Antagonistic role of IL-1 beta and NLRP3/IL-18 genetics in chronic HIV-1 infection

Autor(es)

Reis, Edione C. ^[1] ; Leal, Vinicius N. C. ^[1] ; da Silva, Lais T. ^[2] ; dos Reis, Marilia M. L. ^[3] ; Arganaraz, Enrique R. ^[3] ; Oshiro, Telma M. ^[2] ; Pontillo, Alessandra ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Imunol, Lab Imunogenet, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Fac Med, Hosp Clin HCFMUSP, Lab Invest Dermatol & Imunodeficiencias LIM 56, Sao Paulo, SP - Brazil

^[3] Univ Brasilia UNB, Fac Ciencias Saude, Lab Virol Mol, Brasilia, DF - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Clinical Immunology; v. 209, DEC 2019.
• Citações Web of Science: 1

Resumo

Host genetics affects both susceptibility and progression of HIV-1 infection. NLRP3 inflammasome provides a first-line defense in viral infections, and, accordingly, gain-of-function variants in NLRP3 have been associated with protection against HIV-1. Despite antiretroviral treatment (ART), HIV-infected patients continue to present systemic inflammation with a heterogeneous prognosis. As NLRP3 inflammasome is involved in several chronic diseases by amplifying ``sterile{''} inflammation, its role in chronic phase of HIV infection has been postulated. Little is known about inflammasome genetics in HIV-infected patients and whether it may play a role in the different clinical outcomes. Therefore, we questioned whether NLRP3 inflammasome genetics could affect the clinical course of HIV-1 infection as it does in host/virus interaction. For this purpose, we analyzed selected single nucleotide polymorphisms (SNPs) in ART-treated HIV-infected patients (n = 300), in Long Term Non-Progressors/Elite Controllers and progressors (n = 133), and in HIV-infected individuals submitted to dendritic cell (DC)-based immunotherapy (n = 19). SNPs leading to increased activation of NLRP3 inflammasome are beneficial for patients, while SNPs that negatively affect NLRP3 activation or IL-18 production, detrimental. In contrast, gain-of-function variant in IL1B is also detrimental for patients, suggesting that while IL-1 beta possible contributes to immune exhaustion, the axis NLRP3-inflammasome/IL-18 could act positively in chronic infection. Functional assays supported genetic results: NLRP3 variants associated with good quality HIV + DC, and ILIB -511C > T with a poor one. Loss-of-function SNPs affect HIV + T cells proliferation. These findings proposed for the first time that NLRP3 inflammasome, mainly through IL-18, play a protective role in chronic HIV infection. (AU)

• Processo FAPESP: 15/23395-6 - Imunogenetica do inflamassoma, estudo translacional "da clinica a bancada,da bancada a clinica":analise das variações nos genes do inflamassoma em doenças autoinflamatorias monogênicas e multifatoriais para diagnostico diferencial e aplicações terapêutica
• Beneficiário: Alessandra Pontillo
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/06142-1 - Perfil genômico da resposta imune ao HIV-1 e implicações para a vacina terapêutica com células dendríticas contra o HIV-1
• Beneficiário: Alessandra Pontillo
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/50650-7 - Caracterização de novos alvos moleculares no controle da obesidade e da inflamação induzida pela obesidade
• Beneficiário: Alessandra Pontillo
• Modalidade de apoio: Auxílio à Pesquisa - Regular