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

Abstract

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-1+cART+ individuals by qRT-PCR. Results: All IL-32 isoforms were significantly upregulated in HIV-1+cART+ compared to HIVneg 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.

Prevalence and Characterization of Subclinical Coronary Atherosclerotic Plaque with CT among Individuals with HIV: Results from the Canadian HIV and Aging Cohort Study

“…Data from some participants in this study were previously reported, however, only for technical validation (15,16), protocol description (14), or for correlation with immunologic markers (17)(18)(19)(20)(21)(22), not to assess coronary plaque versus HIV status.…”

Molecular interactions and functions of IL-32

“…36 During HIV infection, IL-32 is increased in immune cells (CD4+ T cells, B cells, macrophages, DCs, and epithelial cells). 14,145 Whether it has a positive or negative influence on disease outcome is, however, Yet, others found that endogenous IL-32 contributed to control of HIV infection in human PBMCs and in the U1 macrophage cell line, as measured by p24 viral protein levels. 76 Exogenous rhIL-32 also inhibited viral replication, and this activity was dependent on INF-.…”

“…146 In a recent study, IL-32 , but not IL-32 or IL-32 , induced HIV-1 production in latently infected CD4+ T cells. 145 Interestingly, a recent paper by Palstra et al found that a single-nucleotide polymorphism (SNP), rs4349147, statistically associated with HIV susceptibility in a genome-wide association study, 147 resides in a genomic region that function as a long-distance enhancer element for IL32. 148 Deletion of this intergenic variant in Jurkat T cells abrogated IL-32 expression.…”

“…During HIV infection, IL‐32 is increased in immune cells (CD4+ T cells, B cells, macrophages, DCs, and epithelial cells) 14,145 . Whether it has a positive or negative influence on disease outcome is, however, debated.…”

Loss of CD96 Expression as a Marker of HIV-Specific CD8+ T-Cell Differentiation and Dysfunction

“…Of note, LPS is known to be a strong inducer of IL-32 ( 19 , 20 ). Our data demonstrated that the dominantly expressed IL-32β and IL-32γ isoforms ( 21 ) significantly downregulated CD96 on CD8 + T-cells upon PBMC stimulation ( Figure 1C p=0.031 for both). Together, these results indicated that CD96 expression on CD8 + T cells is subject to downregulation by IL-32, which further links this mechanism to disease progression in HIV infection.…”