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Abstract
The interaction between the HIV-1 envelope glycoprotein, Env, and the host receptor, CD4, marks the first step of viral entry. This event leads to coreceptor association and subsequent conformational rearrangements of Env that promote fusion of the viral and target-cell membranes. Env is crucial to viral replication and, as the sole viral protein on the surface of HIV-1, is under constant pressure by the host’s immune response.
Rhesus macaques have been developed as a model organism to study HIV-1 transmission and pathogenesis. However, rhesus macaques differ from humans in aspects that prevent replication of HIV-1. Therefore, simian immunodeficiency viruses, SIVs, have been utilized to model human HIV-1 infection. In Chapter 2 we show that SIV utilizes rhesus CD4 less efficiently than HIV-1 does human CD4. We identified a single residue in CD4, isoleucine 39, that largely accounted for this difference. We further identified two residue changes in the CD4-binding site of Env that improved SIVmac239 use of rhesus CD4. We propose that rhesus macaques infected with an SIVmac239 variant bearing these mutations might better reflect some aspects of human HIV-1 disease, for example infection of cells that express lower levels of CD4 in the brain.
In Chapter 3 we study the inhibitor eCD4-Ig, which bears CD4 domains 1 and 2 and a coreceptor mimetic peptide. We show that virus escapes this inhibitor more slowly than the potent broadly neutralizing antibody NIH45-46 and that escape likely associates with a fitness loss. We analyzed viruses from in vitro and in vivo studies and identified escape mutations in the apex region, V3 loop and CD4-binding site. In one in vivo case, SIVmac239 exploited a single residue difference between cellular rhesus CD4 and eCD4-Ig. It did so by acquiring one of the two CD4-binding site mutations described in Chapter 2, linking the two chapters in an unexpected way.
Collectively these studies add to our understanding of the CD4-Env interaction, which is especially important for the development of eCD4-Ig as an antiretroviral agent in a clinical setting. In Chapter 4, we compare eCD4-Ig with its major competitors, broadly neutralizing antibodies and conventional vaccine strategies.
