Grant: Project Grant

HIV, the etiological agent of AIDS, eludes human immune defenses in part because it encodes a set of small accessory proteins, whose function is to overcome antiviral immune responses. One frequent strategy used by viruses is to eliminate host proteins that are critical for these immune responses from the surface of infected cells. The HIV-1 Vpu accessory protein induces the cell-surface removal of BST2 (also called Tetherin), an antiviral molecule that strongly inhibits the exit of new viruses from infected cells by retaining them at the cell surface. Importantly, this BST2-mediated tethering of nascent virus at the cell-surface has also widespread immunological consequences as it sensitizes infected cells to immune clearance, it activates viral immune detection and production of soluble antiviral molecules, and promotes interferon production by specialized immune cells, thus emphasizing the need for HIV to efficiently counteract BST2. Indeed, this property appears associated to the extraordinary transmission fitness and virulence of some HIV-1 strains as well as to the ability of the virus to cause disease. In this project, we will define the mechanisms by which Vpu counteracts BST2 and notably how Vpu redirects BST2 location in cells away from virus assembly sites, and which cellular proteins and machineries Vpu uses to accomplish this task. Additionally, we will characterize a novel cell-surface protein, CD47, which is targeted by Vpu. CD47 modulates the engulfment of infected and tumor cells by immune scavenger cells called macrophages and we postulate that targeting of CD47 promotes the infection of macrophages to facilitate HIV spread in vivo. We will also identify new host factors targeted by Vpu, which are relevant to the pathogenesis of HIV/AIDS. Overall, these studies will provide important insight regarding the role of Vpu in HIV-1 pathogenesis and will reveal novel targets for effective therapeutic intervention.