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

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• HIV infection progressively causes immune dysfunction, leading to AIDS.
• Dendritic cells (DCs) are crucial for HIV spread to CD4+ T cells, causing their depletion.
• Type I interferons (IFNs) are vital in acute infection but cause chronic immune activation and exhaustion in later HIV stages.

Purpose of the Study:

• To investigate the mechanisms of HIV-induced immune dysfunction.
• To elucidate the role of type I IFNs in HIV disease progression.
• To evaluate the therapeutic potential of targeting IFN signaling in HIV.

Main Methods:

• Utilized a dendritic cell (DC) and T cell co-culture model.
• Exposed co-cultures to HIV-1 and analyzed immune cell responses.
• Investigated the involvement of STING and IFNα/β receptor signaling pathways.
• Assessed the efficacy of anifrolumab in restoring immune function.

Main Results:

• HIV exposure impaired T cell proliferation and effector functions in a type I IFN-dependent manner.
• HIV-derived ssDNA activated IFI16/cGAS and STING signaling in DCs, initiating immune impairment.
• Anifrolumab treatment restored DC and T cell functions, including cytokine secretion (IL-2, IFNγ) and granzyme B release.
• Immune impairments in HIV-infected individuals (untreated or ART-treated) are linked to type I IFN effects.

Conclusions:

• Type I IFNs mediate HIV-induced immune dysfunction by negatively impacting DCs and T cells.
• Targeting the IFNα/β receptor with anifrolumab shows promise for immune restoration in HIV.
• Anifrolumab may serve as a valuable combination therapy with ART to improve quality of life for people living with HIV.