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

Hanna Mari Baldauf, Lena Stegmann, Sarah Marie Schwarz, Ina Ambiel, Maud Trotard, Margarethe Martin, Manja Burggraf, Gina M. Lenzi, Helena Lejk, Xiaoyu Pan, Oliver I. Fregoso, Efrem S. Lim, Libin Abraham, Laura A. Nguyen, Frank Rutsch, Renate König, Baek Kim, Michael Emerman, Oliver T. Fackler, Oliver T. Keppler

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2729-2734
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number10
DOIs
StatePublished - Mar 7 2017

Keywords

  • HIV
  • Resting CD4 T cells
  • Restriction factors
  • SAMHD1
  • Vpx

ASJC Scopus subject areas

  • General

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    Baldauf, H. M., Stegmann, L., Schwarz, S. M., Ambiel, I., Trotard, M., Martin, M., Burggraf, M., Lenzi, G. M., Lejk, H., Pan, X., Fregoso, O. I., Lim, E. S., Abraham, L., Nguyen, L. A., Rutsch, F., König, R., Kim, B., Emerman, M., Fackler, O. T., & Keppler, O. T. (2017). Vpx overcomes a SAMHD1-independent block to HIV reverse transcription that is specific to resting CD4 T cells. Proceedings of the National Academy of Sciences of the United States of America, 114(10), 2729-2734. https://doi.org/10.1073/pnas.1613635114