Human Immunodeficiency Virus Type 2 Vpx-mediated Degradation of TASOR Activates Innate Immune Sensing of Nucleic Acids in Infected Cells

The HIV-2/SIV_sm lineage of lentiviruses encodes for Vpx, which is a virus-associated protein that is absent from HIV-1. Vpx enhances HIV-2 replication by degrading host proteins that possess antiviral activity. For example, Vpx is known to degrade the host dNTPase SAMHD1 (which reduces dNTP levels to inhibit viral DNA synthesis in macrophages) and components of the epigenetic regulator complex HUSH (where degradation enhances proviral gene expression and viral replication). Here, we used a transcriptomic analysis to investigate host gene expression response to HIV-2 infection of THP-1 cells in the presence and absence of Vpx. Analysis of HIV-2 WT and ΔVpx infected cells revealed an increase of gene expression of several interferon stimulating genes (ISGs), with an increase in ISG expression in HIV-2 WT infected cells relative to that of HIV-2 ΔVpx infected cells. Analysis of Vpx mutants implicated that Vpx-mediated induction of ISG expression was due to Vpx-mediated degradation of TASOR, one protein of the HUSH complex. Based upon these observations, we sought to determine whether Vpx-mediated degradation of TASOR and subsequent inhibition of HUSH complex activity induces ISG expression. We found that TASOR degradation by Vpx led to increased LINE-1 activity. Furthermore, we found that Vpx-mediated ISG induction relied on both RNA sensing that was mediated by MAVS signaling and DNA sensing mediated by cGAS/STING signaling. Taken together, these findings support a model in which Vpx-mediated inhibition of the HUSH complex is a key variable how Vpx affects the host response to HIV-2 replication in monocytic cells.