NDLI: Host SAMHD1 Protein Promotes HIV-1 Recombination in Macrophages

Content Provider	Journal of Biological Chemistry (JBC)
Author	Nguyen, Laura A. Kim, Dong-Hyun Daly, Michele B. Allan, Kevin C. Kim, Baek
Abstract	Template switching can occur during the reverse transcription of HIV-1. Deoxynucleotide triphosphate (dNTP) concentrations have been biochemically shown to impact HIV-1 reverse transcriptase (RT)-mediated strand transfer. Lowering the dNTP concentrations promotes RT pausing and RNA template degradation by RNase H activity of the RT, subsequently leading to strand transfer. Terminally differentiated/nondividing macrophages, which serve as a key HIV-1 reservoir, contain extremely low dNTP concentrations (20–50 nm), which results from the cellular dNTP hydrolyzing sterile α motif and histidine aspartic domain containing protein 1 (SAMHD1) protein, when compared with activated CD4+ T cells (2–5 μm). In this study, we first observed that HIV-1 template switching efficiency was nearly doubled in human primary macrophages when compared with activated CD4+ T cells. Second, SAMHD1 degradation by viral protein X (Vpx), which elevates cellular dNTP concentrations, decreased HIV-1 template switching efficiency in macrophages to the levels comparable with CD4+ T cells. Third, differentiated SAMHD1 shRNA THP-1 cells have a 2-fold increase in HIV-1 template switching efficiency. Fourth, SAMHD1 degradation by Vpx did not alter HIV-1 template switching efficiency in activated CD4+ T cells. Finally, the HIV-1 V148I RT mutant that is defective in dNTP binding and has DNA synthesis delay promoted RT stand transfer when compared with wild type RT, particularly at low dNTP concentrations. Here, we report that SAMHD1 regulation of the dNTP concentrations influences HIV-1 template switching efficiency, particularly in macrophages.
Related Links	http://www.jbc.org/content/289/5/2489.abstract
Ending Page	2496
Starting Page	2489
Page Count	8
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	5
Volume Number	289
DOI	10.1074/jbc.C113.522326
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2014-01-31
Access Restriction	Open
Subject Keyword	HIV-1 Homologous Recombination Macrophages Nucleotide Reverse Transcription SAMHD1 Vpx DNA and Chromosomes
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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