Role of viral protein R in infection of human dendritic cells by primate lentiviruses
Miller, Caitlin Michelle
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Viral protein R (Vpr) is an evolutionarily conserved but poorly understood protein encoded by all primate lentiviruses, including the lineages that gave rise to both human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2), the causative agents of AIDS in humans. In this work, I sought to define the contribution of primate lentiviral Vpr to viral replication and evasion from cell-intrinsic antiviral defenses. I found that HIV-1 infection of human dendritic cells (MDDCs) is substantially attenuated upon infection with Vpr-deficient (HIV-1/ΔVpr) virus compared to wild-type (WT) infection. This replication defect to HIV-1/ΔVpr is evident in a single round of infection, results in reduced levels of viral transcription, and is relieved upon complementation by virion-associated Vpr. The block to transcription is alleviated through Vpr-engagement with the Cul4A/DCAF/DDB1 (DCAFCRL4) ubiquitin ligase complex and a yet-to-be identified host factor, hypothesized to induce the DNA damage response (DDR) in infected cells. MDDCs are critical immune cells that are poised to detect invading viruses through a variety of cell-intrinsic antiviral sensors, resulting in the production of type I interferon (IFN) and restriction of virus replication. Surprisingly, infection of MDDCs with Vpr-deficient lentiviruses (HIV-2 or SIVmac) resulted in production of type I IFN indicating that this pathway is targeted by Vpr. I determined that signaling cascades that induce NF-κB-dependent type I IFN production are triggered in response to lentiviral integration, an obligatory process in lentivirus life cycle that results in host DNA lesions and subsequent repair by cellular DNA repair machinery. I also demonstrated that mutations in SIVmac Vpr that ablate the ability to initiate DDR are unable to counteract the antiviral type I IFN response. Together, our work suggests the existence of a novel host factor that detects lentiviral integration in MDDCs to trigger an innate immune response that blocks virus dissemination. I hypothesize that Vpr by overcoming this cell intrinsic block to integration would be a critical viral adaptation to facilitate cross-species transmission that resulted in the HIV pandemic.
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