Journal article
People with HIV-1 demonstrate type 1 interferon refractoriness associated with upregulated USP18
Journal of virology, Vol.95(10), e01777-20
04/26/2021
DOI: 10.1128/JVI.01777-20
PMCID: PMC8139647
PMID: 33658340
Abstract
HIV-1 infection persists in humans despite expression of antiviral type 1 interferons (IFN). Even exogenous administration of IFNα 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 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
in CD4+ T cells from another cohort of HIV-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 PBMCs, inhibiting
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.
People living with HIV-1 (PLWH) have elevated constitutive expression of type 1 interferons (IFN). However, it is unclear whether this impacts 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.
, 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.
Details
- Title: Subtitle
- People with HIV-1 demonstrate type 1 interferon refractoriness associated with upregulated USP18
- Creators
- Sho Sugawara - Beth Israel Deaconess Medical CenterRamy El-Diwany - Johns Hopkins University School of MedicineLaura K Cohen - Johns Hopkins University School of MedicineKimberly E Rousseau - Johns Hopkins University School of MedicineChristopher Y K Williams - University of CambridgeRebecca T Veenhuis - Johns Hopkins University School of MedicineShruti H Mehta - Johns Hopkins UniversityJoel N Blankson - Johns Hopkins University School of MedicineDavid L Thomas - Johns Hopkins University School of MedicineAndrea L Cox - Johns Hopkins University School of MedicineAshwin Balagopal - Johns Hopkins University School of Medicine
- Resource Type
- Journal article
- Publication Details
- Journal of virology, Vol.95(10), e01777-20
- DOI
- 10.1128/JVI.01777-20
- PMID
- 33658340
- PMCID
- PMC8139647
- NLM abbreviation
- J Virol
- ISSN
- 0022-538X
- eISSN
- 1098-5514
- Grant note
- R01 AI116868 / NIAID NIH HHS R01 AI108403 / NIAID NIH HHS R01 DA016078 / NIDA NIH HHS U19 AI088791 / NIAID NIH HHS U01 DA036297 / NIDA NIH HHS R01 AI140789 / NIAID NIH HHS R37 DA013806 / NIDA NIH HHS P30 AI094189 / NIAID NIH HHS R01 DA013806 / NIDA NIH HHS T32 GM007309 / NIGMS NIH HHS
- Language
- English
- Date published
- 04/26/2021
- Academic Unit
- Surgery
- Record Identifier
- 9984966848102771
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