Study of the effects of HIV-1 Nef on the host-cell endomembrane system and their implications in viral pathogenesis

• Grant number: 18/00297-7
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2018
• End date: June 30, 2020
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Luis Lamberti Pinto da Silva
• Grantee: Luis Lamberti Pinto da Silva
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Nef is an important HIV-1 virulence factor that acts in the maintenance of high viral loads and progression to AIDS. As one the most abundantly produced viral proteins in early infection (first 8-12h), Nef optimizes the cellular environment to maximize viral replication and infectivity of the viral progeny. Nef hijacks the cell machinery that controls the intracellular trafficking of proteins by physically interacting with these molecules and, thereby, modulates the expression of cell surface proteins. A well-known target of Nef is CD4, the main HIV receptor. Nef downregulates the expression of CD4 in the surface of infected cells to avoid superinfection (and cell death) and to facilitate the externalization of newly synthesized HIV particles. Nef also reduces the expression of MHC-I molecules and of the recently discovered host viral restriction factor SERINC5. In this way, Nef impairs both viral antigen presentation and the incorporation of SERINC5 in nascent particles, which otherwise would compromise viral entry into the target cells. Our research group described the mechanism by which Nef redirects internalized CD4 to lysosomes to remove these molecules from the host endomembrane system. In this project, we will use this "know-how" to study the mechanisms involved in the downregulation of MHC-I and SERINC5. Nef is also abundant in the serum of HIV+ individuals. Although Nef does not use the classical secretory pathway, it is capable to induce the release of extracellular vesicles (EVs) and to get incorporated into these EVs in an active form. Besides this, Nef also modifies the protein constitution of EVs, however, the implications of these actions in viral pathogenesis are mostly unknown. Therefore, the aims of this project also include to study the mechanism involved in the secretion of Nef within EVs and to map the global changes induced by Nef in the proteome of EVs to be able to fully describe the pleotropic effects of this HIV virulence factor. (AU)

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

JANUARIO, YUNAN C.; EDEN, JESSICA; DE OLIVEIRA, LUAN S.; DE PACE, RAFFAELLA; TAVARES, LUCAS A.; DA SILVA-JANUARIO, MARA E.; APOLLONI, VINICIUS B.; WILBY, ELISE L.; ALTMEYER, RANDOLF; BURGOS, PATRICIA, V; et al. Clathrin adaptor AP-1-mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments. Journal of Biological Chemistry, v. 298, n. 8, p. 19-pg., 2022-07-31. (19/08461-3, 17/18477-9, 21/01182-1, 17/12022-0, 18/00297-7, 20/08831-2)

DASILVA, LUIS L. P.. The Ambiguous Roles of Extracellular Vesicles in HIV Replication and Pathogenesis. FRONTIERS IN MICROBIOLOGY, v. 9, OCT 10 2018. (14/02438-6, 18/00297-7)

TAVARES, LUCAS A.; DE CARVALHO, V, JULIANNE; COSTA, CRISTINA S.; SILVEIRA, ROBERTA M.; DE CARVALHO, ANDREIA N.; DONADI, EDUARDO A.; DASILVA, LUIS L. P.. Two Functional Variants of AP-1 Complexes Composed of either gamma 2 or gamma 1 Subunits Are Independently Required for Major Histocompatibility Complex Class I Downregulation by HIV-1 Nef. Journal of Virology, v. 94, n. 7, APR 2020. (16/05945-1, 16/18207-9, 15/26667-7, 14/02438-6, 18/08966-5, 18/00297-7)

TAVARES, LUCAS A.; JANUARIO, YUNAN C.; DASILVA, LUIS L. P.. HIV-1 Hijacking of Host ATPases and GTPases That Control Protein Trafficking. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 9, JUL 8 2021. (17/12022-0, 18/00297-7, 16/18207-9)

JANUARIO, YUNAN C.; DASILVA, LUIS L. P.. Hijacking of endocytosis by HIV-1 Nef is becoming crystal clear. NATURE STRUCTURAL & MOLECULAR BIOLOGY, v. 27, n. 9, p. 3-pg., 2020-08-19. (18/00297-7, 17/12022-0, 19/02418-9)