038/nature00939]

27. Anderson, B.D.; Ikeda, T.; Moghadasi, S.A.; Martin, A.S.; Brown, W.L.; Harris, R.S. Natural APOBEC3C variants can elicit differential HIV-1 restriction activity. Retrovirology; 2018; 15, 78. [DOI: https://dx.doi.org/10.1186/s12977-018-0459-5]

28. Ooms, M.; Brayton, B.; Letko, M.; Maio, S.M.; Pilcher, C.D.; Hecht, F.M.; Barbour, J.D.; Simon, V. HIV-1 Vif adaptation to human APOBEC3H haplotypes. Cell Host Microbe; 2013; 14, pp. 411-421. [DOI: https://dx.doi.org/10.1016/j.chom.2013.09.006]

29. Refsland, E.W.; Hultquist, J.F.; Luengas, E.M.; Ikeda, T.; Shaban, N.M.; Law, E.K.; Brown, W.L.; Reilly, C.; Emerman, M.; Harris, R.S. Natural polymorphisms in human APOBEC3H and HIV-1 Vif combine in primary T lymphocytes to affect viral G-to-A mutation levels and infectivity. PLoS Genet.; 2014; 10, e1004761. [DOI: https://dx.doi.org/10.1371/journal.pgen.1004761]

30. Hultquist, J.F.; Lengyel, J.A.; Refsland, E.W.; LaRue, R.S.; Lackey, L.; Brown, W.L.; Harris, R.S. Human and rhesus APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H demonstrate a conserved capacity to restrict Vif-deficient HIV-1. J. Virol.; 2011; 85, pp. 11220-11234. [DOI: https://dx.doi.org/10.1128/JVI.05238-11]

31. Refsland, E.W.; Hultquist, J.F.; Harris, R.S. Endogenous origins of HIV-1 G to A hypermutation and restriction in the nonpermissive T cell line CEM2n. PLoS Pathog.; 2012; 8, e1002800. [DOI: https://dx.doi.org/10.1371/journal.ppat.1002800] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22807680]

32. Wittkopp, C.J.; Adolph, M.B.; Wu, L.I.; Chelico, L.; Emerman, M. A Single Nucleotide Polymorphism in Human APOBEC3C Enhances Restriction of Lentiviruses. PLoS Pathog.; 2016; 12, e1005865. [DOI: https://dx.doi.org/10.1371/journal.ppat.1005865] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27732658]

33. Ebrahimi, D.; Richards, C.M.; Carpenter, M.A.; Wang, J.; Ikeda, T.; Becker, J.T.; Cheng, A.Z.; McCann, J.L.; Shaban, N.M.; Salamango, D.J. et al. Genetic and mechanistic basis for APOBEC3H alternative splicing, retrovirus restriction, and counteraction by HIV-1 protease. Nat. Commun.; 2018; 9, 4137. [DOI: https://dx.doi.org/10.1038/s41467-018-06594-3] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30297863]

34. Ikeda, T.; Shimizu, R.; Nasser, H.; Carpenter, M.A.; Cheng, A.Z.; Brown, W.L.; Sauter, D.; Harris, R.S. APOBEC3 degradation is the primary function of HIV-1 Vif determining virion infectivity in the myeloid cell line THP-1. mBio; 2023; 14, e0078223. [DOI: https://dx.doi.org/10.1128/mbio.00782-23]

35. Belanger, K.; Savoie, M.; Rosales Gerpe, M.C.; Couture, J.F.; Langlois, M.A. Binding of RNA by APOBEC3G controls deamination-independent restriction of retroviruses. Nucleic Acids Res.; 2013; 41, pp. 7438-7452. [DOI: https://dx.doi.org/10.1093/nar/gkt527]

36. Newman, E.N.; Holmes, R.K.; Craig, H.M.; Klein, K.C.; Lingappa, J.R.; Malim, M.H.; Sheehy, A.M. Antiviral function of APOBEC3G can be dissociated from cytidine deaminase activity. Curr. Biol.; 2005; 15, pp. 166-170. [DOI: https://dx.doi.org/10.1016/j.cub.2004.12.068]

37. Huthoff, H.; Autore, F.; Gallois-Montbrun, S.; Fraternali, F.; Malim, M.H. RNA-dependent oligomerization of APOBEC3G is required for restriction of HIV-1. PLoS Pathog.; 2009; 5, e1000330. [DOI: https://dx.doi.org/10.1371/journal.ppat.1000330]

38. Navarro, F.; Bollman, B.; Chen, H.; Konig, R.; Yu, Q.; Chiles, K.; Landau, N.R. Complementary function of the two catalytic domains of APOBEC3G. Virology; 2005; 333, pp. 374-386. [DOI: https://dx.doi.org/10.1016/j.virol.2005.01.011]

39. Bishop, K.N.; Verma, M.; Kim, E.Y.; Wolinsky, S.M.; Malim, M.H. APOBEC3G inhibits elongation of HIV-1 reverse transcripts. PLoS Pathog.; 2008; 4, e1000231. [DOI: https://dx.doi.org/10.1371/journal.ppat.1000231]

40. Iwatani, Y.; Chan, D.S.; Wang, F.; Stewart-Maynard, K.; Sugiura, W.; Gronenborn, A.M.; Rouzina, I.; Williams, M.C.; Musier-Forsyth, K.; Levin, J.G. Deaminase-independent inhibition of HIV-1 reverse transcription by APOBEC3G. Nucleic Acids Res.; 2007; 35, pp. 7096-7108. [DOI: https://dx.doi.org/10.1093/nar/gkm750]

41. Li, X.Y.; Guo, F.; Zhang, L.; Kleiman, L.; Cen, S. APOBEC3G inhibits DNA strand transfer during HIV-1 reverse transcription. J. Biol. Chem.; 2007; 282, pp. 32065-32074. [DOI: https://dx.doi.org/10.1074/jbc.M703423200]

42. Salamango, D.J.; Harris, R.S. Dual Functionality of HIV-1 Vif in APOBEC3 Counteraction and Cell Cycle Arrest. Front. Microbiol.; 2020; 11, 622012. [DOI: https://dx.doi.org/10.3389/fmicb.2020.622012] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33510734]

43. Derse, D.; Heidecker, G.; Mitchell, M.; Hill, S.; Lloyd, P.; Princler, G. Infectious transmission and replication of human T-cell leukemia virus type 1. Front. Biosci.; 2004; 9, pp. 2495-2499. [DOI: https://dx.doi.org/10.2741/1411] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15353302]

44. Matsuoka, M.; Jeang, K.T. Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat. Rev. Cancer; 2007; 7, pp. 270-280. [DOI: https://dx.doi.org/10.1038/nrc2111]

45. Matsuoka, M.; Jeang, K.T. Human T-cell leukemia virus type 1 (HTLV-1) and leukemic transformation: Viral infectivity, Tax, HBZ and therapy. Oncogene; 2011; 30, pp. 1379-1389. [DOI: https://dx.doi.org/10.1038/onc.2010.537]

46. Tsuge, M.; Noguchi, C.; Akiyama, R.; Matsushita, M.; Kunihiro, K.; Tanaka, S.; Abe, H.; Mitsui, F.; Kitamura, S.; Hatakeyama, T. et al. G to A hypermutation of TT virus. Virus Res.; 2010; 149, pp. 211-216. [DOI: https://dx.doi.org/10.1016/j.virusres.2010.01.019]

47. Suspene, R.; Aynaud, M.M.; Koch, S.; Pasdeloup, D.; Labetoulle, M.; Gaertner, B.; Vartanian, J.P.; Meyerhans, A.; Wain-Hobson, S. Genetic editing of herpes simplex virus 1 and Epstein-Barr herpesvirus genomes by human APOBEC3 cytidine deaminases in culture and in vivo. J. Virol.; 2011; 85, pp. 7594-7602. [DOI: https://dx.doi.org/10.1128/JVI.00290-11]

48. Cheng, A.Z.; Yockteng-Melgar, J.; Jarvis, M.C.; Malik-Soni, N.; Borozan, I.; Carpenter, M.A.; McCann, J.L.; Ebrahimi, D.; Shaban, N.M.; Marcon, E. et al. Epstein-Barr virus BORF2 inhibits cellular APOBEC3B to preserve viral genome integrity. Nat. Microbiol.; 2019; 4, pp. 78-88. [DOI: https://dx.doi.org/10.1038/s41564-018-0284-6]

49. Vartanian, J.P.; Guetard, D.; Henry, M.; Wain-Hobson, S. Evidence for editing of human papillomavirus DNA by APOBEC3 in benign and precancerous lesions. Science; 2008; 320, pp. 230-233. [DOI: https://dx.doi.org/10.1126/science.1153201]

50. Poulain, F.; Lejeune, N.; Willemart, K.; Gillet, N.A. Footprint of the host restriction factors APOBEC3 on the genome of human viruses. PLoS Pathog.; 2020; 16, e1008718. [DOI: https://dx.doi.org/10.1371/journal.ppat.1008718]

51. Verhalen, B.; Starrett, G.J.; Harris, R.S.; Jiang, M. Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses. J. Virol.; 2016; 90, pp. 6379-6386. [DOI: https://dx.doi.org/10.1128/JVI.00771-16] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27147740]

52. Forni, D.; Cagliani, R.; Pozzoli, U.; Sironi, M. An APOBEC3 Mutational Signature in the Genomes of Human-Infecting Orthopoxviruses. mSphere; 2023; 8, e0006223. [DOI: https://dx.doi.org/10.1128/msphere.00062-23] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36920219]

53. Delamonica, B.; Davalos, L.; Larijani, M.; Anthony, S.J.; Liu, J.; MacCarthy, T. Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes. Virus Evol.; 2023; 9, vead047. [DOI: https://dx.doi.org/10.1093/ve/vead047] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37577211]

54. Suspene, R.; Raymond, K.A.; Boutin, L.; Guillier, S.; Lemoine, F.; Ferraris, O.; Tournier, J.N.; Iseni, F.; Simon-Loriere, E.; Vartanian, J.P. APOBEC3F Is a Mutational Driver of the Human Monkeypox Virus Identified in the 2022 Outbreak. J. Infect. Dis.; 2023; 228, pp. 1421-1429. [DOI: https://dx.doi.org/10.1093/infdis/jiad165] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37224627]

55. O’Toole, A.; Neher, R.A.; Ndodo, N.; Borges, V.; Gannon, B.; Gomes, J.P.; Groves, N.; King, D.J.; Maloney, D.; Lemey, P. et al. APOBEC3 deaminase editing in mpox virus as evidence for sustained human transmission since at least 2016. Science; 2023; 382, pp. 595-600. [DOI: https://dx.doi.org/10.1126/science.adg8116]

56. Baumert, T.F.; Rosler, C.; Malim, M.H.; von Weizsacker, F. Hepatitis B virus DNA is subject to extensive editing by the human deaminase APOBEC3C. Hepatology; 2007; 46, pp. 682-689. [DOI: https://dx.doi.org/10.1002/hep.21733]

57. Beggel, B.; Munk, C.; Daumer, M.; Hauck, K.; Haussinger, D.; Lengauer, T.; Erhardt, A. Full genome ultra-deep pyrosequencing associates G-to-A hypermutation of the hepatitis B virus genome with the natural progression of hepatitis B. J. Viral Hepat.; 2013; 20, pp. 882-889. [DOI: https://dx.doi.org/10.1111/jvh.12110]

58. Chen, Z.; Eggerman, T.L.; Bocharov, A.V.; Baranova, I.N.; Vishnyakova, T.G.; Patterson, A.P. APOBEC3-induced mutation of the hepatitis virus B DNA genome occurs during its viral RNA reverse transcription into (-)-DNA. J. Biol. Chem.; 2021; 297, 100889. [DOI: https://dx.doi.org/10.1016/j.jbc.2021.100889]

59. Suspene, R.; Guetard, D.; Henry, M.; Sommer, P.; Wain-Hobson, S.; Vartanian, J.P. Extensive editing of both hepatitis B virus DNA strands by APOBEC3 cytidine deaminases in vitro and in vivo. Proc. Natl. Acad. Sci. USA; 2005; 102, pp. 8321-8326. [DOI: https://dx.doi.org/10.1073/pnas.0408223102]

60. Simmonds, P. Rampant C-->U Hypermutation in the Genomes of SARS-CoV-2 and Other Coronaviruses: Causes and Consequences for Their Short- and Long-Term Evolutionary Trajectories. mSphere; 2020; 5, 10-1128. [DOI: https://dx.doi.org/10.1128/mSphere.00408-20]

61. Nakata, Y.; Ode, H.; Kubota, M.; Kasahara, T.; Matsuoka, K.; Sugimoto, A.; Imahashi, M.; Yokomaku, Y.; Iwatani, Y. Cellular APOBEC3A deaminase drives mutations in the SARS-CoV-2 genome. Nucleic Acids Res.; 2023; 51, pp. 783-795. [DOI: https://dx.doi.org/10.1093/nar/gkac1238] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36610792]

62. Di Giorgio, S.; Martignano, F.; Torcia, M.G.; Mattiuz, G.; Conticello, S.G. Evidence for host-dependent RNA editing in the transcriptome of SARS-CoV-2. Sci. Adv.; 2020; 6, eabb5813. [DOI: https://dx.doi.org/10.1126/sciadv.abb5813] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32596474]

63. Kim, K.; Calabrese, P.; Wang, S.; Qin, C.; Rao, Y.; Feng, P.; Chen, X.S. The roles of APOBEC-mediated RNA editing in SARS-CoV-2 mutations, replication and fitness. Sci. Rep.; 2022; 12, 14972. [DOI: https://dx.doi.org/10.1038/s41598-022-19067-x]

64. Simmonds, P. C-->U transition biases in SARS-CoV-2: Still rampant 4 years from the start of the COVID-19 pandemic. mBio; 2024; 15, e0249324. [DOI: https://dx.doi.org/10.1128/mbio.02493-24] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39475243]

65. Chen, H.; Lilley, C.E.; Yu, Q.; Lee, D.V.; Chou, J.; Narvaiza, I.; Landau, N.R.; Weitzman, M.D. APOBEC3A is a potent inhibitor of adeno-associated virus and retrotransposons. Curr. Biol.; 2006; 16, pp. 480-485. [DOI: https://dx.doi.org/10.1016/j.cub.2006.01.031] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16527742]

66. Narvaiza, I.; Linfesty, D.C.; Greener, B.N.; Hakata, Y.; Pintel, D.J.; Logue, E.; Landau, N.R.; Weitzman, M.D. Deaminase-independent inhibition of parvoviruses by the APOBEC3A cytidine deaminase. PLoS Pathog.; 2009; 5, e1000439. [DOI: https://dx.doi.org/10.1371/journal.ppat.1000439]

67. Nguyen, D.H.; Gummuluru, S.; Hu, J. Deamination-independent inhibition of hepatitis B virus reverse transcription by APOBEC3G. J. Virol.; 2007; 81, pp. 4465-4472. [DOI: https://dx.doi.org/10.1128/JVI.02510-06]

68. Bonvin, M.; Achermann, F.; Greeve, I.; Stroka, D.; Keogh, A.; Inderbitzin, D.; Candinas, D.; Sommer, P.; Wain-Hobson, S.; Vartanian, J.P. et al. Interferon-inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication. Hepatology; 2006; 43, pp. 1364-1374. [DOI: https://dx.doi.org/10.1002/hep.21187]

69. Milewska, A.; Kindler, E.; Vkovski, P.; Zeglen, S.; Ochman, M.; Thiel, V.; Rajfur, Z.; Pyrc, K. APOBEC3-mediated restriction of RNA virus replication. Sci. Rep.; 2018; 8, 5960. [DOI: https://dx.doi.org/10.1038/s41598-018-24448-2]

70. Begum, M.M.; Bokani, A.; Rajib, S.A.; Soleimanpour, M.; Maeda, Y.; Yoshimura, K.; Satou, Y.; Ebrahimi, D.; Ikeda, T. Potential Role of APOBEC3 Family Proteins in SARS-CoV-2 Replication. Viruses; 2024; 16, 1141. [DOI: https://dx.doi.org/10.3390/v16071141]

71. Ito, J.; Gifford, R.J.; Sato, K. Retroviruses drive the rapid evolution of mammalian APOBEC3 genes. Proc. Natl. Acad. Sci. USA; 2020; 117, pp. 610-618. [DOI: https://dx.doi.org/10.1073/pnas.1914183116] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31843890]

72. Conticello, S.G.; Thomas, C.J.; Petersen-Mahrt, S.K.; Neuberger, M.S. Evolution of the AID/APOBEC family of polynucleotide (deoxy)cytidine deaminases. Mol. Biol. Evol.; 2005; 22, pp. 367-377. [DOI: https://dx.doi.org/10.1093/molbev/msi026] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15496550]

73. Krishnan, A.; Iyer, L.M.; Holland, S.J.; Boehm, T.; Aravind, L. Diversification of AID/APOBEC-like deaminases in metazoa: Multiplicity of clades and widespread roles in immunity. Proc. Natl. Acad. Sci. USA; 2018; 115, pp. E3201-E3210. [DOI: https://dx.doi.org/10.1073/pnas.1720897115]

74. Severi, F.; Chicca, A.; Conticello, S.G. Analysis of reptilian APOBEC1 suggests that RNA editing may not be its ancestral function. Mol. Biol. Evol.; 2011; 28, pp. 1125-1129. [DOI: https://dx.doi.org/10.1093/molbev/msq338]

75. Wang, W.; Han, G.Z. A Long-Running Arms Race between APOBEC1 Genes and Retroviruses in Tetrapods. J. Virol.; 2023; 97, e0179522. [DOI: https://dx.doi.org/10.1128/jvi.01795-22]

76. Teng, B.; Burant, C.F.; Davidson, N.O. Molecular cloning of an apolipoprotein B messenger RNA editing protein. Science; 1993; 260, pp. 1816-1819. [DOI: https://dx.doi.org/10.1126/science.8511591]

77. Hadjiagapiou, C.; Giannoni, F.; Funahashi, T.; Skarosi, S.F.; Davidson, N.O. Molecular cloning of a human small intestinal apolipoprotein B mRNA editing protein. Nucleic Acids Res.; 1994; 22, pp. 1874-1879. [DOI: https://dx.doi.org/10.1093/nar/22.10.1874]

78. Koito, A.; Ikeda, T. Apolipoprotein B mRNA-editing, catalytic polypeptide cytidine deaminases and retroviral restriction. Wiley Interdiscip. Rev. RNA; 2012; 3, pp. 529-541. [DOI: https://dx.doi.org/10.1002/wrna.1117]

79. Keegan, L.P.; Gallo, A.; O’Connell, M.A. The many roles of an RNA editor. Nat Rev Genet; 2001; 2, pp. 869-878. [DOI: https://dx.doi.org/10.1038/35098584]

80. Pecori, R.; Di Giorgio, S.; Paulo Lorenzo, J.; Nina Papavasiliou, F. Functions and consequences of AID/APOBEC-mediated DNA and RNA deamination. Nat. Rev. Genet.; 2022; 23, pp. 505-518. [DOI: https://dx.doi.org/10.1038/s41576-022-00459-8]

81. Harris, R.S.; Petersen-Mahrt, S.K.; Neuberger, M.S. RNA editing enzyme APOBEC1 and some of its homologs can act as DNA mutators. Mol. Cell; 2002; 10, pp. 1247-1253. [DOI: https://dx.doi.org/10.1016/S1097-2765(02)00742-6] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12453430]

82. Ikeda, T.; Abd El Galil, K.H.; Tokunaga, K.; Maeda, K.; Sata, T.; Sakaguchi, N.; Heidmann, T.; Koito, A. Intrinsic restriction activity by apolipoprotein B mRNA editing enzyme APOBEC1 against the mobility of autonomous retrotransposons. Nucleic Acids Res.; 2011; 39, pp. 5538-5554. [DOI: https://dx.doi.org/10.1093/nar/gkr124] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21398638]

83. Ikeda, T.; Shimoda, M.; Ebrahimi, D.; VandeBerg, J.L.; Harris, R.S.; Koito, A.; Maeda, K. Opossum APOBEC1 is a DNA mutator with retrovirus and retroelement restriction activity. Sci. Rep.; 2017; 7, 46719. [DOI: https://dx.doi.org/10.1038/srep46719] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28429755]

84. Ikeda, T.; Ong, E.B.; Watanabe, N.; Sakaguchi, N.; Maeda, K.; Koito, A. Creation of chimeric human/rabbit APOBEC1 with HIV-1 restriction and DNA mutation activities. Sci. Rep.; 2016; 6, 19035. [DOI: https://dx.doi.org/10.1038/srep19035]

85. Ikeda, T.; Ohsugi, T.; Kimura, T.; Matsushita, S.; Maeda, Y.; Harada, S.; Koito, A. The antiretroviral potency of APOBEC1 deaminase from small animal species. Nucleic Acids Res.; 2008; 36, pp. 6859-6871. [DOI: https://dx.doi.org/10.1093/nar/gkn802]

86. Bishop, K.N.; Holmes, R.K.; Sheehy, A.M.; Davidson, N.O.; Cho, S.J.; Malim, M.H. Cytidine deamination of retroviral DNA by diverse APOBEC proteins. Curr. Biol.; 2004; 14, pp. 1392-1396. [DOI: https://dx.doi.org/10.1016/j.cub.2004.06.057]

87. Bishop, K.N.; Holmes, R.K.; Sheehy, A.M.; Malim, M.H. APOBEC-mediated editing of viral RNA. Science; 2004; 305, 645. [DOI: https://dx.doi.org/10.1126/science.1100658]

88. Esnault, C.; Heidmann, O.; Delebecque, F.; Dewannieux, M.; Ribet, D.; Hance, A.J.; Heidmann, T.; Schwartz, O. APOBEC3G cytidine deaminase inhibits retrotransposition of endogenous retroviruses. Nature; 2005; 433, pp. 430-433. [DOI: https://dx.doi.org/10.1038/nature03238]

89. Lindic, N.; Budic, M.; Petan, T.; Knisbacher, B.A.; Levanon, E.Y.; Lovsin, N. Differential inhibition of LINE1 and LINE2 retrotransposition by vertebrate AID/APOBEC proteins. Retrovirology; 2013; 10, 156. [DOI: https://dx.doi.org/10.1186/1742-4690-10-156]

90. Nakamuta, M.; Oka, K.; Krushkal, J.; Kobayashi, K.; Yamamoto, M.; Li, W.H.; Chan, L. Alternative mRNA splicing and differential promoter utilization determine tissue-specific expression of the apolipoprotein B mRNA-editing protein (Apobec1) gene in mice. Structure and evolution of Apobec1 and related nucleoside/nucleotide deaminases. J. Biol. Chem.; 1995; 270, pp. 13042-13056. [DOI: https://dx.doi.org/10.1074/jbc.270.22.13042]

91. Muramatsu, M.; Sankaranand, V.S.; Anant, S.; Sugai, M.; Kinoshita, K.; Davidson, N.O.; Honjo, T. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J. Biol. Chem.; 1999; 274, pp. 18470-18476. [DOI: https://dx.doi.org/10.1074/jbc.274.26.18470] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10373455]

92. Feng, Y.; Seija, N.; Di Noia, J.M.; Martin, A. AID in Antibody Diversification: There and Back Again. Trends Immunol.; 2020; 41, pp. 586-600. [DOI: https://dx.doi.org/10.1016/j.it.2020.04.009] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32434680]

93. Methot, S.P.; Di Noia, J.M. Molecular Mechanisms of Somatic Hypermutation and Class Switch Recombination. Adv. Immunol.; 2017; 133, pp. 37-87. [DOI: https://dx.doi.org/10.1016/bs.ai.2016.11.002]

94. Larijani, M.; Martin, A. Single-stranded DNA structure and positional context of the target cytidine determine the enzymatic efficiency of AID. Mol. Cell Biol.; 2007; 27, pp. 8038-8048. [DOI: https://dx.doi.org/10.1128/MCB.01046-07]

95. Ohtsubo, H.; Sato, Y.; Suzuki, T.; Mizunoya, W.; Nakamura, M.; Tatsumi, R.; Ikeuchi, Y. APOBEC2 negatively regulates myoblast differentiation in muscle regeneration. Int. J. Biochem. Cell Biol.; 2017; 85, pp. 91-101. [DOI: https://dx.doi.org/10.1016/j.biocel.2017.02.005]

96. Sato, Y.; Ohtsubo, H.; Nihei, N.; Kaneko, T.; Sato, Y.; Adachi, S.I.; Kondo, S.; Nakamura, M.; Mizunoya, W.; Iida, H. et al. Apobec2 deficiency causes mitochondrial defects and mitophagy in skeletal muscle. FASEB J.; 2018; 32, pp. 1428-1439. [DOI: https://dx.doi.org/10.1096/fj.201700493R]

97. Marino, D.; Perkovic, M.; Hain, A.; Jaguva Vasudevan, A.A.; Hofmann, H.; Hanschmann, K.M.; Muhlebach, M.D.; Schumann, G.G.; Konig, R.; Cichutek, K. et al. APOBEC4 Enhances the Replication of HIV-1. PLoS ONE; 2016; 11, e0155422. [DOI: https://dx.doi.org/10.1371/journal.pone.0155422]

98. Shi, M.; Tan, L.; Zhang, Y.; Meng, C.; Wang, W.; Sun, Y.; Song, C.; Liu, W.; Liao, Y.; Yu, S. et al. Characterization and functional analysis of chicken APOBEC4. Dev. Comp. Immunol.; 2020; 106, 103631. [DOI: https://dx.doi.org/10.1016/j.dci.2020.103631]

99. Chahwan, R.; Wontakal, S.N.; Roa, S. Crosstalk between genetic and epigenetic information through cytosine deamination. Trends Genet.; 2010; 26, pp. 443-448. [DOI: https://dx.doi.org/10.1016/j.tig.2010.07.005]

100. Knisbacher, B.A.; Gerber, D.; Levanon, E.Y. DNA Editing by APOBECs: A Genomic Preserver and Transformer. Trends Genet.; 2015; 32, pp. 16-28. [DOI: https://dx.doi.org/10.1016/j.tig.2015.10.005]

101. Guo, J.U.; Su, Y.; Zhong, C.; Ming, G.L.; Song, H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell; 2011; 145, pp. 423-434. [DOI: https://dx.doi.org/10.1016/j.cell.2011.03.022] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21496894]

102. Morgan, H.D.; Dean, W.; Coker, H.A.; Reik, W.; Petersen-Mahrt, S.K. Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: Implications for epigenetic reprogramming. J. Biol. Chem.; 2004; 279, pp. 52353-52360. [DOI: https://dx.doi.org/10.1074/jbc.M407695200] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15448152]

103. Chen, X.S. Insights into the Structures and Multimeric Status of APOBEC Proteins Involved in Viral Restriction and Other Cellular Functions. Viruses; 2021; 13, 497. [DOI: https://dx.doi.org/10.3390/v13030497] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33802945]

104. Chemudupati, M.; Kenney, A.D.; Bonifati, S.; Zani, A.; McMichael, T.M.; Wu, L.; Yount, J.S. From APOBEC to ZAP: Diverse mechanisms used by cellular restriction factors to inhibit virus infections. Biochim. Biophys. Acta Mol. Cell Res.; 2019; 1866, pp. 382-394. [DOI: https://dx.doi.org/10.1016/j.bbamcr.2018.09.012]

105. Schoggins, J.W. Interferon-Stimulated Genes: What Do They All Do?. Annu. Rev. Virol.; 2019; 6, pp. 567-584. [DOI: https://dx.doi.org/10.1146/annurev-virology-092818-015756]

106. Delviks-Frankenberry, K.A.; Desimmie, B.A.; Pathak, V.K. Structural Insights into APOBEC3-Mediated Lentiviral Restriction. Viruses; 2020; 12, 587. [DOI: https://dx.doi.org/10.3390/v12060587]

107. Salter, J.D.; Smith, H.C. Modeling the Embrace of a Mutator: APOBEC Selection of Nucleic Acid Ligands. Trends Biochem Sci; 2018; 43, pp. 606-622. [DOI: https://dx.doi.org/10.1016/j.tibs.2018.04.013]

108. Rathore, A.; Carpenter, M.A.; Demir, O.; Ikeda, T.; Li, M.; Shaban, N.M.; Law, E.K.; Anokhin, D.; Brown, W.L.; Amaro, R.E. et al. The local dinucleotide preference of APOBEC3G can be altered from 5′-CC to 5′-TC by a single amino acid substitution. J. Mol. Biol.; 2013; 425, pp. 4442-4454. [DOI: https://dx.doi.org/10.1016/j.jmb.2013.07.040]

109. Kohli, R.M.; Maul, R.W.; Guminski, A.F.; McClure, R.L.; Gajula, K.S.; Saribasak, H.; McMahon, M.A.; Siliciano, R.F.; Gearhart, P.J.; Stivers, J.T. Local sequence targeting in the AID/APOBEC family differentially impacts retroviral restriction and antibody diversification. J. Biol. Chem.; 2010; 285, pp. 40956-40964. [DOI: https://dx.doi.org/10.1074/jbc.M110.177402]

110. Carpenter, M.A.; Rajagurubandara, E.; Wijesinghe, P.; Bhagwat, A.S. Determinants of sequence-specificity within human AID and APOBEC3G. DNA Repair.; 2010; 9, pp. 579-587. [DOI: https://dx.doi.org/10.1016/j.dnarep.2010.02.010]

111. Shi, K.; Carpenter, M.A.; Banerjee, S.; Shaban, N.M.; Kurahashi, K.; Salamango, D.J.; McCann, J.L.; Starrett, G.J.; Duffy, J.V.; Demir, O. et al. Structural basis for targeted DNA cytosine deamination and mutagenesis by APOBEC3A and APOBEC3B. Nat. Struct. Mol. Biol.; 2017; 24, pp. 131-139. [DOI: https://dx.doi.org/10.1038/nsmb.3344]

112. Liddament, M.T.; Brown, W.L.; Schumacher, A.J.; Harris, R.S. APOBEC3F properties and hypermutation preferences indicate activity against HIV-1 in vivo. Curr. Biol.; 2004; 14, pp. 1385-1391. [DOI: https://dx.doi.org/10.1016/j.cub.2004.06.050] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15296757]

113. Beale, R.C.; Petersen-Mahrt, S.K.; Watt, I.N.; Harris, R.S.; Rada, C.; Neuberger, M.S. Comparison of the differential context-dependence of DNA deamination by APOBEC enzymes: Correlation with mutation spectra in vivo. J. Mol. Biol.; 2004; 337, pp. 585-596. [DOI: https://dx.doi.org/10.1016/j.jmb.2004.01.046] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15019779]

114. McDaniel, Y.Z.; Wang, D.; Love, R.P.; Adolph, M.B.; Mohammadzadeh, N.; Chelico, L.; Mansky, L.M. Deamination hotspots among APOBEC3 family members are defined by both target site sequence context and ssDNA secondary structure. Nucleic Acids Res.; 2020; 48, pp. 1353-1371. [DOI: https://dx.doi.org/10.1093/nar/gkz1164]

115. Feng, Y.; Baig, T.T.; Love, R.P.; Chelico, L. Suppression of APOBEC3-mediated restriction of HIV-1 by Vif. Front. Microbiol.; 2014; 5, 450. [DOI: https://dx.doi.org/10.3389/fmicb.2014.00450]

116. Maiti, A.; Hou, S.; Schiffer, C.A.; Matsuo, H. Interactions of APOBEC3s with DNA and RNA. Curr. Opin. Struct. Biol.; 2021; 67, pp. 195-204. [DOI: https://dx.doi.org/10.1016/j.sbi.2020.12.004]

117. Xiao, X.; Yang, H.; Arutiunian, V.; Fang, Y.; Besse, G.; Morimoto, C.; Zirkle, B.; Chen, X.S. Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation. Nucleic Acids Res.; 2017; 45, pp. 7494-7506. [DOI: https://dx.doi.org/10.1093/nar/gkx362]

118. Polevoda, B.; Joseph, R.; Friedman, A.E.; Bennett, R.P.; Greiner, R.; De Zoysa, T.; Stewart, R.A.; Smith, H.C. DNA mutagenic activity and capacity for HIV-1 restriction of the cytidine deaminase APOBEC3G depend on whether DNA or RNA binds to tyrosine 315. J. Biol. Chem.; 2017; 292, pp. 8642-8656. [DOI: https://dx.doi.org/10.1074/jbc.M116.767889]

119. Yang, H.; Pacheco, J.; Kim, K.; Bokani, A.; Ito, F.; Ebrahimi, D.; Chen, X.S. Molecular mechanism for regulating APOBEC3G DNA editing function by the non-catalytic domain. Nat. Commun.; 2024; 15, 8773. [DOI: https://dx.doi.org/10.1038/s41467-024-52671-1]

120. Shaban, N.M.; Shi, K.; Lauer, K.V.; Carpenter, M.A.; Richards, C.M.; Salamango, D.; Wang, J.; Lopresti, M.W.; Banerjee, S.; Levin-Klein, R. et al. The Antiviral and Cancer Genomic DNA Deaminase APOBEC3H Is Regulated by an RNA-Mediated Dimerization Mechanism. Mol. Cell; 2018; 69, pp. 75-86.e79. [DOI: https://dx.doi.org/10.1016/j.molcel.2017.12.010]

121. Caval, V.; Bouzidi, M.S.; Suspene, R.; Laude, H.; Dumargne, M.C.; Bashamboo, A.; Krey, T.; Vartanian, J.P.; Wain-Hobson, S. Molecular basis of the attenuated phenotype of human APOBEC3B DNA mutator enzyme. Nucleic Acids Res.; 2015; 43, pp. 9340-9349. [DOI: https://dx.doi.org/10.1093/nar/gkv935] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26384561]

122. Gallois-Montbrun, S.; Kramer, B.; Swanson, C.M.; Byers, H.; Lynham, S.; Ward, M.; Malim, M.H. Antiviral protein APOBEC3G localizes to ribonucleoprotein complexes found in P bodies and stress granules. J. Virol.; 2007; 81, pp. 2165-2178. [DOI: https://dx.doi.org/10.1128/JVI.02287-06]

123. Chiu, Y.L.; Witkowska, H.E.; Hall, S.C.; Santiago, M.; Soros, V.B.; Esnault, C.; Heidmann, T.; Greene, W.C. High-molecular-mass APOBEC3G complexes restrict Alu retrotransposition. Proc. Natl. Acad. Sci. USA; 2006; 103, pp. 15588-15593. [DOI: https://dx.doi.org/10.1073/pnas.0604524103]

124. Kozak, S.L.; Marin, M.; Rose, K.M.; Bystrom, C.; Kabat, D. The anti-HIV-1 editing enzyme APOBEC3G binds HIV-1 RNA and messenger RNAs that shuttle between polysomes and stress granules. J. Biol. Chem.; 2006; 281, pp. 29105-29119. [DOI: https://dx.doi.org/10.1074/jbc.M601901200] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16887808]

125. Niewiadomska, A.M.; Tian, C.; Tan, L.; Wang, T.; Sarkis, P.T.; Yu, X.F. Differential inhibition of long interspersed element 1 by APOBEC3 does not correlate with high-molecular-mass-complex formation or P-body association. J. Virol.; 2007; 81, pp. 9577-9583. [DOI: https://dx.doi.org/10.1128/JVI.02800-06] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17582006]

126. Soros, V.B.; Yonemoto, W.; Greene, W.C. Newly synthesized APOBEC3G is incorporated into HIV virions, inhibited by HIV RNA, and subsequently activated by RNase H. PLoS Pathog.; 2007; 3, e15. [DOI: https://dx.doi.org/10.1371/journal.ppat.0030015]

127. Stopak, K.S.; Chiu, Y.L.; Kropp, J.; Grant, R.M.; Greene, W.C. Distinct patterns of cytokine regulation of APOBEC3G expression and activity in primary lymphocytes, macrophages, and dendritic cells. J. Biol. Chem.; 2007; 282, pp. 3539-3546. [DOI: https://dx.doi.org/10.1074/jbc.M610138200]

128. Shirakawa, K.; Takaori-Kondo, A.; Yokoyama, M.; Izumi, T.; Matsui, M.; Io, K.; Sato, T.; Sato, H.; Uchiyama, T. Phosphorylation of APOBEC3G by protein kinase A regulates its interaction with HIV-1 Vif. Nat. Struct. Mol. Biol.; 2008; 15, pp. 1184-1191. [DOI: https://dx.doi.org/10.1038/nsmb.1497]

129. Sugiyama, R.; Nishitsuji, H.; Furukawa, A.; Katahira, M.; Habu, Y.; Takeuchi, H.; Ryo, A.; Takaku, H. Heat shock protein 70 inhibits HIV-1 Vif-mediated ubiquitination and degradation of APOBEC3G. J. Biol. Chem.; 2011; 286, pp. 10051-10057. [DOI: https://dx.doi.org/10.1074/jbc.M110.166108]

130. Gallois-Montbrun, S.; Holmes, R.K.; Swanson, C.M.; Fernandez-Ocana, M.; Byers, H.L.; Ward, M.A.; Malim, M.H. Comparison of cellular ribonucleoprotein complexes associated with the APOBEC3F and APOBEC3G antiviral proteins. J. Virol.; 2008; 82, pp. 5636-5642. [DOI: https://dx.doi.org/10.1128/JVI.00287-08]

131. Maeda, K.; Almofty, S.A.; Singh, S.K.; Eid, M.M.; Shimoda, M.; Ikeda, T.; Koito, A.; Pham, P.; Goodman, M.F.; Sakaguchi, N. GANP Interacts with APOBEC3G and Facilitates Its Encapsidation into the Virions To Reduce HIV-1 Infectivity. J. Immunol.; 2013; 191, pp. 6030-6039. [DOI: https://dx.doi.org/10.4049/jimmunol.1302057] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24198285]

132. Pion, M.; Granelli-Piperno, A.; Mangeat, B.; Stalder, R.; Correa, R.; Steinman, R.M.; Piguet, V. APOBEC3G/3F mediates intrinsic resistance of monocyte-derived dendritic cells to HIV-1 infection. J. Exp. Med.; 2006; 203, pp. 2887-2893. [DOI: https://dx.doi.org/10.1084/jem.20061519] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17145955]

133. Ito, F.; Yang, H.; Xiao, X.; Li, S.X.; Wolfe, A.; Zirkle, B.; Arutiunian, V.; Chen, X.S. Understanding the structure, multimerization, subcellular localization and mC selectivity of a genomic mutator and anti-HIV factor APOBEC3H. Sci. Rep.; 2018; 8, 3763. [DOI: https://dx.doi.org/10.1038/s41598-018-21955-0] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29491387]

134. Chen, Z.; Eggerman, T.L.; Bocharov, A.V.; Baranova, I.N.; Vishnyakova, T.G.; Kurlander, R.; Patterson, A.P. Heat shock proteins stimulate APOBEC-3-mediated cytidine deamination in the hepatitis B virus. J. Biol. Chem.; 2017; 292, pp. 13459-13479. [DOI: https://dx.doi.org/10.1074/jbc.M116.760637]

135. Pan, T.; Song, Z.; Wu, L.; Liu, G.; Ma, X.; Peng, Z.; Zhou, M.; Liang, L.; Liu, B.; Liu, J. et al. USP49 potently stabilizes APOBEC3G protein by removing ubiquitin and inhibits HIV-1 replication. Elife; 2019; 8, e48318. [DOI: https://dx.doi.org/10.7554/eLife.48318]

136. Yoshino, S.; Matsui, Y.; Fukui, Y.; Seki, M.; Yamaguchi, K.; Kanamori, A.; Saitoh, Y.; Shimamura, T.; Suzuki, Y.; Furukawa, Y. et al. EXOSC9 depletion attenuates P-body formation, stress resistance, and tumorigenicity of cancer cells. Sci. Rep.; 2020; 10, 9275. [DOI: https://dx.doi.org/10.1038/s41598-020-66455-2]

137. Vieira, V.C.; Soares, M.A. The role of cytidine deaminases on innate immune responses against human viral infections. Biomed. Res. Int.; 2013; 2013, 683095. [DOI: https://dx.doi.org/10.1155/2013/683095]

138. Cheng, A.Z.; Moraes, S.N.; Attarian, C.; Yockteng-Melgar, J.; Jarvis, M.C.; Biolatti, M.; Galitska, G.; Dell’Oste, V.; Frappier, L.; Bierle, C.J. et al. A Conserved Mechanism of APOBEC3 Relocalization by Herpesviral Ribonucleotide Reductase Large Subunits. J. Virol.; 2019; 93, 10-1128. [DOI: https://dx.doi.org/10.1128/JVI.01539-19]

139. Lackey, L.; Law, E.K.; Brown, W.L.; Harris, R.S. Subcellular localization of the APOBEC3 proteins during mitosis and implications for genomic DNA deamination. Cell Cycle; 2013; 12, pp. 762-772. [DOI: https://dx.doi.org/10.4161/cc.23713]

140. Kinomoto, M.; Kanno, T.; Shimura, M.; Ishizaka, Y.; Kojima, A.; Kurata, T.; Sata, T.; Tokunaga, K. All APOBEC3 family proteins differentially inhibit LINE-1 retrotransposition. Nucleic Acids Res.; 2007; 35, pp. 2955-2964. [DOI: https://dx.doi.org/10.1093/nar/gkm181]

141. Burns, M.B.; Lackey, L.; Carpenter, M.A.; Rathore, A.; Land, A.M.; Leonard, B.; Refsland, E.W.; Kotandeniya, D.; Tretyakova, N.; Nikas, J.B. et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature; 2013; 494, pp. 366-370. [DOI: https://dx.doi.org/10.1038/nature11881] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23389445]

142. Stenglein, M.D.; Matsuo, H.; Harris, R.S. Two regions within the amino-terminal half of APOBEC3G cooperate to determine cytoplasmic localization. J. Virol.; 2008; 82, pp. 9591-9599. [DOI: https://dx.doi.org/10.1128/JVI.02471-07] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18667511]

143. Salamango, D.J.; McCann, J.L.; Demir, O.; Brown, W.L.; Amaro, R.E.; Harris, R.S. APOBEC3B Nuclear Localization Requires Two Distinct N-Terminal Domain Surfaces. J. Mol. Biol.; 2018; 430, pp. 2695-2708. [DOI: https://dx.doi.org/10.1016/j.jmb.2018.04.044] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29787764]

144. Land, A.M.; Law, E.K.; Carpenter, M.A.; Lackey, L.; Brown, W.L.; Harris, R.S. Endogenous APOBEC3A DNA cytosine deaminase is cytoplasmic and nongenotoxic. J. Biol. Chem.; 2013; 288, pp. 17253-17260. [DOI: https://dx.doi.org/10.1074/jbc.M113.458661]

145. Salamango, D.J.; Becker, J.T.; McCann, J.L.; Cheng, A.Z.; Demir, O.; Amaro, R.E.; Brown, W.L.; Shaban, N.M.; Harris, R.S. APOBEC3H Subcellular Localization Determinants Define Zipcode for Targeting HIV-1 for Restriction. Mol. Cell Biol.; 2018; 38, e00356-18. [DOI: https://dx.doi.org/10.1128/MCB.00356-18]

146. Li, M.M.; Emerman, M. Polymorphism in human APOBEC3H affects a phenotype dominant for subcellular localization and antiviral activity. J. Virol.; 2011; 85, pp. 8197-8207. [DOI: https://dx.doi.org/10.1128/JVI.00624-11]

147. Covino, D.A.; Gauzzi, M.C.; Fantuzzi, L. Understanding the regulation of APOBEC3 expression: Current evidence and much to learn. J. Leukoc. Biol.; 2018; 103, pp. 433-444. [DOI: https://dx.doi.org/10.1002/JLB.2MR0717-310R]

148. Koning, F.A.; Newman, E.N.; Kim, E.Y.; Kunstman, K.J.; Wolinsky, S.M.; Malim, M.H. Defining APOBEC3 expression patterns in human tissues and hematopoietic cell subsets. J. Virol.; 2009; 83, pp. 9474-9485. [DOI: https://dx.doi.org/10.1128/JVI.01089-09]

149. Refsland, E.W.; Stenglein, M.D.; Shindo, K.; Albin, J.S.; Brown, W.L.; Harris, R.S. Quantitative profiling of the full APOBEC3 mRNA repertoire in lymphocytes and tissues: Implications for HIV-1 restriction. Nucleic Acids Res.; 2010; 38, pp. 4274-4284. [DOI: https://dx.doi.org/10.1093/nar/gkq174]

150. Ikeda, T.; Molan, A.M.; Jarvis, M.C.; Carpenter, M.A.; Salamango, D.J.; Brown, W.L.; Harris, R.S. HIV-1 restriction by endogenous APOBEC3G in the myeloid cell line THP-1. J. Gen. Virol.; 2019; 100, pp. 1140-1152. [DOI: https://dx.doi.org/10.1099/jgv.0.001276]

151. Ikeda, T.; Symeonides, M.; Albin, J.S.; Li, M.; Thali, M.; Harris, R.S. HIV-1 adaptation studies reveal a novel Env-mediated homeostasis mechanism for evading lethal hypermutation by APOBEC3G. PLoS Pathog.; 2018; 14, e1007010. [DOI: https://dx.doi.org/10.1371/journal.ppat.1007010] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29677220]

152. Leonard, B.; Starrett, G.J.; Maurer, M.J.; Oberg, A.L.; Van Bockstal, M.; Van Dorpe, J.; De Wever, O.; Helleman, J.; Sieuwerts, A.M.; Berns, E.M. et al. APOBEC3G Expression Correlates with T-Cell Infiltration and Improved Clinical Outcomes in High-grade Serous Ovarian Carcinoma. Clin. Cancer Res.; 2016; 22, pp. 4746-4755. [DOI: https://dx.doi.org/10.1158/1078-0432.CCR-15-2910] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27016308]

153. Mulder, L.C.; Ooms, M.; Majdak, S.; Smedresman, J.; Linscheid, C.; Harari, A.; Kunz, A.; Simon, V. Moderate influence of human APOBEC3F on HIV-1 replication in primary lymphocytes. J. Virol.; 2010; 84, pp. 9613-9617. [DOI: https://dx.doi.org/10.1128/JVI.02630-09] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20592068]

154. Hakata, Y.; Miyazawa, M. Deaminase-Independent Mode of Antiretroviral Action in Human and Mouse APOBEC3 Proteins. Microorganisms; 2020; 8, 1976. [DOI: https://dx.doi.org/10.3390/microorganisms8121976] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33322756]

155. Pollpeter, D.; Parsons, M.; Sobala, A.E.; Coxhead, S.; Lang, R.D.; Bruns, A.M.; Papaioannou, S.; McDonnell, J.M.; Apolonia, L.; Chowdhury, J.A. et al. Deep sequencing of HIV-1 reverse transcripts reveals the multifaceted antiviral functions of APOBEC3G. Nat. Microbiol.; 2018; 3, pp. 220-233. [DOI: https://dx.doi.org/10.1038/s41564-017-0063-9]

156. Wang, X.; Ao, Z.; Chen, L.; Kobinger, G.; Peng, J.; Yao, X. The cellular antiviral protein APOBEC3G interacts with HIV-1 reverse transcriptase and inhibits its function during viral replication. J. Virol.; 2012; 86, pp. 3777-3786. [DOI: https://dx.doi.org/10.1128/JVI.06594-11]

157. Holmes, R.K.; Koning, F.A.; Bishop, K.N.; Malim, M.H. APOBEC3F can inhibit the accumulation of HIV-1 reverse transcription products in the absence of hypermutation. Comparisons with APOBEC3G. J. Biol. Chem.; 2007; 282, pp. 2587-2595. [DOI: https://dx.doi.org/10.1074/jbc.M607298200]

158. Mitra, M.; Singer, D.; Mano, Y.; Hritz, J.; Nam, G.; Gorelick, R.J.; Byeon, I.J.; Gronenborn, A.M.; Iwatani, Y.; Levin, J.G. Sequence and structural determinants of human APOBEC3H deaminase and anti-HIV-1 activities. Retrovirology; 2015; 12, 3. [DOI: https://dx.doi.org/10.1186/s12977-014-0130-8]

159. Kobayashi, T.; Koizumi, Y.; Takeuchi, J.S.; Misawa, N.; Kimura, Y.; Morita, S.; Aihara, K.; Koyanagi, Y.; Iwami, S.; Sato, K. Quantification of deaminase activity-dependent and -independent restriction of HIV-1 replication mediated by APOBEC3F and APOBEC3G through experimental-mathematical investigation. J. Virol.; 2014; 88, pp. 5881-5887. [DOI: https://dx.doi.org/10.1128/JVI.00062-14]

160. Ajoge, H.O.; Renner, T.M.; Belanger, K.; Greig, M.; Dankar, S.; Kohio, H.P.; Coleman, M.D.; Ndashimye, E.; Arts, E.J.; Langlois, M.A. et al. Antiretroviral APOBEC3 cytidine deaminases alter HIV-1 provirus integration site profiles. Nat. Commun.; 2023; 14, 16. [DOI: https://dx.doi.org/10.1038/s41467-022-35379-y]

161. Luo, K.; Wang, T.; Liu, B.; Tian, C.; Xiao, Z.; Kappes, J.; Yu, X.F. Cytidine deaminases APOBEC3G and APOBEC3F interact with human immunodeficiency virus type 1 integrase and inhibit proviral DNA formation. J. Virol.; 2007; 81, pp. 7238-7248. [DOI: https://dx.doi.org/10.1128/JVI.02584-06] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17428847]

162. Mbisa, J.L.; Bu, W.; Pathak, V.K. APOBEC3F and APOBEC3G inhibit HIV-1 DNA integration by different mechanisms. J. Virol.; 2010; 84, pp. 5250-5259. [DOI: https://dx.doi.org/10.1128/JVI.02358-09] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20219927]

163. Burdick, R.C.; Delviks-Frankenberry, K.A.; Chen, J.; Janaka, S.K.; Sastri, J.; Hu, W.S.; Pathak, V.K. Dynamics and regulation of nuclear import and nuclear movements of HIV-1 complexes. PLoS Pathog.; 2017; 13, e1006570. [DOI: https://dx.doi.org/10.1371/journal.ppat.1006570]

164. Mangeat, B.; Turelli, P.; Caron, G.; Friedli, M.; Perrin, L.; Trono, D. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature; 2003; 424, pp. 99-103. [DOI: https://dx.doi.org/10.1038/nature01709]

165. Iwatani, Y.; Takeuchi, H.; Strebel, K.; Levin, J.G. Biochemical activities of highly purified, catalytically active human APOBEC3G: Correlation with antiviral effect. J. Virol.; 2006; 80, pp. 5992-6002. [DOI: https://dx.doi.org/10.1128/JVI.02680-05]

166. Alqassim, E.Y.; Sharma, S.; Khan, A.; Emmons, T.R.; Cortes Gomez, E.; Alahmari, A.; Singel, K.L.; Mark, J.; Davidson, B.A.; Robert McGray, A.J. et al. RNA editing enzyme APOBEC3A promotes pro-inflammatory M1 macrophage polarization. Commun. Biol.; 2021; 4, 102. [DOI: https://dx.doi.org/10.1038/s42003-020-01620-x]

167. Sharma, S.; Patnaik, S.K.; Taggart, R.T.; Kannisto, E.D.; Enriquez, S.M.; Gollnick, P.; Baysal, B.E. APOBEC3A cytidine deaminase induces RNA editing in monocytes and macrophages. Nat. Commun.; 2015; 6, 6881. [DOI: https://dx.doi.org/10.1038/ncomms7881]

168. Sharma, S.; Patnaik, S.K.; Kemer, Z.; Baysal, B.E. Transient overexpression of exogenous APOBEC3A causes C-to-U RNA editing of thousands of genes. RNA Biol.; 2017; 14, pp. 603-610. [DOI: https://dx.doi.org/10.1080/15476286.2016.1184387]

169. Sharma, S.; Patnaik, S.K.; Taggart, R.T.; Baysal, B.E. The double-domain cytidine deaminase APOBEC3G is a cellular site-specific RNA editing enzyme. Sci. Rep.; 2016; 6, 39100. [DOI: https://dx.doi.org/10.1038/srep39100]

170. Van Engelenburg, S.B.; Shtengel, G.; Sengupta, P.; Waki, K.; Jarnik, M.; Ablan, S.D.; Freed, E.O.; Hess, H.F.; Lippincott-Schwartz, J. Distribution of ESCRT machinery at HIV assembly sites reveals virus scaffolding of ESCRT subunits. Science; 2014; 343, pp. 653-656. [DOI: https://dx.doi.org/10.1126/science.1247786]

171. Vlach, J.; Saad, J.S. Trio engagement via plasma membrane phospholipids and the myristoyl moiety governs HIV-1 matrix binding to bilayers. Proc. Natl. Acad. Sci. USA; 2013; 110, pp. 3525-3530. [DOI: https://dx.doi.org/10.1073/pnas.1216655110] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23401539]

172. Budhiraja, S.; Liu, H.; Couturier, J.; Malovannaya, A.; Qin, J.; Lewis, D.E.; Rice, A.P. Mining the human complexome database identifies RBM14 as an XPO1-associated protein involved in HIV-1 Rev function. J. Virol.; 2015; 89, pp. 3557-3567. [DOI: https://dx.doi.org/10.1128/JVI.03232-14] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25589658]

173. Jäger, S.; Kim, D.Y.; Hultquist, J.F.; Shindo, K.; LaRue, R.S.; Kwon, E.; Li, M.; Anderson, B.D.; Yen, L.; Stanley, D. et al. Vif hijacks CBF-beta to degrade APOBEC3G and promote HIV-1 infection. Nature; 2011; 481, pp. 371-375. [DOI: https://dx.doi.org/10.1038/nature10693] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22190037]

174. Zhang, W.; Du, J.; Evans, S.L.; Yu, Y.; Yu, X.F. T-cell differentiation factor CBF-beta regulates HIV-1 Vif-mediated evasion of host restriction. Nature; 2012; 481, pp. 376-379. [DOI: https://dx.doi.org/10.1038/nature10718]

175. Yu, X.; Yu, Y.; Liu, B.; Luo, K.; Kong, W.; Mao, P.; Yu, X.F. Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science; 2003; 302, pp. 1056-1060. [DOI: https://dx.doi.org/10.1126/science.1089591]

176. Li, Y.L.; Langley, C.A.; Azumaya, C.M.; Echeverria, I.; Chesarino, N.M.; Emerman, M.; Cheng, Y.; Gross, J.D. The structural basis for HIV-1 Vif antagonism of human APOBEC3G. Nature; 2023; 615, pp. 728-733. [DOI: https://dx.doi.org/10.1038/s41586-023-05779-1]

177. Hu, Y.; Desimmie, B.A.; Nguyen, H.C.; Ziegler, S.J.; Cheng, T.C.; Chen, J.; Wang, J.; Wang, H.; Zhang, K.; Pathak, V.K. et al. Structural basis of antagonism of human APOBEC3F by HIV-1 Vif. Nat. Struct. Mol. Biol.; 2019; 26, pp. 1176-1183. [DOI: https://dx.doi.org/10.1038/s41594-019-0343-6]

178. Huttenhain, R.; Xu, J.; Burton, L.A.; Gordon, D.E.; Hultquist, J.F.; Johnson, J.R.; Satkamp, L.; Hiatt, J.; Rhee, D.Y.; Baek, K. et al. ARIH2 Is a Vif-Dependent Regulator of CUL5-Mediated APOBEC3G Degradation in HIV Infection. Cell Host Microbe; 2019; 26, pp. 86-99.e87. [DOI: https://dx.doi.org/10.1016/j.chom.2019.05.008]

179. Ito, F.; Alvarez-Cabrera, A.L.; Kim, K.; Zhou, Z.H.; Chen, X.S. Structural basis of HIV-1 Vif-mediated E3 ligase targeting of host APOBEC3H. Nat. Commun.; 2023; 14, 5241. [DOI: https://dx.doi.org/10.1038/s41467-023-40955-x]

180. Ito, F.; Alvarez-Cabrera, A.L.; Liu, S.; Yang, H.; Shiriaeva, A.; Zhou, Z.H.; Chen, X.S. Structural basis for HIV-1 antagonism of host APOBEC3G via Cullin E3 ligase. Sci. Adv.; 2023; 9, eade3168. [DOI: https://dx.doi.org/10.1126/sciadv.ade3168]

181. Kouno, T.; Shibata, S.; Shigematsu, M.; Hyun, J.; Kim, T.G.; Matsuo, H.; Wolf, M. Structural insights into RNA bridging between HIV-1 Vif and antiviral factor APOBEC3G. Nat. Commun.; 2023; 14, 4037. [DOI: https://dx.doi.org/10.1038/s41467-023-39796-5] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37419875]

182. Iwatani, Y.; Matsuoka, K.; Ode, H.; Kubota, M.; Nakata, Y.; Setoyama, Y.; Kojima, K.; Imahashi, M.; Yokomaku, Y. The unique structure of the highly conserved PPLP region in HIV-1 Vif is critical for the formation of APOBEC3 recognition interfaces. mBio; 2025; e0333224. [DOI: https://dx.doi.org/10.1128/mbio.03332-24] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39835817]

183. Kim, D.Y.; Kwon, E.; Hartley, P.D.; Crosby, D.C.; Mann, S.; Krogan, N.J.; Gross, J.D. CBFbeta stabilizes HIV Vif to counteract APOBEC3 at the expense of RUNX1 target gene expression. Mol. Cell; 2013; 49, pp. 632-644. [DOI: https://dx.doi.org/10.1016/j.molcel.2012.12.012] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23333304]

184. Anderson, B.D.; Harris, R.S. Transcriptional regulation of APOBEC3 antiviral immunity through the CBF-beta/RUNX axis. Sci. Adv.; 2015; 1, e1500296. [DOI: https://dx.doi.org/10.1126/sciadv.1500296] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26601257]

185. Libre, C.; Seissler, T.; Guerrero, S.; Batisse, J.; Verriez, C.; Stupfler, B.; Gilmer, O.; Cabrera-Rodriguez, R.; Weber, M.M.; Valenzuela-Fernandez, A. et al. A Conserved uORF Regulates APOBEC3G Translation and Is Targeted by HIV-1 Vif Protein to Repress the Antiviral Factor. Biomedicines; 2021; 10, 13. [DOI: https://dx.doi.org/10.3390/biomedicines10010013]

186. Guerrero, S.; Libre, C.; Batisse, J.; Mercenne, G.; Richer, D.; Laumond, G.; Decoville, T.; Moog, C.; Marquet, R.; Paillart, J.C. Translational regulation of APOBEC3G mRNA by Vif requires its 5′UTR and contributes to restoring HIV-1 infectivity. Sci. Rep.; 2016; 6, 39507. [DOI: https://dx.doi.org/10.1038/srep39507]

187. Wang, J.; Shackelford, J.M.; Casella, C.R.; Shivers, D.K.; Rapaport, E.L.; Liu, B.; Yu, X.F.; Finkel, T.H. The Vif accessory protein alters the cell cycle of human immunodeficiency virus type 1 infected cells. Virology; 2007; 359, pp. 243-252. [DOI: https://dx.doi.org/10.1016/j.virol.2006.09.026]

188. DeHart, J.L.; Bosque, A.; Harris, R.S.; Planelles, V. Human immunodeficiency virus type 1 Vif induces cell cycle delay via recruitment of the same E3 ubiquitin ligase complex that targets APOBEC3 proteins for degradation. J. Virol.; 2008; 82, pp. 9265-9272. [DOI: https://dx.doi.org/10.1128/JVI.00377-08]

189. Du, J.; Rui, Y.; Zheng, W.; Li, P.; Kang, J.; Zhao, K.; Sun, T.; Yu, X.F. Vif-CBFbeta interaction is essential for Vif-induced cell cycle arrest. Biochem. Biophys. Res. Commun.; 2019; 511, pp. 910-915. [DOI: https://dx.doi.org/10.1016/j.bbrc.2019.02.136]

190. Sakai, K.; Dimas, J.; Lenardo, M.J. The Vif and Vpr accessory proteins independently cause HIV-1-induced T cell cytopathicity and cell cycle arrest. Proc. Natl. Acad. Sci. USA; 2006; 103, pp. 3369-3374. [DOI: https://dx.doi.org/10.1073/pnas.0509417103]

191. Salamango, D.J.; Ikeda, T.; Moghadasi, S.A.; Wang, J.; McCann, J.L.; Serebrenik, A.A.; Ebrahimi, D.; Jarvis, M.C.; Brown, W.L.; Harris, R.S. HIV-1 Vif triggers cell cycle arrest by degrading cellular PPP2R5 phospho-regulators. Cell Rep.; 2019; 29, pp. 1057-1065.e1054. [DOI: https://dx.doi.org/10.1016/j.celrep.2019.09.057] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31665623]

192. Izumi, T.; Io, K.; Matsui, M.; Shirakawa, K.; Shinohara, M.; Nagai, Y.; Kawahara, M.; Kobayashi, M.; Kondoh, H.; Misawa, N. et al. HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication. Proc. Natl. Acad. Sci. USA; 2010; 107, pp. 20798-20803. [DOI: https://dx.doi.org/10.1073/pnas.1008076107] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21071676]

193. Salamango, D.J.; McCann, J.L.; Demir, O.; Becker, J.T.; Wang, J.; Lingappa, J.R.; Temiz, N.A.; Brown, W.L.; Amaro, R.E.; Harris, R.S. Functional and Structural Insights into a Vif/PPP2R5 Complex Elucidated Using Patient HIV-1 Isolates and Computational Modeling. J. Virol.; 2020; 94, 10-1128. [DOI: https://dx.doi.org/10.1128/JVI.00631-20]

194. Greenwood, E.J.; Matheson, N.J.; Wals, K.; van den Boomen, D.J.; Antrobus, R.; Williamson, J.C.; Lehner, P.J. Temporal proteomic analysis of HIV infection reveals remodelling of the host phosphoproteome by lentiviral Vif variants. Elife; 2016; 5, e18296. [DOI: https://dx.doi.org/10.7554/eLife.18296]

195. Naamati, A.; Williamson, J.C.; Greenwood, E.J.; Marelli, S.; Lehner, P.J.; Matheson, N.J. Functional proteomic atlas of HIV infection in primary human CD4+ T cells. Elife; 2019; 8, e41431. [DOI: https://dx.doi.org/10.7554/eLife.41431]

196. Nagata, K.; Shindo, K.; Matsui, Y.; Shirakawa, K.; Takaori-Kondo, A. Critical role of PP2A-B56 family protein degradation in HIV-1 Vif mediated G2 cell cycle arrest. Biochem. Biophys. Res. Commun.; 2020; 527, pp. 257-263. [DOI: https://dx.doi.org/10.1016/j.bbrc.2020.04.123]

197. Hu, Y.; Delviks-Frankenberry, K.A.; Wu, C.; Arizaga, F.; Pathak, V.K.; Xiong, Y. Structural insights into PPP2R5A degradation by HIV-1 Vif. Nat. Struct. Mol. Biol.; 2024; 31, pp. 1492-1501. [DOI: https://dx.doi.org/10.1038/s41594-024-01314-6]

198. Sadeghpour, S.; Khodaee, S.; Rahnama, M.; Rahimi, H.; Ebrahimi, D. Human APOBEC3 Variations and Viral Infection. Viruses; 2021; 13, 1366. [DOI: https://dx.doi.org/10.3390/v13071366]

199. Lewitus, E.; Li, Y.; Rolland, M. HIV-1 Vif global diversity and possible APOBEC-mediated response since 1980. Virus Evol.; 2025; 11, veae108. [DOI: https://dx.doi.org/10.1093/ve/veae108]

200. Jaguva Vasudevan, A.A.; Hofmann, H.; Willbold, D.; Haussinger, D.; Koenig, B.W.; Munk, C. Enhancing the Catalytic Deamination Activity of APOBEC3C Is Insufficient to Inhibit Vif-Deficient HIV-1. J. Mol. Biol.; 2017; 429, pp. 1171-1191. [DOI: https://dx.doi.org/10.1016/j.jmb.2017.03.015] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28315663]

201. Kitamura, S.; Ode, H.; Nakashima, M.; Imahashi, M.; Naganawa, Y.; Kurosawa, T.; Yokomaku, Y.; Yamane, T.; Watanabe, N.; Suzuki, A. et al. The APOBEC3C crystal structure and the interface for HIV-1 Vif binding. Nat. Struct. Mol. Biol.; 2012; 19, pp. 1005-1010. [DOI: https://dx.doi.org/10.1038/nsmb.2378] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23001005]

202. Zhang, Z.; Gu, Q.; Jaguva Vasudevan, A.A.; Jeyaraj, M.; Schmidt, S.; Zielonka, J.; Perkovic, M.; Heckel, J.O.; Cichutek, K.; Haussinger, D. et al. Vif Proteins from Diverse Human Immunodeficiency Virus/Simian Immunodeficiency Virus Lineages Have Distinct Binding Sites in A3C. J. Virol.; 2016; 90, pp. 10193-10208. [DOI: https://dx.doi.org/10.1128/JVI.01497-16] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27581978]

203. Duggal, N.K.; Fu, W.; Akey, J.M.; Emerman, M. Identification and antiviral activity of common polymorphisms in the APOBEC3 locus in human populations. Virology; 2013; 443, pp. 329-337. [DOI: https://dx.doi.org/10.1016/j.virol.2013.05.016] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23755966]

204. Jaguva Vasudevan, A.A.; Balakrishnan, K.; Gertzen, C.G.W.; Borveto, F.; Zhang, Z.; Sangwiman, A.; Held, U.; Kustermann, C.; Banerjee, S.; Schumann, G.G. et al. Loop 1 of APOBEC3C Regulates its Antiviral Activity against HIV-1. J. Mol. Biol.; 2020; 432, pp. 6200-6227. [DOI: https://dx.doi.org/10.1016/j.jmb.2020.10.014] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33068636]

205. Dang, Y.; Wang, X.; Esselman, W.J.; Zheng, Y.H. Identification of APOBEC3DE as another antiretroviral factor from the human APOBEC family. J. Virol.; 2006; 80, pp. 10522-10533. [DOI: https://dx.doi.org/10.1128/JVI.01123-06]

206. Sato, K.; Takeuchi, J.S.; Misawa, N.; Izumi, T.; Kobayashi, T.; Kimura, Y.; Iwami, S.; Takaori-Kondo, A.; Hu, W.S.; Aihara, K. et al. APOBEC3D and APOBEC3F potently promote HIV-1 diversification and evolution in humanized mouse model. PLoS Pathog.; 2014; 10, e1004453. [DOI: https://dx.doi.org/10.1371/journal.ppat.1004453]

207. Matume, N.D.; Tebit, D.M.; Gray, L.R.; Turner, S.D.; Rekosh, D.; Bessong, P.O.; Hammarskjold, M.L. Characterization of APOBEC3 variation in a population of HIV-1 infected individuals in northern South Africa. BMC Med. Genet.; 2019; 20, 21. [DOI: https://dx.doi.org/10.1186/s12881-018-0740-4]

208. Meissner, M.E.; Willkomm, N.A.; Lucas, J.; Arndt, W.G.; Aitken, S.F.; Julik, E.J.; Baliga, S.; Mansky, L.M. Differential Activity of APOBEC3F, APOBEC3G, and APOBEC3H in the Restriction of HIV-2. J. Mol. Biol.; 2022; 434, 167355. [DOI: https://dx.doi.org/10.1016/j.jmb.2021.167355]

209. Mohammadzadeh, N.; Love, R.P.; Gibson, R.; Arts, E.J.; Poon, A.F.Y.; Chelico, L. Role of co-expressed APOBEC3F and APOBEC3G in inducing HIV-1 drug resistance. Heliyon; 2019; 5, e01498. [DOI: https://dx.doi.org/10.1016/j.heliyon.2019.e01498]

210. Mohammadzadeh, N.; Follack, T.B.; Love, R.P.; Stewart, K.; Sanche, S.; Chelico, L. Polymorphisms of the cytidine deaminase APOBEC3F have different HIV-1 restriction efficiencies. Virology; 2019; 527, pp. 21-31. [DOI: https://dx.doi.org/10.1016/j.virol.2018.11.004]

211. Dang, Y.; Abudu, A.; Son, S.; Harjes, E.; Spearman, P.; Matsuo, H.; Zheng, Y.H. Identification of a single amino acid required for APOBEC3 antiretroviral cytidine deaminase activity. J. Virol.; 2011; 85, pp. 5691-5695. [DOI: https://dx.doi.org/10.1128/JVI.00243-11] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21430060]

212. Lassen, K.G.; Wissing, S.; Lobritz, M.A.; Santiago, M.; Greene, W.C. Identification of two APOBEC3F splice variants displaying HIV-1 antiviral activity and contrasting sensitivity to Vif. J. Biol. Chem.; 2010; 285, pp. 29326-29335. [DOI: https://dx.doi.org/10.1074/jbc.M110.154054] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20624919]

213. Reddy, K.; Winkler, C.A.; Werner, L.; Mlisana, K.; Abdool Karim, S.S.; Ndung’u, T.; Team, C.A.I.S. APOBEC3G expression is dysregulated in primary HIV-1 infection and polymorphic variants influence CD4+ T-cell counts and plasma viral load. AIDS; 2010; 24, pp. 195-204. [DOI: https://dx.doi.org/10.1097/QAD.0b013e3283353bba]

214. Feng, Y.; Chelico, L. Intensity of deoxycytidine deamination of HIV-1 proviral DNA by the retroviral restriction factor APOBEC3G is mediated by the noncatalytic domain. J. Biol. Chem.; 2011; 286, pp. 11415-11426. [DOI: https://dx.doi.org/10.1074/jbc.M110.199604]

215. Reddy, K.; Ooms, M.; Letko, M.; Garrett, N.; Simon, V.; Ndung’u, T. Functional characterization of Vif proteins from HIV-1 infected patients with different APOBEC3G haplotypes. AIDS; 2016; 30, pp. 1723-1729. [DOI: https://dx.doi.org/10.1097/QAD.0000000000001113]

216. An, P.; Bleiber, G.; Duggal, P.; Nelson, G.; May, M.; Mangeat, B.; Alobwede, I.; Trono, D.; Vlahov, D.; Donfield, S. et al. APOBEC3G genetic variants and their influence on the progression to AIDS. J. Virol.; 2004; 78, pp. 11070-11076. [DOI: https://dx.doi.org/10.1128/JVI.78.20.11070-11076.2004]

217. Do, H.; Vasilescu, A.; Diop, G.; Hirtzig, T.; Heath, S.C.; Coulonges, C.; Rappaport, J.; Therwath, A.; Lathrop, M.; Matsuda, F. et al. Exhaustive genotyping of the CEM15 (APOBEC3G) gene and absence of association with AIDS progression in a French cohort. J. Infect. Dis.; 2005; 191, pp. 159-163. [DOI: https://dx.doi.org/10.1086/426826]

218. Valcke, H.S.; Bernard, N.F.; Bruneau, J.; Alary, M.; Tsoukas, C.M.; Roger, M. APOBEC3G genetic variants and their association with risk of HIV infection in highly exposed Caucasians. AIDS; 2006; 20, pp. 1984-1986. [DOI: https://dx.doi.org/10.1097/01.aids.0000247124.35129.e1]

219. Mhandire, K.; Duri, K.; Mhandire, D.; Musarurwa, C.; Stray-Pedersen, B.; Dandara, C. Evaluating the contribution of APOBEC3G haplotypes, on influencing HIV infection in a Zimbabwean paediatric population. S. Afr. Med. J.; 2016; 106, pp. S119-S123. [DOI: https://dx.doi.org/10.7196/SAMJ.2016.v106i6.11013]

220. OhAinle, M.; Kerns, J.A.; Li, M.M.; Malik, H.S.; Emerman, M. Antiretroelement activity of APOBEC3H was lost twice in recent human evolution. Cell Host Microbe; 2008; 4, pp. 249-259. [DOI: https://dx.doi.org/10.1016/j.chom.2008.07.005]

221. Wang, X.; Abudu, A.; Son, S.; Dang, Y.; Venta, P.J.; Zheng, Y.H. Analysis of human APOBEC3H haplotypes and anti-human immunodeficiency virus type 1 activity. J. Virol.; 2011; 85, pp. 3142-3152. [DOI: https://dx.doi.org/10.1128/JVI.02049-10] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21270145]

222. Dang, Y.; Siew, L.M.; Wang, X.; Han, Y.; Lampen, R.; Zheng, Y.H. Human cytidine deaminase APOBEC3H restricts HIV-1 replication. J. Biol. Chem.; 2008; 283, pp. 11606-11614. [DOI: https://dx.doi.org/10.1074/jbc.M707586200] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18299330]

223. Harari, A.; Ooms, M.; Mulder, L.C.; Simon, V. Polymorphisms and splice variants influence the antiretroviral activity of human APOBEC3H. J. Virol.; 2009; 83, pp. 295-303. [DOI: https://dx.doi.org/10.1128/JVI.01665-08] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18945781]

224. Gu, J.; Chen, Q.; Xiao, X.; Ito, F.; Wolfe, A.; Chen, X.S. Biochemical Characterization of APOBEC3H Variants: Implications for Their HIV-1 Restriction Activity and mC Modification. J. Mol. Biol.; 2016; 428, pp. 4626-4638. [DOI: https://dx.doi.org/10.1016/j.jmb.2016.08.012]

225. Chesarino, N.M.; Emerman, M. Polymorphisms in Human APOBEC3H Differentially Regulate Ubiquitination and Antiviral Activity. Viruses; 2020; 12, 378. [DOI: https://dx.doi.org/10.3390/v12040378]

226. Nakano, Y.; Misawa, N.; Juarez-Fernandez, G.; Moriwaki, M.; Nakaoka, S.; Funo, T.; Yamada, E.; Soper, A.; Yoshikawa, R.; Ebrahimi, D. et al. HIV-1 competition experiments in humanized mice show that APOBEC3H imposes selective pressure and promotes virus adaptation. PLoS Pathog.; 2017; 13, e1006348. [DOI: https://dx.doi.org/10.1371/journal.ppat.1006348]

227. Binka, M.; Ooms, M.; Steward, M.; Simon, V. The activity spectrum of Vif from multiple HIV-1 subtypes against APOBEC3G, APOBEC3F, and APOBEC3H. J. Virol.; 2012; 86, pp. 49-59. [DOI: https://dx.doi.org/10.1128/JVI.06082-11]

228. Eckwahl, M.J.; Telesnitsky, A.; Wolin, S.L. Host RNA Packaging by Retroviruses: A Newly Synthesized Story. mBio; 2016; 7, pp. e02015-e02025. [DOI: https://dx.doi.org/10.1128/mBio.02025-15]

229. Rein, A. RNA Packaging in HIV. Trends Microbiol.; 2019; 27, pp. 715-723. [DOI: https://dx.doi.org/10.1016/j.tim.2019.04.003]

230. Tauber, H.; Huttelmaier, S.; Kohn, M. POLIII-derived non-coding RNAs acting as scaffolds and decoys. J. Mol. Cell Biol.; 2019; 11, pp. 880-885. [DOI: https://dx.doi.org/10.1093/jmcb/mjz049]

231. Zhou, S.; Van Bortle, K. The Pol III transcriptome: Basic features, recurrent patterns, and emerging roles in cancer. Wiley Interdiscip. Rev. RNA; 2023; 14, e1782. [DOI: https://dx.doi.org/10.1002/wrna.1782] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36754845]

232. Wang, T.; Tian, C.; Zhang, W.; Luo, K.; Sarkis, P.T.; Yu, L.; Liu, B.; Yu, Y.; Yu, X.F. 7SL RNA mediates virion packaging of the antiviral cytidine deaminase APOBEC3G. J. Virol.; 2007; 81, pp. 13112-13124. [DOI: https://dx.doi.org/10.1128/JVI.00892-07] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17881443]

233. Wang, T.; Tian, C.; Zhang, W.; Sarkis, P.T.; Yu, X.F. Interaction with 7SL RNA but not with HIV-1 genomic RNA or P bodies is required for APOBEC3F virion packaging. J. Mol. Biol.; 2008; 375, pp. 1098-1112. [DOI: https://dx.doi.org/10.1016/j.jmb.2007.11.017]

234. Apolonia, L.; Schulz, R.; Curk, T.; Rocha, P.; Swanson, C.M.; Schaller, T.; Ule, J.; Malim, M.H. Promiscuous RNA binding ensures effective encapsidation of APOBEC3 proteins by HIV-1. PLoS Pathog.; 2015; 11, e1004609. [DOI: https://dx.doi.org/10.1371/journal.ppat.1004609]

235. York, A.; Kutluay, S.B.; Errando, M.; Bieniasz, P.D. The RNA Binding Specificity of Human APOBEC3 Proteins Resembles That of HIV-1 Nucleocapsid. PLoS Pathog.; 2016; 12, e1005833. [DOI: https://dx.doi.org/10.1371/journal.ppat.1005833]

236. Bogerd, H.P.; Cullen, B.R. Single-stranded RNA facilitates nucleocapsid: APOBEC3G complex formation. RNA; 2008; 14, pp. 1228-1236. [DOI: https://dx.doi.org/10.1261/rna.964708]

237. Song, C.; Sutton, L.; Johnson, M.E.; D’Aquila, R.T.; Donahue, J.P. Signals in APOBEC3F N-terminal and C-terminal deaminase domains each contribute to encapsidation in HIV-1 virions and are both required for HIV-1 restriction. J. Biol. Chem.; 2012; 287, pp. 16965-16974. [DOI: https://dx.doi.org/10.1074/jbc.M111.310839]

238. Zhang, X.; Ma, X.; Jing, S.; Zhang, H.; Zhang, Y. Non-coding RNAs and retroviruses. Retrovirology; 2018; 15, 20. [DOI: https://dx.doi.org/10.1186/s12977-018-0403-8]

239. Eckwahl, M.J.; Arnion, H.; Kharytonchyk, S.; Zang, T.; Bieniasz, P.D.; Telesnitsky, A.; Wolin, S.L. Analysis of the human immunodeficiency virus-1 RNA packageome. RNA; 2016; 22, pp. 1228-1238. [DOI: https://dx.doi.org/10.1261/rna.057299.116]

240. Burnett, A.; Spearman, P. APOBEC3G multimers are recruited to the plasma membrane for packaging into human immunodeficiency virus type 1 virus-like particles in an RNA-dependent process requiring the NC basic linker. J. Virol.; 2007; 81, pp. 5000-5013. [DOI: https://dx.doi.org/10.1128/JVI.02237-06]

241. Alce, T.M.; Popik, W. APOBEC3G is incorporated into virus-like particles by a direct interaction with HIV-1 Gag nucleocapsid protein. J. Biol. Chem.; 2004; 279, pp. 34083-34086. [DOI: https://dx.doi.org/10.1074/jbc.C400235200] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15215254]

242. Yang, H.; Kim, K.; Li, S.; Pacheco, J.; Chen, X.S. Structural basis of sequence-specific RNA recognition by the antiviral factor APOBEC3G. Nat. Commun.; 2022; 13, 7498. [DOI: https://dx.doi.org/10.1038/s41467-022-35201-9] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36470880]

243. Schafer, A.; Bogerd, H.P.; Cullen, B.R. Specific packaging of APOBEC3G into HIV-1 virions is mediated by the nucleocapsid domain of the gag polyprotein precursor. Virology; 2004; 328, pp. 163-168. [DOI: https://dx.doi.org/10.1016/j.virol.2004.08.006] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15464836]

244. Zennou, V.; Perez-Caballero, D.; Gottlinger, H.; Bieniasz, P.D. APOBEC3G incorporation into human immunodeficiency virus type 1 particles. J. Virol.; 2004; 78, pp. 12058-12061. [DOI: https://dx.doi.org/10.1128/JVI.78.21.12058-12061.2004]

245. Luo, K.; Liu, B.; Xiao, Z.; Yu, Y.; Yu, X.; Gorelick, R.; Yu, X.F. Amino-terminal region of the human immunodeficiency virus type 1 nucleocapsid is required for human APOBEC3G packaging. J. Virol.; 2004; 78, pp. 11841-11852. [DOI: https://dx.doi.org/10.1128/JVI.78.21.11841-11852.2004]

246. Svarovskaia, E.S.; Xu, H.; Mbisa, J.L.; Barr, R.; Gorelick, R.J.; Ono, A.; Freed, E.O.; Hu, W.S.; Pathak, V.K. Human apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) is incorporated into HIV-1 virions through interactions with viral and nonviral RNAs. J. Biol. Chem.; 2004; 279, pp. 35822-35828. [DOI: https://dx.doi.org/10.1074/jbc.M405761200]

247. Cen, S.; Guo, F.; Niu, M.; Saadatmand, J.; Deflassieux, J.; Kleiman, L. The interaction between HIV-1 Gag and APOBEC3G. J. Biol. Chem.; 2004; 279, pp. 33177-33184. [DOI: https://dx.doi.org/10.1074/jbc.M402062200]

248. Friew, Y.N.; Boyko, V.; Hu, W.S.; Pathak, V.K. Intracellular interactions between APOBEC3G, RNA, and HIV-1 Gag: APOBEC3G multimerization is dependent on its association with RNA. Retrovirology; 2009; 6, 56. [DOI: https://dx.doi.org/10.1186/1742-4690-6-56]

249. Cheng, C.; Zhang, T.; Wang, C.; Lan, W.; Ding, J.; Cao, C. Crystal Structure of Cytidine Deaminase Human APOBEC3F Chimeric Catalytic Domain in Complex with DNA. Chin. J. Chem.; 2018; 36, pp. 1241-1248. [DOI: https://dx.doi.org/10.1002/cjoc.201800508]

250. Cervantes-Gracia, K.; Gramalla-Schmitz, A.; Weischedel, J.; Chahwan, R. APOBECs orchestrate genomic and epigenomic editing across health and disease. Trends Genet.; 2021; 37, pp. 1028-1043. [DOI: https://dx.doi.org/10.1016/j.tig.2021.07.003]

251. Mohanram, V.; Skold, A.E.; Bachle, S.M.; Pathak, S.K.; Spetz, A.L. IFN-alpha induces APOBEC3G, F, and A in immature dendritic cells and limits HIV-1 spread to CD4+ T cells. J. Immunol.; 2013; 190, pp. 3346-3353. [DOI: https://dx.doi.org/10.4049/jimmunol.1201184] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23427247]

252. Peng, G.; Greenwell-Wild, T.; Nares, S.; Jin, W.; Lei, K.J.; Rangel, Z.G.; Munson, P.J.; Wahl, S.M. Myeloid differentiation and susceptibility to HIV-1 are linked to APOBEC3 expression. Blood; 2007; 110, pp. 393-400. [DOI: https://dx.doi.org/10.1182/blood-2006-10-051763] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17371941]

253. Berger, G.; Durand, S.; Fargier, G.; Nguyen, X.N.; Cordeil, S.; Bouaziz, S.; Muriaux, D.; Darlix, J.L.; Cimarelli, A. APOBEC3A is a specific inhibitor of the early phases of HIV-1 infection in myeloid cells. PLoS Pathog.; 2011; 7, e1002221. [DOI: https://dx.doi.org/10.1371/journal.ppat.1002221] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21966267]

254. Koning, F.A.; Goujon, C.; Bauby, H.; Malim, M.H. Target cell-mediated editing of HIV-1 cDNA by APOBEC3 proteins in human macrophages. J. Virol.; 2011; 85, pp. 13448-13452. [DOI: https://dx.doi.org/10.1128/JVI.00775-11]

255. Graziano, F.; Vicenzi, E.; Poli, G. Plastic restriction of HIV-1 replication in human macrophages derived from M1/M2 polarized monocytes. J. Leukoc. Biol.; 2016; 100, pp. 1147-1153. [DOI: https://dx.doi.org/10.1189/jlb.4AB0316-158R]

256. Singh, K.K.; Wang, Y.; Gray, K.P.; Farhad, M.; Brummel, S.; Fenton, T.; Trout, R.; Spector, S.A. Genetic variants in the host restriction factor APOBEC3G are associated with HIV-1-related disease progression and central nervous system impairment in children. J. Acquir. Immune Defic. Syndr.; 2013; 62, pp. 197-203. [DOI: https://dx.doi.org/10.1097/QAI.0b013e31827ab612]

257. An, P.; Penugonda, S.; Thorball, C.W.; Bartha, I.; Goedert, J.J.; Donfield, S.; Buchbinder, S.; Binns-Roemer, E.; Kirk, G.D.; Zhang, W. et al. Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia. PLoS Genet.; 2016; 12, e1005921. [DOI: https://dx.doi.org/10.1371/journal.pgen.1005921]

258. Sakurai, D.; Iwatani, Y.; Ohtani, H.; Naruse, T.K.; Terunuma, H.; Sugiura, W.; Kimura, A. APOBEC3H polymorphisms associated with the susceptibility to HIV-1 infection and AIDS progression in Japanese. Immunogenetics; 2015; 67, pp. 253-257. [DOI: https://dx.doi.org/10.1007/s00251-015-0829-2]

259. De Maio, F.A.; Rocco, C.A.; Aulicino, P.C.; Bologna, R.; Mangano, A.; Sen, L. APOBEC3-mediated editing in HIV type 1 from pediatric patients and its association with APOBEC3G/CUL5 polymorphisms and Vif variability. AIDS Res. Hum. Retroviruses; 2012; 28, pp. 619-627. [DOI: https://dx.doi.org/10.1089/aid.2011.0291]

260. Venkatesan, S.; Rosenthal, R.; Kanu, N.; McGranahan, N.; Bartek, J.; Quezada, S.A.; Hare, J.; Harris, R.S.; Swanton, C. Perspective: APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution. Ann. Oncol.; 2018; 29, pp. 563-572. [DOI: https://dx.doi.org/10.1093/annonc/mdy003]

261. Olson, M.E.; Harris, R.S.; Harki, D.A. APOBEC Enzymes as Targets for Virus and Cancer Therapy. Cell Chem. Biol.; 2018; 25, pp. 36-49. [DOI: https://dx.doi.org/10.1016/j.chembiol.2017.10.007] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29153851]

262. Grant, M.; Larijani, M. Evasion of adaptive immunity by HIV through the action of host APOBEC3G/F enzymes. AIDS Res. Ther.; 2017; 14, 44. [DOI: https://dx.doi.org/10.1186/s12981-017-0173-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28893290]

263. Sadler, H.A.; Stenglein, M.D.; Harris, R.S.; Mansky, L.M. APOBEC3G contributes to HIV-1 variation through sublethal mutagenesis. J. Virol.; 2010; 84, pp. 7396-7404. [DOI: https://dx.doi.org/10.1128/JVI.00056-10]

264. Monajemi, M.; Woodworth, C.F.; Benkaroun, J.; Grant, M.; Larijani, M. Emerging complexities of APOBEC3G action on immunity and viral fitness during HIV infection and treatment. Retrovirology; 2012; 9, 35. [DOI: https://dx.doi.org/10.1186/1742-4690-9-35]

265. Kim, E.Y.; Bhattacharya, T.; Kunstman, K.; Swantek, P.; Koning, F.A.; Malim, M.H.; Wolinsky, S.M. Human APOBEC3G-mediated editing can promote HIV-1 sequence diversification and accelerate adaptation to selective pressure. J. Virol.; 2010; 84, pp. 10402-10405. [DOI: https://dx.doi.org/10.1128/JVI.01223-10]

266. Mulder, L.C.; Harari, A.; Simon, V. Cytidine deamination induced HIV-1 drug resistance. Proc. Natl. Acad. Sci. USA; 2008; 105, pp. 5501-5506. [DOI: https://dx.doi.org/10.1073/pnas.0710190105]

267. Armitage, A.E.; Deforche, K.; Welch, J.J.; Van Laethem, K.; Camacho, R.; Rambaut, A.; Iversen, A.K. Possible footprints of APOBEC3F and/or other APOBEC3 deaminases, but not APOBEC3G, on HIV-1 from patients with acute/early and chronic infections. J. Virol.; 2014; 88, pp. 12882-12894. [DOI: https://dx.doi.org/10.1128/JVI.01460-14]

268. Hernandez, M.M.; Fahrny, A.; Jayaprakash, A.; Gers-Huber, G.; Dillon-White, M.; Audige, A.; Mulder, L.C.F.; Sachidanandam, R.; Speck, R.F.; Simon, V. Impact of Suboptimal APOBEC3G Neutralization on the Emergence of HIV Drug Resistance in Humanized Mice. J. Virol.; 2020; 94, 10-1128. [DOI: https://dx.doi.org/10.1128/JVI.01543-19]

269. Neogi, U.; Shet, A.; Sahoo, P.N.; Bontell, I.; Ekstrand, M.L.; Banerjea, A.C.; Sonnerborg, A. Human APOBEC3G-mediated hypermutation is associated with antiretroviral therapy failure in HIV-1 subtype C-infected individuals. J. Int. AIDS Soc.; 2013; 16, 18472. [DOI: https://dx.doi.org/10.7448/IAS.16.1.18472]

270. Monajemi, M.; Woodworth, C.F.; Zipperlen, K.; Gallant, M.; Grant, M.D.; Larijani, M. Positioning of APOBEC3G/F Mutational Hotspots in the Human Immunodeficiency Virus Genome Favors Reduced Recognition by CD8 T Cells. PLoS ONE; 2014; 9, e93428. [DOI: https://dx.doi.org/10.1371/journal.pone.0093428]

271. Casartelli, N.; Guivel-Benhassine, F.; Bouziat, R.; Brandler, S.; Schwartz, O.; Moris, A. The antiviral factor APOBEC3G improves CTL recognition of cultured HIV-infected T cells. J. Exp. Med.; 2010; 207, pp. 39-49. [DOI: https://dx.doi.org/10.1084/jem.20091933] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20038599]

272. Squires, K.D.; Monajemi, M.; Woodworth, C.F.; Grant, M.D.; Larijani, M. Impact of APOBEC Mutations on CD8+ T Cell Recognition of HIV Epitopes Varies Depending on the Restricting HLA. J. Acquir. Immune Defic. Syndr.; 2015; 70, pp. 172-178. [DOI: https://dx.doi.org/10.1097/QAI.0000000000000689] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26035050]

273. Shahid, A.; Jones, B.R.; Duncan, M.C.; MacLennan, S.; Dapp, M.J.; Kuniholm, M.H.; Aouizerat, B.; Archin, N.M.; Gange, S.; Ofotokun, I. et al. A simple phylogenetic approach to analyze hypermutated HIV proviruses reveals insights into their dynamics and persistence during antiretroviral therapy. Virus Evol.; 2025; 11, veae094. [DOI: https://dx.doi.org/10.1093/ve/veae094] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39802824]

274. Boichard, A.; Tsigelny, I.F.; Kurzrock, R. High expression of PD-1 ligands is associated with kataegis mutational signature and APOBEC3 alterations. Oncoimmunology; 2017; 6, e1284719. [DOI: https://dx.doi.org/10.1080/2162402X.2017.1284719]

275. Martin, J.; Chen, X.; Jia, X.; Shao, Q.; Liu, B. The Disassociation of A3G-Related HIV-1 cDNA G-to-A Hypermutation to Viral Infectivity. Viruses; 2024; 16, 728. [DOI: https://dx.doi.org/10.3390/v16050728]

276. Armenia, D.; Santoro, M.M.; Bellocchi, M.C.; Carioti, L.; Galli, L.; Galli, A.; Scutari, R.; Salsi, E.; Mussini, C.; Sterrantino, G. et al. Viral resistance burden and APOBEC editing correlate with virological response in heavily treatment-experienced people living with multi-drug resistant HIV. Int. J. Antimicrob. Agents; 2022; 59, 106492. [DOI: https://dx.doi.org/10.1016/j.ijantimicag.2021.106492]

277. Alidjinou, E.K.; Coulon, P.; Tetart, M.; Guigon, A.; Diarra, A.; Aissi, E.; Bazus, H.; Derdour, V.; Meybeck, A.; Viget, N. et al. Defective HIV-1 DNA pol sequences are not associated with HIV-1 DNA levels and drive most APOBEC-context drug resistance mutations. J. Antimicrob. Chemother.; 2025; dkaf016. [DOI: https://dx.doi.org/10.1093/jac/dkaf016]

278. Gessain, A.; Cassar, O. Epidemiological Aspects and World Distribution of HTLV-1 Infection. Front. Microbiol.; 2012; 3, 388. [DOI: https://dx.doi.org/10.3389/fmicb.2012.00388]

279. Taylor, G.P.; Matsuoka, M. Natural history of adult T-cell leukemia/lymphoma and approaches to therapy. Oncogene; 2005; 24, pp. 6047-6057. [DOI: https://dx.doi.org/10.1038/sj.onc.1208979]

280. Eusebio-Ponce, E.; Anguita, E.; Paulino-Ramirez, R.; Candel, F.J. HTLV-1 infection: An emerging risk. Pathogenesis, epidemiology, diagnosis and associated diseases. Rev. Esp. Quimioter.; 2019; 32, pp. 485-496.

281. Rocamonde, B.; Carcone, A.; Mahieux, R.; Dutartre, H. HTLV-1 infection of myeloid cells: From transmission to immune alterations. Retrovirology; 2019; 16, 45. [DOI: https://dx.doi.org/10.1186/s12977-019-0506-x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31870397]

282. Afonso, P.V.; Cassar, O.; Gessain, A. Molecular epidemiology, genetic variability and evolution of HTLV-1 with special emphasis on African genotypes. Retrovirology; 2019; 16, 39. [DOI: https://dx.doi.org/10.1186/s12977-019-0504-z] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31842895]

283. Tanaka, A.; Matsuoka, M. HTLV-1 Alters T Cells for Viral Persistence and Transmission. Front. Microbiol.; 2018; 9, 461. [DOI: https://dx.doi.org/10.3389/fmicb.2018.00461] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29615995]

284. Miura, M.; Dey, S.; Ramanayake, S.; Singh, A.; Rueda, D.S.; Bangham, C.R.M. Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling. PLoS Pathog.; 2019; 15, e1008164. [DOI: https://dx.doi.org/10.1371/journal.ppat.1008164]

285. Hiyoshi, M.; Takahashi, N.; Eltalkhawy, Y.M.; Noyori, O.; Lotfi, S.; Panaampon, J.; Okada, S.; Tanaka, Y.; Ueno, T.; Fujisawa, J.I. et al. M-Sec induced by HTLV-1 mediates an efficient viral transmission. PLoS Pathog.; 2021; 17, e1010126. [DOI: https://dx.doi.org/10.1371/journal.ppat.1010126]

286. Carpentier, A.; Barez, P.Y.; Hamaidia, M.; Gazon, H.; de Brogniez, A.; Perike, S.; Gillet, N.; Willems, L. Modes of Human T Cell Leukemia Virus Type 1 Transmission, Replication and Persistence. Viruses; 2015; 7, pp. 3603-3624. [DOI: https://dx.doi.org/10.3390/v7072793]

287. Martin, J.L.; Maldonado, J.O.; Mueller, J.D.; Zhang, W.; Mansky, L.M. Molecular Studies of HTLV-1 Replication: An Update. Viruses; 2016; 8, 31. [DOI: https://dx.doi.org/10.3390/v8020031]

288. Carcone, A.; Journo, C.; Dutartre, H. Is the HTLV-1 Retrovirus Targeted by Host Restriction Factors?. Viruses; 2022; 14, 1611. [DOI: https://dx.doi.org/10.3390/v14081611]

289. Mahgoub, M.; Yasunaga, J.I.; Iwami, S.; Nakaoka, S.; Koizumi, Y.; Shimura, K.; Matsuoka, M. Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells. Proc. Natl. Acad. Sci. USA; 2018; 115, pp. E1269-E1278. [DOI: https://dx.doi.org/10.1073/pnas.1715724115]

290. Satou, Y.; Yasunaga, J.; Yoshida, M.; Matsuoka, M. HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells. Proc. Natl. Acad. Sci. USA; 2006; 103, pp. 720-725. [DOI: https://dx.doi.org/10.1073/pnas.0507631103]

291. Enose-Akahata, Y.; Vellucci, A.; Jacobson, S. Role of HTLV-1 Tax and HBZ in the Pathogenesis of HAM/TSP. Front. Microbiol.; 2017; 8, 2563. [DOI: https://dx.doi.org/10.3389/fmicb.2017.02563] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29312243]

292. Sasada, A.; Takaori-Kondo, A.; Shirakawa, K.; Kobayashi, M.; Abudu, A.; Hishizawa, M.; Imada, K.; Tanaka, Y.; Uchiyama, T. APOBEC3G targets human T-cell leukemia virus type 1. Retrovirology; 2005; 2, 32. [DOI: https://dx.doi.org/10.1186/1742-4690-2-32] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15943885]

293. Mahieux, R.; Suspene, R.; Delebecque, F.; Henry, M.; Schwartz, O.; Wain-Hobson, S.; Vartanian, J.P. Extensive editing of a small fraction of human T-cell leukemia virus type 1 genomes by four APOBEC3 cytidine deaminases. J. Gen. Virol.; 2005; 86, pp. 2489-2494. [DOI: https://dx.doi.org/10.1099/vir.0.80973-0]

294. Ooms, M.; Krikoni, A.; Kress, A.K.; Simon, V.; Munk, C. APOBEC3A, APOBEC3B, and APOBEC3H haplotype 2 restrict human T-lymphotropic virus type 1. J. Virol.; 2012; 86, pp. 6097-6108. [DOI: https://dx.doi.org/10.1128/JVI.06570-11]

295. Fan, J.; Ma, G.; Nosaka, K.; Tanabe, J.; Satou, Y.; Koito, A.; Wain-Hobson, S.; Vartanian, J.P.; Matsuoka, M. APOBEC3G generates nonsense mutations in human T-cell leukemia virus type 1 proviral genomes in vivo. J. Virol.; 2010; 84, pp. 7278-7287. [DOI: https://dx.doi.org/10.1128/JVI.02239-09]

296. Shichijo, T.; Yasunaga, J.I.; Sato, K.; Nosaka, K.; Toyoda, K.; Watanabe, M.; Zhang, W.; Koyanagi, Y.; Murphy, E.L.; Bruhn, R.L. et al. Vulnerability to APOBEC3G linked to the pathogenicity of deltaretroviruses. Proc. Natl. Acad. Sci. USA; 2024; 121, e2309925121. [DOI: https://dx.doi.org/10.1073/pnas.2309925121]

297. Derse, D.; Hill, S.A.; Princler, G.; Lloyd, P.; Heidecker, G. Resistance of human T cell leukemia virus type 1 to APOBEC3G restriction is mediated by elements in nucleocapsid. Proc. Natl. Acad. Sci. USA; 2007; 104, pp. 2915-2920. [DOI: https://dx.doi.org/10.1073/pnas.0609444104]

298. Ohsugi, T.; Koito, A. Human T cell leukemia virus type I is resistant to the antiviral effects of APOBEC3. J. Virol. Methods; 2007; 139, pp. 93-96. [DOI: https://dx.doi.org/10.1016/j.jviromet.2006.08.016]

299. Kataoka, K.; Nagata, Y.; Kitanaka, A.; Shiraishi, Y.; Shimamura, T.; Yasunaga, J.; Totoki, Y.; Chiba, K.; Sato-Otsubo, A.; Nagae, G. et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat. Genet.; 2015; 47, pp. 1304-1315. [DOI: https://dx.doi.org/10.1038/ng.3415]

300. Pique, C.; Tursz, T.; Dokhelar, M.C. Mutations introduced along the HTLV-I envelope gene result in a non-functional protein: A basis for envelope conservation?. EMBO J.; 1990; 9, pp. 4243-4248. [DOI: https://dx.doi.org/10.1002/j.1460-2075.1990.tb07872.x]

301. Geller, R.; Domingo-Calap, P.; Cuevas, J.M.; Rossolillo, P.; Negroni, M.; Sanjuan, R. The external domains of the HIV-1 envelope are a mutational cold spot. Nat. Commun.; 2015; 6, 8571. [DOI: https://dx.doi.org/10.1038/ncomms9571] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26450412]

302. van Hemert, F.J.; Berkhout, B. The tendency of lentiviral open reading frames to become A-rich: Constraints imposed by viral genome organization and cellular tRNA availability. J. Mol. Evol.; 1995; 41, pp. 132-140. [DOI: https://dx.doi.org/10.1007/BF00170664] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/7666442]

303. Nozuma, S.; Matsuura, E.; Kodama, D.; Tashiro, Y.; Matsuzaki, T.; Kubota, R.; Izumo, S.; Takashima, H. Effects of host restriction factors and the HTLV-1 subtype on susceptibility to HTLV-1-associated myelopathy/tropical spastic paraparesis. Retrovirology; 2017; 14, 26. [DOI: https://dx.doi.org/10.1186/s12977-017-0350-9] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28420387]