SAMHD1 specifically affects the antiviral potency of thymidine analog HIV reverse transcriptase inhibitors


Ester Ballana, Roger Badia, Gerard Terradas, Javier Torres-Torronteras, Alba Ruiz, Eduardo Pauls, Eva Riveira-Muñoz, Bonaventura Clotet, Ramón Martí and José A. Esté. Antimicrob Agents Chemother. 2014 Aug;58(8):4804-4813


SAMHD1 is a dNTP triphophohydrolase recently been recognized as an antiviral factor that acts by depleting dNTP availability for viral reverse transcriptase. SAMHD1 restriction is counteracted by the HIV-2 accessory protein Vpx, which targets SAMHD1 for proteosomal degradation, resulting in an increased availability of dNTPs and consequently enhanced viral replication. Nucleoside reverse transcriptase inhibitors (NRTIs), one of the most commonly agents used in antiretroviral therapy, compete with intracellular dNTPs as substrate for viral RT. Consequently, SAMHD1 activity may be influencing NRTI efficacy in inhibiting viral replication. Here, a panel of different RT inhibitors was analyzed for their different antiviral efficacy depending on SAMHD1. Antiviral potency was measured for all the inhibitors in transformed cell lines and primary monocyte-derived macrophages and CD4+ T cells infected with HIV-1 with or without Vpx. No changes in sensitivity to non-NRTIs or the integrase inhibitor raltegravir were observed, but for NRTIs, sensitivity significantly changed only in the case of the thymidine analogs (AZT and d4T). Addition of exogenous thymidine mimicked the change in viral sensitivity observed after Vpx-mediated SAMHD1 degradation pointing towards a differential effect of SAMHD1 activity on thymidine. Accordingly, sensitivity to AZT was also reduced in CD4+ T cells infected with HIV-2 compared to infection with HIV-2 ΔVpx. In conclusion, reduction of SAMHD1 levels significantly decreases HIV sensitivity to thymidine but not other nucleotide RT analog inhibitors in both macrophages and lymphocytes.


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Ester Ballana, Roger Badia, Gerard Terradas, Javier Torres-Torronteras, Alba Ruiz, Eduardo Pauls, Eva Riveira-Muñoz, Bonaventura Clotet, Ramón Martí and José A. Esté


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Grupos de IrsiCaixa vinculados: Patogénesis del VIH