HIV-1 derived replication intermediates/oligonucleotides induce a type I IFN-dependent immune suppression via STING activation that can be restored by targeting IFNARI

Abstract

The hallmark of HIV-1 infection is the progressive development of multicellular and systemic immune dysfunction, culminating in AIDS. Dendritic cells (DCs) play a pivotal role in HIV dissemination to CD4+ T cells, which are subsequently depleted by the virus leading to HIV disease progression. Type I interferons (IFNs) are critical for host defense during acute infection but contribute to chronic immune activation during the later stages of HIV disease. This persistent activation leads to immune cell exhaustion. HIV-1 can activate type I IFN responses via several pathways, including the STING pathway, which is activated by e.g., virus-derived oligonucleotides. Here, we investigated the underlying mechanisms creating HIV-1-mediated immune dysfunction and role of type I IFNs using a DC and T cell co-culture model. HIV-1 exposure in the DC-T cell co-culture promoted the expansion of suppressive T cells with diminished proliferation and effector functions. The impairment required type I IFNs and subsequent IFN-/{beta} receptor signaling, initiated by HIV-derived ssDNA activation of IFI16/cGAS followed by STING signaling in the DCs. Targeting IFNAR1 with Anifrolumab restored the immune functions of both DCs and T cells, as well as T cell proliferation and T cell effector functions, including their secretion of IL-2, IFN-{gamma}, and granzyme B. Our findings support that the immune impairments existing in untreated or antiretroviral therapy (ART) treated HIV-infected individuals are mediated, if not fully in part by type I IFNs negative effect on DC and T cells. Therapeutics targeting IFN-/{beta} receptors, such as Anifrolumab, hold potential as combination treatment alongside ART, to achieve a more complete immune restoration and contribute to improved quality of life among people living with HIV.