HIV-2/SIV Vpx targets a novel functional domain of STING to selectively inhibit cGAS–STING-mediated NF-κB signalling

Innate immunity is the first line of host defence against pathogens. Suppression of innate immune responses is essential for the survival of all viruses. However, the interplay between innate immunity and HIV/SIV is only poorly characterized. We have discovered Vpx as a novel inhibitor of innate immune activation that associates with STING signalosomes and interferes with the nuclear translocation of NF-κB and the induction of innate immune genes. This new function of Vpx could be separated from its role in mediating degradation of the antiviral factor SAMHD1, and is conserved among diverse HIV-2/SIV Vpx. Vpx selectively suppressed cGAS–STING-mediated nuclear factor-κB signalling. Furthermore, Vpx and Vpr had complementary activities against cGAS–STING activity. Since SIVMAC lacking both Vpx and Vpr was less pathogenic than SIV deficient for Vpr or Vpx alone, suppression of innate immunity by HIV/SIV is probably a key pathogenic determinant, making it a promising target for intervention. Depletion of SAMHD1 has been shown to generate DNA damage and trigger cGAS–STING-mediated immunity. How HIV-2 and SIV bypass this activation, given Vpx-mediated depletion of SAMHD1, is unknown. Vpx is now shown to efficiently inhibit cGAS–STING-induced innate immunity through association with a new STING domain.