OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA , 114 ( 10 ) ISSN 0027-8424

Significance HIV infection can be restricted by different host cell proteins. One such restriction factor is SAM domain and HD domain-containing protein 1 (SAMHD1), a triphosphohydrolase that cleaves dNTPs, which are required for HIV reverse transcription. The accessory lentiviral protein X (Vpx) from simian immunodeficiency viruses (SIV) of sooty mangabeys and rhesus macaques or from HIV-2 degrade SAMHD1. Here we show that Vpx proteins from SIVs of red-capped mangabeys and mandrills enhance HIV infection of resting CD4 T cells, but not macrophages, without affecting levels of either SAMHD1 or dNTPs. These Vpx proteins overcome a previously unrecognized SAMHD1-independent, cell-type–specific restriction at the level of reverse transcription and highlight the plasticity of lentiviruses to counteract the innate immune system. Early after entry into monocytes, macrophages, dendritic cells, and resting CD4 T cells, HIV encounters a block, limiting reverse transcription (RT) of the incoming viral RNA genome. In this context, dNTP triphosphohydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) has been identified as a restriction factor, lowering the concentration of dNTP substrates to limit RT. The accessory lentiviral protein X (Vpx) proteins from the major simian immunodeficiency virus of rhesus macaque, sooty mangabey, and HIV-2 (SIVsmm/SIVmac/HIV-2) lineage packaged into virions target SAMHD1 for proteasomal degradation, increase intracellular dNTP pools, and facilitate HIV cDNA synthesis. We find that virion-packaged Vpx proteins from a second SIV lineage, SIV of red-capped mangabeys or mandrills (SIVrcm/mnd-2), increased HIV infection in resting CD4 T cells, but not in macrophages, and, unexpectedly, acted in the absence of SAMHD1 degradation, dNTP pool elevation, or changes in SAMHD1 phosphorylation. Vpx rcm/mnd-2 virion incorporation resulted in a dramatic increase of HIV-1 RT intermediates and viral cDNA in infected resting CD4 T cells. These analyses also revealed a barrier limiting HIV-1 infection of resting CD4 T cells at the level of nuclear import. Single amino acid changes in the SAMHD1-degrading Vpx mac239 allowed it to enhance early postentry steps in a Vpx rcm/mnd-2–like fashion. Moreover, Vpx enhanced HIV-1 infection of SAMHD1-deficient resting CD4 T cells of a patient with Aicardi-Goutières syndrome. These results indicate that Vpx, in addition to SAMHD1, overcomes a previously unappreciated restriction for lentiviruses at the level of RT that acts independently of dNTP concentrations and is specific to resting CD4 T cells.