HIV-1 Vpr antagonizes cGAS sensing by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

HIV-1 must replicate in cells that are equipped to defend themselves from infection through the intracellular innate immune system. Hence, HIV-1 evades innate immune sensing through encapsidated DNA synthesis and encodes accessory genes that antagonize specific antiviral effectors. Here we show that the HIV-1 Vpr protein antagonizes the stimulatory effect of a variety of pathogen associated molecular patterns, including cytoplasmic DNA, by inhibiting IRF3 and NF-κB nuclear transport. Both particle associated, and expressed Vpr, antagonized innate immune signaling. Phosphorylation of IRF3 at S396, but not S386, was also inhibited by Vpr. We provide evidence that Vpr interacts with karyopherins and disturbs their recruitment of IRF3 and NF-κB to prevent nuclear transport. Our data demonstrate Vpr rescue of HIV-1 replication in human macrophages from inhibition by cGAMP, the product of activated cGAS. We propose that Vpr inhibition of innate immune activation serves a critical function in promoting HIV-1 replication and transmission.