SAMHD1 Has Differential Impact on the Efficacies of HIV Nucleoside Reverse Transcriptase Inhibitors

Huber, Andrew D.; Michailidis, Eleftherios; Schultz, Megan L.; Ong, Yee Tsuey; Bloch, Nicolin; Puray-Chavez, Maritza; Leslie, Maxwell D.; Ji, Juan; Lucas, Anthony D.; Kirby, Karen A.; Landau, Nathaniel R.; Sarafianos, Stefan G.

doi:10.1128/aac.02745-14

Cited by 25 publications

(39 citation statements)

References 61 publications

(81 reference statements)

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“…Lack of antiviral potency for NRTI has already been suggested after SAMHD1 degradation (18). In line with our results, SAMHD1 has been associated to a differential efficacy of NRTI (28), although differences were found in all analogs tested in macrophages but not in activated T cells (18) or in the THP1 cell line (18,28). In contrast, our work uses an extended panel of NRTI as well as relevant controls such as NNRTI and the integrase inhibitor raltegravir, which allow us to better demonstrate the specificity of the effect.…”

Section: Discussionsupporting

confidence: 80%

“…Considering that SAMHD1 is not able to efficiently hydrolyze NRTI (18,28) and the observation that exogenous addition of nucleosides mimicked SAMHD1 activity, our results are in accordance with the idea that reduced efficacy of thymidine analogs observed upon degradation of SAMHD1 may be the result of direct competition with increased intracellular dNTPs ( Fig. 2 and 3) (18) but not to the NRTI activation pathway (28).…”

Section: Discussionsupporting

confidence: 80%

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SAMHD1 Specifically Affects the Antiviral Potency of Thymidine Analog HIV Reverse Transcriptase Inhibitors

Ballana

Badía

Terradas

et al. 2014

Antimicrob Agents Chemother

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bSterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase recently recognized as an antiviral factor that acts by depleting dNTP availability for viral reverse transcriptase (RT). SAMHD1 restriction is counteracted by the human immunodeficiency virus type 2 (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 (NRTI), one of the most common agents used in antiretroviral therapy, compete with intracellular dNTPs as the 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 monocytederived macrophages and CD4؉ T cells infected with HIV-1 with or without Vpx. No changes in sensitivity to non-NRTI or the integrase inhibitor raltegravir were observed, but for NRTI, sensitivity significantly changed only in the case of the thymidine analogs (AZT and d4T). The addition of exogenous thymidine mimicked the change in viral sensitivity observed after Vpx-mediated SAMHD1 degradation, pointing toward 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 the HIV-2⌬Vpx strain. In conclusion, reduction of SAMHD1 levels significantly decreases HIV sensitivity to thymidine but not other nucleotide RT analog inhibitors in both macrophages and lymphocytes. Sterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) is a recently identified human immunodeficiency virus type 1 (HIV-1) host restriction factor that limits retroviral replication at the reverse transcription stage of the viral life cycle (1-5). SAMHD1 functions as a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that regulates the intracellular pool of dNTPs (6). It restricts HIV-1 infection in immune cells of myeloid lineage and in quiescent CD4-positive T lymphocytes (1, 2, 4). SAMHD1 reduces cellular dNTP levels to concentrations below the threshold required for reverse transcription of the viral RNA genome into DNA (4, 5). SAMHD1 is counteracted by the retroviral Vpx protein that is encoded by simian immunodeficiency virus (SIV) and HIV-2, but this gene is lacking from the HIV-1 and feline immunodeficiency virus (FIV) genomes (7). However, and despite the lack of Vpx function, HIV-1 is still able to replicate in noncycling myeloid cells, albeit at low levels (7).Most current standard three-drug antiretroviral regimens involve RT inhibitors combined with a protease inhibitor. [EFV], and etravirine). NRTI are phosphorylated to their triphosphate form to act as competitive inhibitors of HIV RT. In contrast, NNRTI bind at...

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 80%

SAMHD1 Specifically Affects the Antiviral Potency of Thymidine Analog HIV Reverse Transcriptase Inhibitors

Ballana

Badía

Terradas

et al. 2014

Antimicrob Agents Chemother

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“…In addition, it is possible that the promiscuous dNTPase activity of SAMHD1 could also degrade the active triphosphate forms of some antiviral and anticancer nucleoside drugs, which has not been thoroughly explored. 19 …”

Section: Resultsmentioning

confidence: 99%

“…18 SAMHD1 expression also increases the efficacy of nucleoside drugs that are used to treat viral infections and cancer, likely by decreasing the concentration of competing intracellular dNTPs. 19 …”

Section: Introductionmentioning

confidence: 99%

A High-Throughput Enzyme-Coupled Assay for SAMHD1 dNTPase

Seamon

Stivers

2015

SLAS Discovery

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Sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) is a recently discovered enzyme that plays a central role in nucleotide metabolism and innate immunity. SAMHD1 has deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase activity that depletes the dNTP substrates required for DNA synthesis in cells. The involvement of SAMHD1 in biological processes as varied as viral restriction, endogenous retroelement control, cancer, and modulation of anticancer/antiviral nucleoside drug efficacy makes it a valuable target for the development of small-molecule inhibitors. We report a high-throughput colorimetric assay for SAMHD1 dNTP hydrolase activity that takes advantage of Escherichia coli inorganic pyrophosphatase to convert PPPi to 3 Pi. The assay was validated by screening a library of 2653 clinically used compounds. Fifteen primary hits were obtained (0.57% hit rate); 80% of these were confirmed in a direct secondary assay for dNTP hydrolysis. The zinc salt of the antibiotic cephalosporin C was a potent inhibitor of SAMHD1 with an IC50 of 1.1 ± 0.1 μM, and this inhibition was largely attributable to the presence of zinc. The assay also screened a targeted library of nucleosides and their analogs, revealing that the antiviral drug acycloguanosine (acyclovir) is an inhibitor possessing excellent properties for future fragment-based drug development efforts.

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“…This minimizes the efficacy of the treatment to such an extent that SAMHD1 expression levels were negatively correlated with Ara-C treatment success in individuals with AML. Additionally, SAMHD1 appears to reduce the efficacy of thymidine based analogs used to treat HIV, and depletion of SAMHD1 from monocyte cells affects the susceptibility of HIV-1 infections to nucleoside reverse transcriptase inhibitors (79, 213, 214). Based on these finding, the development of a robust SAMHD1 inhibitor that can potentiate nucleotide analogue therapeutic regimens should become a priority for SAMHD1 researchers.…”

Section: Samhd1 Mutations Results In Diseasementioning

confidence: 99%

SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

Mauney

Hollis

2018

Autoimmunity

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SAMHD1 is a deoxynucleotide triphosphate (dNTP) hydrolase that plays an important role in the homeostatic balance of cellular dNTPs. Its emerging role as an effector of innate immunity is affirmed by mutations in the SAMHD1 gene that cause the severe autoimmune disease, Aicardi-Goutieres syndrome (AGS) and that are linked to cancer. Additionally, SAMHD1 functions as a restriction factor for retroviruses such as HIV. Here we review the current biochemical and biological properties of the enzyme including its structure, activity, and regulation by post-translational modifications in the context of its cellular function. We outline open questions regarding the biology of SAMHD1 whose answers will be important for understanding its function as a regulator of cell cycle progression, genomic integrity, and in autoimmunity.

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SAMHD1 Has Differential Impact on the Efficacies of HIV Nucleoside Reverse Transcriptase Inhibitors

Cited by 25 publications

References 61 publications

SAMHD1 Specifically Affects the Antiviral Potency of Thymidine Analog HIV Reverse Transcriptase Inhibitors

SAMHD1 Specifically Affects the Antiviral Potency of Thymidine Analog HIV Reverse Transcriptase Inhibitors

A High-Throughput Enzyme-Coupled Assay for SAMHD1 dNTPase

SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

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