People with HIV-1 Demonstrate Type 1 Interferon Refractoriness Associated with Upregulated USP18

HIV-1 infection persists in humans despite expression of antiviral type 1 interferons (IFN). Even exogenous administration of IFN alpha only marginally reduces HIV-1 abundance, raising the hypothesis that people living with HIV-1 (PLWH) are refractory to type 1 IFN. We demonstrated type 1 IFN refractoriness in CD4(+) and CD8(+) T cells isolated from HIV-1-infected persons by detecting diminished STAT1 phosphorylation (pSTAT1) and interferon-stimulated gene (ISG) induction upon type 1 IFN stimulation compared to those in cells from healthy controls. Importantly, HIV-1-infected people who were virologically suppressed with antiretrovirals also showed type 1 IFN refractoriness. We found that USP18 levels were elevated in people with refractory pSTAT1 and ISG induction and confirmed this finding ex vivo in CD4(+) T cells from another cohort of HIV-hepatitis C virus (HCV) coinfected persons who received exogenous pegylated interferon-alpha 2b in a clinical trial. We used a cell culture model to recapitulate type 1 IFN refractoriness in uninfected CD4(+) T cells that were conditioned with media from HIV-1 inoculated peripheral blood mononuclear cells (PBMCs), inhibiting de novo infection with antiretroviral agents. In this model, RNA interference against USP18 partly restored type 1 IFN responses in CD4(+) T cells. We found evidence of type 1 IFN refractoriness in PLWH irrespective of virologic suppression that was associated with upregulated USP18, a process that might be therapeutically targeted to improve endogenous control of infection. IMPORTANCE People living with HIV-1 (PLWH) have elevated constitutive expression of type 1 interferons (IFN). However, it is unclear whether this affects downstream innate immune responses. We identified refractory responses to type 1 IFN stimulation in T cells from PLWH, independent of antiretroviral treatment. Type 1 IFN refractoriness was linked to elevated USP18 levels in the same cells. Moreover, we found that USP18 levels predicted the anti-HIV-1 effect of type 1 IFN-based therapy on PLWH. In vitro, we demonstrated that refractory type 1 IFN responses were transferrable to HIV-1-uninfected target CD4(+) T cells, and this phenomenon was mediated by type 1 IFN from HIV-1-infected cells. Type 1 IFN responses were partially restored by USP18 knockdown. Our findings illuminate a new mechanism by which HIV-1 contributes to innate immune dysfunction in PLWH through the continuous production of type 1 IFN that induces a refractory state of responsiveness.