Date of Award
Doctor of Philosophy (PhD)
Cell & Molecular Biology
Ronald G. Collman
The pathogenesis of HIV and SIV infection is determined to a large extent by adaptations of the virus that enable it to infect different cell types and either destroy these cells, or establish long-term reservoirs of viral replication. CD4+ T cells are the predominant targets of HIV and SIV infection in vivo, although some variants of these viruses have the ability to efficiently infect macrophages, which express exceedingly low levels of CD4. I sought to understand the selective forces that normally favor CD4+ T cell infection while restricting macrophage infection in vivo. To investigate these forces, I examined viral envelope glycoprotein (Env) variants that emerged during an in vivo SIV infection model in which extensive tissue macrophage infection was observed in experimentally CD4+ T cell-depleted rhesus macaques. I found that plasma-derived viral Envs from these animals had a remarkable ability to mediate entry into cells expressing CCR5 but lacking CD4, a phenotypic hallmark of macrophage-tropic viruses. These CD4-independent Env variants were highly sensitive to neutralization by anti-Env antibodies, as well as to control SIV+ plasma. However, plasma from CD4+ T cell-depleted animals could not neutralize CD4-independent Envs. This suggests that CD4+ T cells enforce CD4-dependent SIV entry by supporting the production of anti-Env antibodies that normally prevent the emergence of macrophage-tropic virus. In further studies, I asked whether other forces might restrict the emergence of CD4-independent Envs in vivo by examining entry coreceptor use by these Envs. Despite the ability of CD4-independent Envs to mediate robust entry in the presence of high cell surface levels of rhesus macaque CCR5, they were impaired in their use of human CCR5, rhesus macaque GPR15, and low levels of rhesus macaque CCR5. These phenotypes indicated that CD4-independent entry is accompanied by reduced plasticity in coreceptor usage, possibly restricting the virus in its range of potential target cells in vivo. Future studies will examine whether antibody-mediated enforcement of CD4 tropism and coreceptor usage are selective pressures that also explain the conservation of CD4-dependent entry during HIV-1 infection. It is possible that these forces can be manipulated to reshape viral tropism and eliminate HIV-1 macrophage reservoirs.
Francella, Nicholas, "Restriction of Macrophage infection During HIV and SIV infection: The Role of Antibodies and Coreceptor Use Plasticity in Enforcing Cd4-Dependent Entry and Shaping Tropism in Vivo" (2013). Publicly Accessible Penn Dissertations. 860.