Abstract
HIV-1 infection persists in humans despite expression of antiviral type 1 interferons (IFN). Even exogenous administration of IFNa 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 CD41 and CD81 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-α2b 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.
Original language | English (US) |
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Article number | e01777-20 |
Journal | Journal of virology |
Volume | 95 |
Issue number | 10 |
DOIs | |
State | Published - May 2021 |
Keywords
- HIV-1
- Innate immunity
- Type 1 IFN
ASJC Scopus subject areas
- Microbiology
- Immunology
- Insect Science
- Virology