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Study of molecular mechanisms associated with the modulation of the signaling pathway stimulated by type I interferons (JAK/STAT) by HIV-1

Grant number: 19/15280-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): November 01, 2019
Effective date (End): April 30, 2023
Field of knowledge:Biological Sciences - Morphology
Principal Investigator:Luis Lamberti Pinto da Silva
Grantee:Roger Luiz Rodrigues
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Viral infections stimulate the JAK/STAT signaling pathway induced by interferon type I (IFN-±/²) and increase the expression of a class of effector molecules encoded by Interferon-Stimulated Genes (ISGs). These effectors molecules inhibit viral replication and its dissemination to non-infected acceptor cells. Despite this ability to activate the antiviral state, low clinical response to IFN-I treatment is observed in HIV-1 infected patients. Previous studies have shown that accessory proteins of HIV-1 have an inhibitory action on the JAK/STAT signaling pathway. In order to understand how this modulation occurs, previous results in our laboratory have shown an effect of the Nef protein on inhibition of STAT-1 phosphorylation induced by IFN-I. EVs are involved both in the process of assembling of the antiviral response and in transporting HIV-1 proteins to acceptor cells capable of inhibiting immune activity and increasing infectivity. Our group recently showed that EVs released by CD4 + T lymphocytes expressing Nef has decreased CD4 content and that these EVs are efficient in promoting viral infectivity. Moreover, proteomic analysis showed that Nef is present in these vesicles. Taken together, these results indicate the possible involvement of HIV-1 Nef in the modulation of the innate immunity activated by IFN-I and infectivity in infected and bystander T cells. However, the mechanism by which Nef modulates innate immunity is not completely elucidated. Thus, the present research project aims to investigate how Nef antagonizes the cellular defense mechanisms mediated by IFN-I and the importance of this antagonism for HIV-1 infectivity in infected and bystander T cells. (AU)