| The quest for an effective HIV vaccine has proven challenging on a number of levels; the immune correlates of viral control are not fully understood and the virus is exceptionally adept at immune evasion. Many of the neutralizing determinants shared by multiple isolates and subtypes of HIV are well concealed by variable regions, recessed pockets, and carbohydrate moieties, while the exposed epitopes are highly variable. An important question that remains unanswered lies in the boundaries of variation that exist as the virus evolves in individual hosts and the relationship between these changes and the adaptive immune response. This has been difficult to address in HIV-1 infection of humans due to the distinct viruses in each individual. Using a macaque model of infection where multiple individuals received the same starting virus, this dissertation aimed to examine commonalities in the way that the viral Envelope evolves within the host and how the Envelope evolution translates to neutralization sensitivity. I observed a remarkable degree of conservation in HIV Envelope glycosylation and documented that consistent patterns of change occur in a small number of carbohydrates proximal to the CD4 binding site. These changes were under positive selection. In order to investigate possible selective pressures, representative Envelope variants that arose in each macaque were used to create pseudoviruses. The majority of variants mediated escape from a broad modality of neutralizing agents, including homologous and heterologous plasma, monoclonal antibodies, and sCD4. This was seen even in variants that arose in the absence of neutralizing antibody pressure. In addition, the majority of variants also demonstrated enhanced CD4 binding and infectivity. These phenotypic changes correlated with enhanced Envelope processing, suggesting a previously unrecognized mechanism by which virions can both enhance infectivity and enhance escape from diverse neutralizing antibodies. |
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