Abstract
Untreated Human Immunodeficiency Virus (HIV) infection is characterized by intestinal epithelial barrier dysfunction and chronic inflammation, related features that are attenuated to variable degrees by suppressive antiretroviral therapy (ART). Specific mediators of intestinal epithelial cell (IEC) dysfunction and restoration during HIV disease and treatment have yet to be identified. We studied IECs isolated from intestinal biopsies by RNAseq and found that mRNA levels for the ubiquitin-modifying enzyme, A20, are upregulated in ART-treated individuals and are positively correlated with markers of epithelial function (e.g., CTNNB, CLDN4, and TJP1). In a murine intestinal organoid model, A20 expression was suppressed by interferon-alpha (IFNα), which is highly expressed during HIV viremia and induces IFN-mediated signaling. Notably, A20 deletion rendered intestinal organoids more susceptible to cell death and inhibition of barrier-related genes mediated by interferon-gamma (IFNγ), a cytokine also present at elevated levels during untreated infection. Furthermore, A20 specifically restricted expression of IL-17A-induced inflammatory genes in organoids. Finally, ART-suppressed chronically infected individuals treated with pegylated IFNα2a for five weeks demonstrated reduced expression of A20 in peripheral blood mononuclear cells. Our results are thus consistent with a model in which enhanced type I interferons suppress A20 levels, leading to IFNγ-mediated dysfunction. As such, variation in A20 expression during the course of HIV infection could underlie both the development of epithelial dysfunction before the initiation of ART and the recovery of intestinal epithelial integrity thereafter.Trial registrationClinicalTrials.gov Clinical Trial NCT00594880
Highlights
Infection with Human Immunodeficiency Virus (HIV) results in widespread inflammation in infected individuals with key changes in the immune system that have important clinical implications
Though the advent of antiretroviral therapy (ART) has significantly improved the lives of individuals infected with the Human Immunodeficiency Virus (HIV), those on therapy still suffer from an enhanced risk of morbidities and mortalities that is caused, at least in part by, overactivation of the immune system
In a culture system that parallels features of the intact gut barrier, we saw that a cytokine induced by HIV suppressed the expression of A20
Summary
Infection with Human Immunodeficiency Virus (HIV) results in widespread inflammation in infected individuals with key changes in the immune system that have important clinical implications. Untreated HIV disease is characterized by high levels of systemic and tissuelocalized proinflammatory cytokines such as an increase in type I interferon activity and interferon-gamma (IFNγ), each of which is thought to contribute to tissue damage [1,2]. These hallmarks of infection result in immune dysfunction that can often persist despite the initiation of antiretroviral therapy (ART). Progressive SIV/HIV disease is associated with the preferential depletion of CD4+ T helper type 17 (Th17) cells producing the cytokine interleukin 17 (IL-17), a key epithelial support cytokine whose depletion during viremia is proposed to be the mechanistic basis for epithelial barrier dysfunction and pathogenesis [15,16,17,18,19]
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