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SAMHD1 Impairs HIV-1 Gene Expression and Reactivation of Viral Latency in CD4+ T-cells

Jenna M. Antonucci, Sun Hee Kim, Corine St. Gelais, Serena Bonifati, Olga Buzovetsky, Kirsten Knecht, Alice A. Duchon, Yong Xiong, Karin M Musier-Forsyth, View ORCID ProfileLi Wu
doi: https://doi.org/10.1101/270843
Jenna M. Antonucci
The Ohio State University;
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Sun Hee Kim
The Ohio State University;
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Corine St. Gelais
The Ohio State University;
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Serena Bonifati
The Ohio State University;
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Olga Buzovetsky
Yale University
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Kirsten Knecht
Yale University
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Alice A. Duchon
The Ohio State University;
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Yong Xiong
Yale University
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Karin M Musier-Forsyth
The Ohio State University;
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Li Wu
The Ohio State University;
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  • For correspondence: wu.840@osu.edu
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Abstract

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) restricts human immunodeficiency virus type 1 (HIV-1) replication in non-dividing cells by degrading intracellular deoxynucleoside triphosphates (dNTPs). SAMHD1 is highly expressed in resting CD4+ T-cells that are important for the HIV-1 reservoir and viral latency; however, whether SAMHD1 affects HIV-1 latency is unknown. Recombinant SAMHD1 binds HIV-1 DNA or RNA fragments in vitro, but the function of this binding remains unclear. Here we investigate the effect of SAMHD1 on HIV-1 gene expression and reactivation of viral latency. We found that endogenous SAMHD1 impaired HIV-1 LTR activity in monocytic THP-1 cells and HIV-1 reactivation in latently infected primary CD4+ T-cells. Overexpression of wild-type (WT) SAMHD1 suppressed HIV-1 long terminal repeat (LTR)-driven gene expression at the level of transcription. SAMHD1 overexpression also suppressed LTR activity from human T-cell leukemia virus type 1 (HTLV-1), but not from murine leukemia virus (MLV), suggesting specific suppression of retroviral LTR-driven gene expression. WT SAMHD1 bound to proviral DNA and impaired reactivation of HIV-1 gene expression in latently infected J-Lat cells. In contrast, a nonphosphorylated mutant (T592A) and a dNTP triphosphohydrolase (dNTPase) inactive mutant (H206D/R207N, or HD/RN) of SAMHD1 failed to efficiently suppress HIV-1 LTR-driven gene expression and reactivation of latent virus. Purified recombinant WT SAMHD1, but not T592A and HD/RN mutants, bound to fragments of the HIV-1 LTR in vitro. These findings suggest that SAMHD1-mediated suppression of HIV-1 LTR-driven gene expression contributes to regulation of viral latency in CD4+ T-cells.

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Posted February 23, 2018.
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SAMHD1 Impairs HIV-1 Gene Expression and Reactivation of Viral Latency in CD4+ T-cells
Jenna M. Antonucci, Sun Hee Kim, Corine St. Gelais, Serena Bonifati, Olga Buzovetsky, Kirsten Knecht, Alice A. Duchon, Yong Xiong, Karin M Musier-Forsyth, Li Wu
bioRxiv 270843; doi: https://doi.org/10.1101/270843
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SAMHD1 Impairs HIV-1 Gene Expression and Reactivation of Viral Latency in CD4+ T-cells
Jenna M. Antonucci, Sun Hee Kim, Corine St. Gelais, Serena Bonifati, Olga Buzovetsky, Kirsten Knecht, Alice A. Duchon, Yong Xiong, Karin M Musier-Forsyth, Li Wu
bioRxiv 270843; doi: https://doi.org/10.1101/270843

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