Nef is an HIV-1 accessory protein that plays crucial roles in viral pathogenesis. Nef interacts with components of the intracellular protein sorting machinery to create a favorable environment for HIV replication. These interactions lead to modifications in the trafficking itinerary of cell surface proteins involved in immune responses, redirecting them to multivesicular bodies (MVBs), and subsequently to lysosomes for degradation. Targeting of proteins to the MVB-pathway requires the function of ESCRT complexes and accessory proteins, such as Alix. Interestingly, Nef interacts with Alix and this interaction is essential for Nef-induced targeting of CD4 to lysosomes. The MVBs are also implicated on exocytic routes, as they can fuse with the plasma membrane and release their intralumenal vesicles (ILVs) as exosomes. Nef expression induces cellular production of exosomes, and Nef promotes its own secretion through these vesicles. Nef is present in the serum HIV infected individuals, and recent data suggest that secreted Nef play important functions on HIV pathogenesis. However, the mechanisms involved in the recruitment of Nef to ILVs/exosomes and the release of these vesicles are not well understood. We postulate that Alix and other ESCRT machinery components play crucial roles in the extracellular release of Nef. Therefore, this project proposes to elucidate the molecular mechanisms involved in the biogenesis and release of exosomes containing HIV-1 Nef by the host cell.
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