STINGing CD4+T cells to induce refractoriness to HIV infection

Abstract HIV rapidly infects CD4+ T cells where it can establish latent infection. Identifying immune mechanisms which can render CD4+ T cells refractory to infection represents a critical step in limiting infection and viral spread. Using purified memory CD4+ T cells from healthy donors, we found that activation of the STING signaling pathway with 0.5 mM of the STING agonist diABZI was sufficient to induce a state of refractoriness to in vitro HIV infection in memory CD4+ T cells, a major source of the HIV reservoir. We observed that STING activation in CD4+ T cells induces Type I IFN production and activates p-IRF3. CRISPR KD of STING in memory CD4+ T cells led to a significant increase in HIV infection, demonstrating a cell intrinsic role for STING signaling in limiting HIV infection/replication. Using proteomics, we identified that diABZI significantly and potently induces restriction factors and proteins involved in antiviral immunity and Type 1 IFN signaling. Importantly, proteins that were significantly reduced mapped to pathways including RNA processing and protein translation which are aspects of the host machinery which HIV needs to co-opt to replicate and produce infectious virions. Our data provide mechanistic insight into the STING pathway as a means to render CD4+ T cells refractory to HIV infection and highlights that this pathway lands a “1–2” punch by increasing expression of antiviral proteins that directly target the virus while suppressing the cellular machinery needed for the viral life cycle. The potential to use a STING agonist as a post-exposure therapeutic which directly limits viral infection while promoting global antiviral immunity represents a novel strategy that may stop HIV infection in its tracks.