Molecular mechanisms involved in IFITM3 subcellular redistribution by HIV-1

• Grant number: 22/03485-4
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: October 20, 2022
• End date: October 19, 2023
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Luis Lamberti Pinto da Silva
• Grantee: Cristina Santos da Costa
• Supervisor: Akira Ono
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: University of Michigan, United States
• Associated to the scholarship: 19/27725-1 - Study of the mechanisms by which HIV-1 Nef promotes viral infectivity neutralising host cell restriction factors, BP.DD

Abstract

The HIV-1 envelope comprises plasma membrane-derived lipids with inserted viral glycoproteins trimers and host membrane proteins. This complex assembly process is mainly orchestrated by HIV-1 Gag, a structural protein that is key to organize viral assembly and budding domains at the plasma membrane. The interferon-induced transmembrane protein 3 (IFITM3) is a host antiviral protein that may incorporate into HIV-1 envelope during the assembly, resulting in a decreased viral infectivity. Although the anti-HIV-1 activity of IFITM3 is well documented, the molecular mechanisms involved in IFITM3 recruitment to viral assembly sites, as well the factors responsible for HIV-1 escape from its antiviral activity are poorly understood. Our preliminary results showed a possible role of Gag in IFITM3 recruitment to the plasma membrane. Furthermore, our preliminary data also suggested that the HIV-1 accessory protein Nef can modify IFITM3 subcellular distribution, probably interfering with its antiviral function. Therefore, we propose to investigate the role of Gag and Nef on IFITM3 trafficking in further detail. Furthermore, we would like to investigate the consequences of IFITM3 redistribution mediated by Gag and Nef in the context of infection. The present study will extend the knowledge on host cell intrinsic antiviral immunity and how HIV-1 evades these innate immune responses, contributing to a better understanding of host-pathogen interactions. (AU)