Genetic and functional characterization of NLRP3 in lymphocytes and monocytes of chronically HIV-1 infected individuals

Author(s)

Vinícius Nunes Cordeiro Leal

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2021-04-29

Examining board members

Alessandra Pontillo; Tárcio Teodoro Braga; Lucio Gama; Maria Notomi Sato

• Advisor: Alessandra Pontillo

Abstract

HIV-1 activates the NLRP3 inflammasome in monocytes, macrophages and dendritic cells, inducing the release of IL-1 &#223 and/or IL-18, important cytokines in the antiviral response. Accordingly, genetic variants that lead to increased activation of the NLRP3 inflammasome were associated to protection against HIV-1 infection, emphasizing the importance of the genetic background of the host in responding to the virus. With the introduction of antiretroviral therapy (ART), the morbidity related to HIV-1 chronic infection is nowadays mainly related to the state of chronic inflammation of the patients. Taking into account the high production of the cytokines IL-1 &#223 and IL-18, the participation of inflammasome in the pathogenesis of chronic HIV infection has been postulated. Constitutive activation of the inflammasome has been reported in peripheral blood mononuclear cells (PBMC) from patients. However, it is still unclear in which cells the inflammasome would be constitutively activated, especially considering that in addition to monocytes, NLRP3 inflammasome activation has recently been demonstrated in T and B lymphocytes. Furthermore, we observe a gap in genetic association studies in cohorts of HIV patients on ART. Therefore, we hypothesized that the activation of the inflammasome may occur both in monocytes and in T and B lymphocytes of HIV patients, and it may contribute to the chronic inflammation status of these patients and/or affecting the biology of the leukocytes. We decided to focus the study on the NLRP3 receptor taking into account its expression in the different PBMCs. Considering that variants in HIV susceptibility genes were also associated with the prognosis of the disease, we also propose to conduct an association study in a cohort of HIV patients on ART, analyzing single nucleotide polymorphisms (SNPs) in NLRP3 inflammasome. The NLRP3 inflammasome resulted constitutively activated in monocytes, CD4&#43 T and CD19&#43 B lymphocytes, but the inflammasome\'s response to stimuli was scarce only in monocytes. Both CD4&#43 T and B lymphocytes responded with hyper activation of the complex, suggesting that there is a dysregulation of the NLRP3 inflammasome in the PBMC of HIV patients, but with different consequences depending on the cell. These data may partly explain the results obtained from the genetic study where SNPs that lead to increased activation of NLRP3 and IL-1 &#223 are associated with better and worse clinical status of HIV patients, respectively. Taken together, the data obtained describe for the first time in detail the deregulation of NLRP3 inflammasome in HIV patients on ART, which is related both to the individual genetic background and to its pro-inflammatory state, and affects in a cell-specific way the biology of different leukocytes. (AU)

• FAPESP's process: 17/10824-1 - Genetic and functional characterization of NLRP-3 in lymphocytes and monocytes from chronically infected HIV-1 individuals
• Grantee: Vinícius Nunes Cordeiro Leal
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)