The NLRP3 Inflammasome Is Upregulated in HIV-Infected Antiretroviral Therapy-Treated Individuals with Defective Immune Recovery.

Alessandra Bandera,Michela Masetti,Mara Biasin,Mario Clerici,Daria Trabattoni,Antonio Muscatello,Andrea Gori,Massimiliano Fabbiani,Nicola Squillace

doi:10.3389/fimmu.2018.00214

Abstract

Inflammasome-mediated activation of caspase-1 regulates inflammatory responses and pyroptosis. We analyzed possible associations between inflammasome-related genes and immune reconstitution in HIV-infected antiretroviral therapy (ART)-treated patients. Cross-sectional, case-control study. HIV-infected patients on ART for ≥24 months with HIV-RNA<50 cp/mL for ≥12 months were enrolled and defined as immunological responders (IR) or non-responders (INR) if CD4 count was ≥500 or ≤350 cells/μL, respectively. Expression of inflammasome genes, caspases 1, 3, 4, 5 and γ-interferon-inducible protein 16 (IFI16) was measured in unstimulated and LPS- or aldrithiol-2-treated HIV-1BaL virions-stimulated peripheral blood mononuclear cells. Microbial translocation markers were evaluated. Thirty-nine patients (22 IRs; 17 INRs) were enrolled. LPS-stimulated inflammasome genes were significantly upregulated in INRs. Whereas HIV-1BaL stimulation induced (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) expression in both IRs and INRs, NLRP3 and IL-18 expression was significantly increased in INRs compared to IRs. Significant higher caspase-1 expression was seen as well, whereas caspase 3, 4, and 5 expression was similar in both groups. No differences in microbial translocation markers (LPS and soluble CD14) were detected in the two groups. Upregulation of NLRP3 and caspase-1 is observed in INR patients. This could play a role in persistent immune activation that characterize INRs. Caspase-1 upregulation could induce CD4 T-cell loss via pyroptosis, contributing to unsatisfactory CD4 T-cells recovery.

Highlights

Elevated levels of inflammation and immune activation, which can persevere in HIV-infected individuals on virologically effective antiretroviral therapy (ART), have been associated to morbidity and mortality from non-AIDS events, such as cardiovascular disease, neurocognitive dysfunction, and kidney and bone disorders [1, 2]
Nadir CD4 T-cell count was significantly lower in immunological non-responders (INR) as compared to immunological responders (IRs) [median 44 (IQR 25–83) cells/μL vs 196 (IQR 85–298) cells/μL, p < 0.01] Median CD4 count was 295 (IQR 256–343) cells/μL in INRs vs 840 (IQR 718–1131) cells/μL in IRs, median CD4 percentage was 19% (IQR 16–21) in INRs, and 34% (IQR 28–40) in IRs
Upon LPS stimulation, we observed a significant increase of IL-1β (p < 0.05), IL-18, and caspase-1 (p < 0.02) in INRs compared to IRs

Summary

Introduction

Elevated levels of inflammation and immune activation, which can persevere in HIV-infected individuals on virologically effective antiretroviral therapy (ART), have been associated to morbidity and mortality from non-AIDS events, such as cardiovascular disease, neurocognitive dysfunction, and kidney and bone disorders [1, 2]. These events are more frequently observed in HIV-infected patients unable to reach a CD4+ T-cell count of 500/mm, defined as INR. We analyzed possible associations between inflammasomerelated genes and immune reconstitution in HIV-infected antiretroviral therapy (ART)treated patients

Methods

Results

Conclusion