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Study of the molecular mechanisms used by the HIV-1 Nef protein to neutralize host cell defense strategies

Grant number: 22/15928-8
Support Opportunities:Regular Research Grants
Duration: March 01, 2023 - February 28, 2025
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

Although dispensable for HIV replication in vitro, the Nef viral protein is critical for maintaining high viral loads in animal models and progression to AIDS in human patients. Nef interferes with the intracellular transport of host proteins involved in the virus replicative cycle and immunity. Among the targets of Nef is the SERINC5 protein, which, when incorporated into nascent viral particles, makes them less infectious. Nef neutralizes SERINC5 by removing it from virion biogenesis sites. Another important host viral restriction factor is the IFITM3 protein, which compromises the infection when present in the viral particles and the viral entry sites in the recipient cell. However, the viral factor that potentially antagonizes IFITM3 is unknown. Preliminary results from our group show that Nef modifies the intracellular transport of IFITM3. In this project, we intend to dissect how Nef interferes in the subcellular distribution and IFITM3 and SERINC5 and investigate whether (and how) these Nef actions compromise the antiviral activity of these restriction factors. Although constitutively expressed at low levels in some cell types, both Serinc5 and IFITM3 are encoded by interferon-stimulated genes (ISGs). Previous work suggests that Nef interferes with the JAK/STAT pathway-mediated antiviral response by reducing phosphorylated STAT-1 in interferon-stimulated cells. However, the mechanism involved remains elusive. Our preliminary results confirm that Nef inhibits the induction of ISGs in T cells and show the reduction of total STAT-1 levels due to Nef expression. We suggest that the inhibitory effect of the viral protein on the pathway precedes STAT-1 phosphorylation. In this project, the mechanism by which Nef controls the JAK/STAT pathway will be investigated in depth to map the Nef sequence motifs involved, as well as the host factors required for this poorly characterized Nef activity. (AU)

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