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Study of molecular mechanisms associated to the modulation of HIV pathogenesis mediated by extracellular vesicles

Grant number: 17/18477-9
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): November 01, 2017
Effective date (End): October 31, 2020
Field of knowledge:Biological Sciences - Morphology
Principal Investigator:Luis Lamberti Pinto da Silva
Grantee:Mara Elisama da Silva Januário
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Cells actively secrete Extracellular Vesicles (EVs) that may participate in different biological processes in acceptor cells. One of the recently described functions of EVs is their role in modulating pathogenesis of different viruses. Specifically in the case of HIV, it is known that EVs play a dual role in infection. EVs may mediate intercellular communication and activate antiviral responses in acceptor cells. On the other hand, EVs can carry viral proteins that inhibit host defense mechanisms and contribute to increased virulence. The HIV accessory protein Nef enhances the release of EVs by host cells and has the ability to promote its own export within EVs by an unknown mechanism, affecting uninfected acceptor cells. Our research group demonstrated that Nef has the ability to modulate levels of the HIV receptor CD4 in EVs. Further experiments allowed us to conclude that the presence of CD4 in EVs play an inhibitory role in HIV infectivity. However, the mechanism by which CD4+ EVs inhibits HIV infection has not been determined. These data also raised the question of whether Nef modulates the levels of other proteins with antiviral activity in EVs. In addition, we observed that the depletion of Alix reduces the export of Nef in EVs. Indeed, Nef physically interacts with Alix and Alix is known to participate in the selection of cargo to EVs, suggesting that this interaction mediates the export of Nef in EVs. This data may help to understand the molecular mechanism used by Nef to promote its own export in EVs. Thus, the present research project aims to understand the importance of Alix for the release of Nef in EVs, to characterize new molecules that have their levels modulated in EVs in a Nef-dependent manner and to characterize the role of CD4+ EVs in the inhibition of HIV infectivity. It is expected that the results obtained will contribute to the understanding of how EVs modulate the HIV pathogenesis, specifically the role of Nef in this process. (AU)