HIV-1 Gag and Vpr impair the inflammasome activation and contribute to the establishment of chronic infection in human primary macrophages

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Galvao-Lima, Leonardo J. ; Zambuzi, Fabiana A. ; Soares, Luana S. ; Fontanari, Caroline ; Meirele, Aline F. Galva ; Brauer, Veronica S. ; Faccioli, Lucia H. ; Gama, Lucio ; Figueiredo, Luiz T. M. ; Bou-Habib, Dumith Chequer ; Frantz, Fabiani G.

• Tipo de documento: Artigo Científico
• Fonte: Molecular Immunology; v. 148, p. 13-pg., 2022-08-01.

Resumo

The successful establishment of HIV-1 infection is related to inflammasome blocking or inactivation, which can result in the viral evasion of the immune responses and formation of reservoirs in several tissues. In this sense, we aimed to evaluate the viral and cellular mechanisms activated during HIV-1 infection in human primary macrophages that allow an effective viral replication in these cells. We found that resting HIV-1-infected macrophages, but not those activated in classical or alternative patterns, released IL-1 beta and other pro-inflammatory cytokines, and showed increased CXCL10 expression, without changes in the NLRP3, AIM2 or RIG-I inflammasome pathways. Also, similar levels of Casp-1, phosphorylated NF-kappa B (p65) and NLRP3 proteins were found in uninfected and HIV-1-infected macrophages. Likewise, no alterations were detected in ASC specks released in the culture supernatant after HIV-1 infection, suggesting that macrophages remain viable after infection. Using in silico prediction studies, we found that the HIV-1 proteins Gag and Vpr interact with several host proteins. Comparable levels of trans-LTB4 were found in the supernatants of uninfected and HIV-1-infected macrophages, whereas ROS production was impaired in infected cells, which was not reversed after the PMA stimulus. Immunofluorescence analysis showed structural alterations in the mitochondrial architecture and an increase of BIM in the cytoplasm of infected cells. Our data suggest that HIV-1 proteins Gag and Vpr, through interacting with cellular proteins in the early steps of infection, preclude the inflammasome activation and the development of effective immune responses, thus allowing the establishment of the infection. (AU)

• Processo FAPESP: 18/15066-0 - Programação epigenética em doenças infecciosas crônicas: exaustão e training do sistema imune inato
• Beneficiário: Fabiani Gai Frantz
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores - Fase 2
• Processo FAPESP: 11/12199-0 - Estudo de disfunções na resposta imune inata em pacientes HIV+: correlação com alterações imunológicas e epigenéticas
• Beneficiário: Fabiani Gai Frantz
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores