# HIV-1 derived oligonucleotides induce a type I IFN/STING dependent immune suppression reversible by targeting IFNARI

## TL;DR

HIV-1 causes immune dysfunction by triggering type I interferon signaling, which can be reversed by blocking IFNAR1 with anifrolumab.

## Contribution

Identifies a novel mechanism of HIV-induced immune suppression via STING pathway activation and demonstrates reversal using IFNAR1 targeting.

## Key findings

- HIV-derived ssDNA activates STING in dendritic cells, leading to type I IFN production and suppressive T cell expansion.
- Blocking IFNAR1 with anifrolumab restores immune cell function and cytokine secretion in co-cultures.
- Persistent type I IFN signaling contributes to immune dysfunction in HIV-1 infection.

## Abstract

The hallmark of HIV-1 (HIV) 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 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-mediated immune dysfunction and role of type I IFNs using a DC and T cell co-culture model. HIV 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 IFNα/β receptor signaling, and our data indicate that this was 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, IFNγ, 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 IFN’s negative effect on DC and T cells. Therapeutics targeting IFNα/β 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.

HIV-1 infection causes progressive immune dysfunction that leads to AIDS. Dendritic cells (DCs) play a central role in spreading HIV to CD4 ⁺ T cells, which are subsequently depleted. Type I interferons (IFNs) are vital for antiviral defense during acute infection, but chronic activation of this pathway contributes to immune exhaustion and dysfunction. In this study, we investigated how HIV-1 triggers type I IFN signaling and impairs immune responses using a DC–T cell co-culture model. We found that HIV and HIV derived ss DNA activates the STING pathway in DCs, inducing type I IFN production that drives the expansion of suppressive T cells with reduced proliferation and effector function. Blocking IFN-α/β receptor (IFNAR1) signaling with the monoclonal antibody Anifrolumab restored DC and T cell functions, enhancing proliferation and cytokine secretion. These findings reveal that persistent type I IFN signaling contributes to immune dysfunction in HIV-1 infection and highlight IFNAR-targeting therapies as promising adjuncts to antiretroviral treatment to promote immune restoration.