PRJNA762357
Cross-talk between HIV-1 and TLR agonists
HIV-1 replicates in cells that express a wide array of innate immune sensors and may do so simultaneously with other pathogens. How a coexisting innate immune stimulus influences the outcome of HIV-1 sensing, however, remains poorly understood. Here, we demonstrate that the activation of a second signaling pathway enables a cGAS-dependent type I interferon (IFN-I) response to HIV-1 infection. We used RNA sequencing to determine that HIV-1 alone induced little or no signs of an IFN-I response in THP-1 cells. In contrast, when supplemented with suboptimal levels of bacterial lipopolysaccharide (LPS), HIV-1 infection triggered the production of elevated levels of IFN-I and significant upregulation of interferon-stimulated genes. LPS-mediated enhancement of IFN-I production upon HIV-1 infection, which was observed in primary macrophages, was lost by blocking reverse transcription and with a hyper-stable capsid, pointing to viral DNA being an essential immunostimulatory molecule. LPS also synergistically enhanced IFN-I production by cGAMP, a second messenger of cGAS. These observations suggest that the DNA sensor cGAS is responsible for a type I IFN response to HIV-1 in concert with LPS receptor toll-like receptor (TLR) 4. Small amounts of a TLR2 agonist also cooperate with HIV-1 to induce type I IFN production. These results demonstrate how subtle immunomodulatory activity renders HIV-1 capable of eliciting an IFN-I response through positive cross-talk between cGAS and TLR sensing pathways.