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Vpx overcomes a SAMHD1-independent block to HIV reverse transcription that is specific to resting CD4 T cells.

Vpx overcomes a SAMHD1-independent block to HIV reverse transcription that is specific to resting CD4 T cells.
Author Information (click to view)

Baldauf HM, Stegmann L, Schwarz SM, Ambiel I, Trotard M, Martin M, Burggraf M, Lenzi GM, Lejk H, Pan X, Fregoso OI, Lim ES, Abraham L, Nguyen LA, Rutsch F, König R, Kim B, Emerman M, Fackler OT, Keppler OT,


Baldauf HM, Stegmann L, Schwarz SM, Ambiel I, Trotard M, Martin M, Burggraf M, Lenzi GM, Lejk H, Pan X, Fregoso OI, Lim ES, Abraham L, Nguyen LA, Rutsch F, König R, Kim B, Emerman M, Fackler OT, Keppler OT, (click to view)

Baldauf HM, Stegmann L, Schwarz SM, Ambiel I, Trotard M, Martin M, Burggraf M, Lenzi GM, Lejk H, Pan X, Fregoso OI, Lim ES, Abraham L, Nguyen LA, Rutsch F, König R, Kim B, Emerman M, Fackler OT, Keppler OT,

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Proceedings of the National Academy of Sciences of the United States of America 2017 02 22() pii 10.1073/pnas.1613635114

Abstract

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.

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