TY - JOUR
T1 - HIV-1 Gag and Vpr impair the inflammasome activation and contribute to the establishment of chronic infection in human primary macrophages
AU - Galvão-Lima, Leonardo J.
AU - Zambuzi, Fabiana A.
AU - Soares, Luana S.
AU - Fontanari, Caroline
AU - Meireles, Aline F.Galvão
AU - Brauer, Verônica S.
AU - Faccioli, Lúcia H.
AU - Gama, Lúcio
AU - Figueiredo, Luiz T.M.
AU - Bou-Habib, Dumith Chequer
AU - Frantz, Fabiani G.
N1 - Funding Information:
The funding for this work was provided by The São Paulo Research Foundation , Brazil (FAPESP grants # 2011/12199-0 , 2015/04342-9 , 2018/15066-0 ) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil ( CAPES ) - Finance Code 001 .
Funding Information:
The authors are grateful to the Fundaçao Hemocentro de Ribeirão Preto - FMRP/USP and Dr. Benedito P. A. Prado-Júnior; The Virology Research Center and Ms. Soraya B. Jabur; Dr. Fernando L. B. Silva, Dr. Yara M. L. Valim, Dr. Andréia M. Leopoldino, Dr. Marinaldo P. C. Neto for technical support, and The Microscopy Facility at FCFRP/USP. Part of this work was conducted during the International Graduate Scholarship Program – CAPES at the Johns Hopkins University – School of Medicine and supported by CAPES – Brazilian Federal Agency for Support and Evaluation of Graduate Education within the Ministry of Education of Brazil.
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/8
Y1 - 2022/8
N2 - 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-1β 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-κB (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.
AB - 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-1β 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-κB (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.
KW - HIV-1
KW - Immune Evasion
KW - Inflammasome
KW - Macrophages
KW - Viral Infection
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U2 - 10.1016/j.molimm.2022.04.018
DO - 10.1016/j.molimm.2022.04.018
M3 - Article
C2 - 35659727
AN - SCOPUS:85131245930
SN - 0161-5890
VL - 148
SP - 68
EP - 80
JO - Molecular Immunology
JF - Molecular Immunology
ER -