UC San Diego

Acute HIV-1 infection is characterized by a robust type I interferon response, resulting in the induction of several host restriction factors. HIV-1 has evolved to counteract these restriction factors, and one such adaptation, the ability of Vpu to counteract BST2/tetherin, has been proposed as having been essential for the evolution of SIVcpz into the pandemic group M HIV-1. Vpu also downmodulates the expression of CD4, counteracting a negative effect on the infectivity of virions that could in principle inhibit viral transmission. During transmission between individuals, very few or even a single virus, the "transmitted/founder (T/F) virus", gives rise to the new infection, but in the new host the selective pressure of the immune response yields the diverse "quasispecies" of chronic infection. In this study we examine the functional characteristics of Vpu proteins encoded by T/F viruses compared to those from acute and chronic viruses from longitudinally sampled subjects. T/F Vpu proteins showed a trend towards optimized CD4 downregulation compared to chronic Vpu proteins but did not differ in their ability to downregulate BST2, although individual clones from each group were impaired in their ability to counteract BST2. Analysis of the functionally impaired clones identified a C-terminal residue, W76, as important for Vpu enhancement of virion release. Vpu clones with a W76G substitution, or site-directed mutants, are impaired in their ability to enhance virion release, but they are not defective for BST2 surface downregulation, challenging the notion that Vpu enhances virion release by removing BST2 from the cell surface