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Study of the mechanisms by which HIV-1 Nef promotes viral infectivity neutralising host cell restriction factors

Grant number: 19/27725-1
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): November 01, 2020
Effective date (End): February 28, 2023
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal researcher:Luis Lamberti Pinto da Silva
Grantee:Cristina Santos da Costa
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

HIV-1 is a lentivirus that infects CD4 expressing cells of the immune system. During its replication, HIV-1 subverts cell machineries in its favor, leading to the production of thousands of new particles and ultimately the death of the producing cells. This compromises the levels of CD4 + cells in the host organism, consequently leading to AIDS. SERINC5 and IFITMs are transmembrane proteins that have high activity against HIV-1, acting through a common mechanism to contain the infection, as both can be incorporated into newly synthesized viral particles, reducing viral progeny infectivity. Different studies have pointed out that the antiviral effectiveness of these proteins is determined by their subcellular localization, which is regulated by intracellular vesicle trafficking machinery. Conversely, viral proteins may neutralize the action of cellular restriction factors, important for the inhibition of HIV-1 at different stages of the replicative cycle. In the case of SERINC5, it is known that the HIV-1 Nef accessory protein acts by counteracting its activity by impairing its expression on the cell surface; however, the cellular factors and molecular mechanisms involved are poorly understood. Regarding IFITMs, to date no HIV-1 proteins responsible for their evasion have been identified and our preliminary results point to the participation of Nef in this process. Based on the above, the present project aims to elucidate the mechanisms by which HIV-1 Nef neutralizes the antiviral activity of SERINC5 and IFITMs and their implications on viral pathogenesis. (AU)

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