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KEY WORDS: RRE, RNA export, NES, exportin 1
ABSTRACT
The nuclear export of intron-containing HIV-1 RNA is critically dependent on the activity of Rev, a virally encoded sequence-specific RNA-binding protein. Rev shuttles between th,e nucleus and the cytoplasm and harbors both a nuclear localization signal and a nuclear export signal. These essential peptide motifs have now been shown to function by accessing cellular signal-mediated pathways for nuclear import and nucLear export. HIV-1 Rev therefore represents an excellent system with which to study aspects of transport across the nuclear envelope.
INTRODUCTION
A molecular understanding of viral functions frequently provides fundamental insights into basic cellular mechanisms. This philosophy has been richly rewarded in the study of the human immunodeficiency virus type-1 (HIV-1) Rev protein. It is generally accepted that Rev functions by activating the nuclear export of unspliced (intron-containing) viral mRNAs. The analysis of Rev has therefore become one of the preferred model systems with which one can study the signal-mediated export of macromolecules from the nucleus to the cytoplasm. For simplicity, this review is organized chronologically, starting with the discovery of Rev in 1986, proceeding through its assignment as a trans-activator of RNA nuclear export, and culminating with descriptions of interacting cellular proteins and a molecular model for its mechanism of action. In addition, the fact that Rev is essential for HIV- 1 replication makes it an attractive target for antiviral approaches. The development of novel methods for preventing and controlling HIV-1 infections remains a critical objective in HIV research as the number of people infected worldwide continues to escalate.
RETROVIRAL GENE EXPRESSION
Overview of the Retroviral Life Cycle
HIV- 1 is regarded as the prototype member of the lentivirus subfamily of retroviruses. The other two subfamilies are the comparatively obscure foamy viruses (also known as spumaviruses) and the long-studied oncoretroviruses (RNA tumor viruses); examples of the latter subfamily are avian leukosis viruses (ALVs) and murine leukemia viruses (MLVs). The major features of the lentivirus and oncoretrovirus life cycles are well conserved and have been reviewed in detail (20, 27, 62, 105, 128). Infectious virions initially bind to cellular receptors on the surface of susceptible cells via envelope (Env) glycoproteins. Fusion of the viral and cellular lipid membranes ensues, and the viral core...