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Vpx overcomes a SAMHD1-independent block to HIV reverse transcription that is specific to resting CD4 T cells.
Proc. Natl. Acad. Sci. U.S.A. 114, 2729-2734 (2017)
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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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Hiv ; Samhd1 ; Vpx ; Resting Cd4 T Cells ; Restriction Factors
Language
Publication Year
2017
HGF-reported in Year
2017
ISSN (print) / ISBN
0027-8424
e-ISSN
1091-6490
Quellenangaben
Volume: 114,
Issue: 10,
Pages: 2729-2734
Publisher
National Academy of Sciences
Reviewing status
Peer reviewed
Institute(s)
Institute of Virology (VIRO)
POF-Topic(s)
30203 - Molecular Targets and Therapies
Research field(s)
Immune Response and Infection
PSP Element(s)
G-554300-001
WOS ID
WOS:000395511400090
Scopus ID
85014681285
PubMed ID
28228523
Erfassungsdatum
2018-02-21