Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein

Abstract

Macrophages and dendritic cells play key roles in viral infections, providing virus reservoirs that frequently resist anti-viral therapies and linking innate virus detection to anti-viral adaptive immune responses ^{1, 2} . HIV-1 fails to transduce dendritic cells and has a reduced ability to transduce macrophages, due to an as yet uncharacterized mechanism that inhibits infection by interfering with efficient synthesis of viral cDNA ^{3, 4} . In contrast, HIV-2 and related simian immunodeficiency viruses (SIVsm/mac) transduce myeloid cells efficiently owing to their virion-associated Vpx accessory proteins, which counteract the restrictive mechanism ^{5, 6} . Here we show that the inhibition of HIV-1 infection in macrophages involves the cellular SAM domain HD domain-containing protein 1 (SAMHD1). Vpx relieves the inhibition of lentivirus infection in macrophages by loading SAMHD1 onto the CRL4 ^DCAF1 E3 ubiquitin ligase, leading to highly efficient proteasome-dependent degradation of the protein. Mutations in SAMHD1 cause Aicardi-Goutieres syndrome (AGS), a disease that produces a phenotype that mimics the effects of a congenital viral infection ^{7, 8} . Failure to dispose of endogenous nucleic acid debris in AGS results in inappropriate triggering of innate immune responses via cytosolic nucleic acids sensors ^{9, 10} . Thus, our findings reveal that macrophages are defended from HIV-1 infection by a mechanism that prevents an unwanted interferon response triggered by self nucleic acids, and uncover an intricate relationship between innate immune mechanisms that control response to self and to retroviral pathogens.