Human Immunodeficiency Virus-1 Infection and Type 1 Interferon Responses
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Date
2019-09-30
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Johns Hopkins University
Abstract
HIV-1 infects 37 million people worldwide. Despite the success of antiretroviral therapy (ART), there are still several adverse health outcomes in people living with HIV-1 (PLWH). In addition, most PLWH face lifelong therapy as there is no cure. Type 1 interferons (IFN) are broadly-acting cytokines that promote endogenous antiviral activities. Exogenous type 1 IFN-based therapy can control several viral infections, but its efficacy on HIV-1 is limited. Thus, we hypothesized that antiviral responses to exogenous type 1 IFN are dampened during HIV-1 infection. We confirmed the dampened response to exogenous type 1 IFN in total CD4+ T cells from PLWH with uncontrolled viremia (HIV-UC) compared to healthy controls (HC). Surprisingly, type 1 IFN responses in PLWH with ART (HIV-ART) were not fully restored even after a year of virologic suppression. The dampened type 1 IFN response was associated with upregulation of type 1 IFN regulatory genes, particularly USP18. We confirmed the finding in a separate cohort of HIV-1/HCV co-infected persons who were administered pegylated type 1 IFN (PEG-IFN): baseline expression of USP18 was strongly and inversely associated with the induction of antiviral interferon-stimulated genes (ISGs). Moreover, baseline USP18 levels were inversely associated with the subsequent plasma HIV-1 RNA decline. We also demonstrated that the diminished type 1 IFN response can be transferred to HIV-1 uninfected target cells by soluble mediators, particularly by type 1 IFN from HIV-1 infected cells, and knockdown of USP18 can restore the diminished response. Targeting USP18 may represent an alternative approach to improve type 1 IFN responses in PLWH.
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Keywords
HIV-1 infection, type 1 IFN