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HIV-1 and BST-2 : interactions and effects on viral spread


The relationship between a virus and its host involves a complicated interplay between host restriction factors and immune system components and their viral antagonists. HIV- 1 has a number of accessory genes that have evolved to counteract specific host factors. This work focuses on the interaction of one of these accessory genes, Vpu and one of the proteins it counteracts- BST-2. BST-2 is an interferon-inducible protein that acts as a molecular tether, preventing the release of newly formed enveloped viruses including HIV-1 from the cell. This dissertation focuses on three main questions. The first is whether or not the host restriction factor BST-2 is located at virus- budding sites, where it seems likely to act, and whether it is actually incorporated into HIV-1 virions during budding. I found, through electron microscopy, immunocapture, and immunoblot techniques, that BST-2 is located at budding sites and is incorporated into virions. The second question entails what the mechanism of tethering and orientation of the BST-2 protein in the tether is. The findings in this section suggest that the coiled-coil motif in the ectodomain of BST-2 is indispensible for the tethering phenotype. A specific residue, L70, that when mutated abolishes the ability of BST-2 to tetramerize, contributes to tethering. Moreover, a parallel dimer model in which BST-2 links the host cell and virion lipid bilayers was not supported, since enzymatic cleavage of the GPI-anchor of BST-2 did not release tethered virions. The final goal of the research was to determine the role of BST-2 during viral growth and spread in suspension cultures. By using T-cell lines as well as primary cultures of human lymphocytes, I found that Vpu-deficient HIV-1 spreads more quickly than wild type HIV-1, regardless of the presence or absence of BST- 2. These data suggest that Vpu's influence on viral growth rate is likely multifaceted and is not a direct reflection of its ability to counteract the restriction imposed by BST-2. Moreover, the data suggest that the genetically conserved ability of HIV-1 Vpu to affect the expression of BST-2 might reflect activities of each protein that are not recapitulated in simple in vitro culture systems

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