Upregulation of IL-32 Isoforms in Virologically Suppressed HIV-Infected Individuals: Potential Role in Persistent Inflammation and Transcription From Stable HIV-1 Reservoirs

• Published in: Journal of acquired immune deficiency syndromes (1999) Vol. 82; no. 5; pp. 503 - 513
• Main Authors: Zaidan, Sarah M, Leyre, Louise, Bunet, Rémi, Larouche-Anctil, Etienne, Turcotte, Isabelle, Sylla, Mohamed, Chamberland, Annie, Chartrand-Lefebvre, Carl, Ancuta, Petronela, Routy, Jean-Pierre, Baril, Jean-Guy, Trottier, Benoit, MacPherson, Paul, Trottier, Sylvie, Harris, Marianne, Walmsley, Sharon, Conway, Brian, Wong, Alexander, Thomas, Réjean, Kaplan, Robert C, Landay, Alan L, Durand, Madeleine, Chomont, Nicolas, Tremblay, Cécile L, El-Far, Mohamed
• Format: Journal Article
• Language: English
• Published: United States Copyright Wolters Kluwer Health, Inc. All rights reserved 15-12-2019; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Anti-HIV Agents - therapeutic use; Antiretroviral agents; Antiretroviral therapy; Case-Control Studies; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; Cytokines; Drug Therapy, Combination; HIV; HIV Infections - blood; HIV Infections - drug therapy; HIV-1 - genetics; HIV-1 - metabolism; Human immunodeficiency virus; Humans; Inflammation; Inflammation - genetics; Inflammation - metabolism; Interleukin 10; Interleukin 6; Interleukins - blood; Interleukins - genetics; Interleukins - pharmacology; Isoforms; Latent infection; Leukocytes, Mononuclear; Lymphocytes T; Peripheral blood mononuclear cells; Phenotypes; Protein Isoforms - blood; Protein Isoforms - genetics; Protein Isoforms - pharmacology; Recombinant Proteins - pharmacology; T cell receptors; Transcription; Transcription, Genetic - drug effects; Up-Regulation; Viral Load; γ-Interferon
• ISSN: 1525-4135; 1944-7884; 1944-7884
• DOI: 10.1097/QAI.0000000000002185

BACKGROUND:Human IL-32 is a polyfunctional cytokine that was initially reported to inhibit HIV-1 infection. However, recent data suggest that IL-32 may enhance HIV-1 replication by activating the HIV-1 primary targets, CD4 T-cells. Indeed, IL-32 is expressed in multiple isoforms, some of which are proinflammatory, whereas others are anti-inflammatory.
SETTING AND METHODS:Here, we aimed to determine the relative expression of IL-32 isoforms and to test their inflammatory nature and potential to induce HIV-1 production in latently infected cells from virologically suppressed HIV-infected individuals. IL-32 and other cytokines were quantified from plasma and supernatant of CD4 T-cells by ELISA. Transcripts of IL-32 isoforms were quantified by qRT-PCR in peripheral blood mononuclear cells. The impact of recombinant human IL-32 isoforms on HIV-1 transcription was assessed in CD4 T-cells from HIV-1cART individuals by qRT-PCR.
RESULTS:All IL-32 isoforms were significantly upregulated in HIV-1cART compared to HIV individuals with IL-32β representing the dominantly expressed isoform, mainly in T-cells and NK-cells. At the functional level, although IL-32γ induced typical proinflammatory cytokines (IL-6 and IFN-γ) in TCR-activated CD4 T-cells, IL-32α showed an anti-inflammatory profile by inducing IL-10 but not IL-6 or IFN-γ. However, IL-32β showed a dual phenotype by inducing both pro- and anti-inflammatory cytokines. Interestingly, consistent with its highly pro-inflammatory nature, IL-32γ, but not IL-32α or IL-32β, induced HIV-1 production in latently infected CD4 T-cells isolated from combined antiretroviral therapy–treated individuals.
CONCLUSIONS:Our data report on the differential expression of IL-32 isoforms and highlight the potential role of IL-32, particularly the γ isoform, in fueling persistent inflammation and transcription of viral reservoir in HIV-1 infection.