title: SAMHD1 specifically affects the antiviral potency of thymidine analog HIV reverse transcriptase inhibitors.
abstract: Sterile 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 monocyte-derived 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-2ΔVpx 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.
authors.affiliation: AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Ballana
authors.affiliation: AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Badia
authors.affiliation: AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Gerard
authors.initials: G
authors.lastname: Terradas
authors.affiliation: Research Group on Neuromuscular and Mitochondrial Disorders, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Torres-Torronteras
authors.affiliation: AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Ruiz
authors.affiliation: AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pauls
authors.affiliation: AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Riveira-Muñoz
authors.affiliation: AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.affiliation: Research Group on Neuromuscular and Mitochondrial Disorders, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Martí
authors.affiliation: AIDS Research Institute-IrsiCaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain jaeste@irsicaixa.es.
authors.forename: José A
authors.initials: JA
authors.lastname: Esté
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D015870:Gene Expression; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015498:HIV-2 / Q000187:drug effects* / Q000201:enzymology; D054884:Host-Pathogen Interactions; D006801:Humans; D019169:Jurkat Cells; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D000076106:SAM Domain and HD Domain-Containing Protein 1; D018119:Stavudine / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology*
chemical_list: D018894:Reverse Transcriptase Inhibitors; C074286:VPX protein, Human immunodeficiency virus 2; D054334:Viral Regulatory and Accessory Proteins; D015215:Zidovudine; D018119:Stavudine; D054303:HIV Reverse Transcriptase; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins; D013936:Thymidine