Anti-HIV Host Factor SAMHD1 Regulates Viral Sensitivity to Nucleoside Reverse Transcriptase Inhibitors via Modulation of Cellular Deoxyribonucleoside Triphosphate (dNTP) Levels

University of Rochester Medical Center, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2013; 288(28). DOI: 10.1074/jbc.M113.472159
Source: PubMed

ABSTRACT Newly identified anti-HIV host factor, SAMHD1, restricts replication of lentiviruses such as HIV-1, HIV-2, and SIV in macrophages by enzymatically hydrolyzing and depleting cellular dNTPs, which are the substrates of viral DNA polymerases. HIV-2 and some SIVs express Vpx, which counteracts SAMHD1 and elevates cellular dNTPs, enhancing viral replication in macrophages. Since nucleoside reverse transcriptase inhibitors (NRTIs), the most commonly used anti-HIV drugs, compete against cellular dNTPs for incorporation into proviral DNA, we tested whether SAMHD1 directly affects the efficacy of NRTIs in inhibiting HIV-1. We found that reduction of SAMHD1 levels with the use of virus-like particles (VLPs) expressing Vpx and SAMHD1 specific shRNA, subsequently elevates cellular dNTPs and significantly decreases HIV-1 sensitivity to various NRTIs in macrophages. However, VLP +Vpx treatment of activated CD4+ T cells only minimally reduced NRTI efficacy. Furthermore, our HPLC-based assay could not detect SAMHD1-mediated hydrolysis of various NRTI-triphosphates tested in this study, suggesting that the reduced sensitivity of HIV-1 to NRTIs upon SAMHD1 degradation is most likely caused by the elevation of the cellular dNTP levels.

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    • "For instance, SAMHD1 expression limits the synthesis of HIV-1 provirus of macrophages in vitro [40] [45] [46] [48], yet this cell type can serve as a viral reservoir in vivo [118] [119]. One in vitro study reported that the removal of SAMHD1 significantly reduced azidothymidine-mediated restriction of HIV-1 replication in MDM [53], suggesting that SAMHD1 may play a role in enhancing the effects of antiretroviral therapy during HIV-1 infection. A recent in vivo study reported that SAMHD1-deficient mice were not more susceptible to HIV-1 infection but were susceptible to a mutant virus that had a lower affinity for dNTP [120]. "
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