title: Differential regulatory activities of viral protein X for anti-viral efficacy of nucleos(t)ide reverse transcriptase inhibitors in monocyte-derived macrophages and activated CD4(+) T cells.
abstract: Vpx encoded by HIV-2 and SIVsm enhances retroviral reverse transcription in macrophages in vitro by mediating the degradation of the host SAMHD1 protein that hydrolyzes dNTPs and by elevating cellular dNTP levels. Here we employed RT-SHIV constructs (SIV encoding HIV-1 RT) to investigate the contribution of Vpx to the potency of NRTIs, which compete against dNTPs, in monocyte-derived macrophages (MDMs) and activated CD4(+) T cells. Relative to HIV-1, both SIV and RT-SHIV exhibited reduced sensitivities to AZT, 3TC and TDF in MDMs but not in activated CD4(+) T cells. However, when SIV and RT-SHIV constructs not coding for Vpx were utilized, we observed greater sensitivities to all NRTIs tested using activated CD4(+) T cells relative to the Vpx-coding counterparts. This latter phenomenon was observed for AZT only when using MDMs. Our data suggest that Vpx in RT-SHIVs may underestimate the antiviral efficacy of NRTIs in a cell type dependent manner.
authors: Center for Drug Discovery, Department of Pediatrics, Emory University, Atlanta, GA, USA.
authors: Joseph A
authors: JA
authors: Hollenbaugh
authors: Center for Drug Discovery, Department of Pediatrics, Emory University, Atlanta, GA, USA.
authors: Susan M
authors: SM
authors: Schader
authors: Center for Drug Discovery, Department of Pediatrics, Emory University, Atlanta, GA, USA; Veterans Affairs Medical Center, Atlanta, GA, USA.
authors: Raymond F
authors: RF
authors: Schinazi
authors: Center for Drug Discovery, Department of Pediatrics, Emory University, Atlanta, GA, USA; College of Pharmacy, Kyung Hee University, Seoul, South Korea. Electronic address: baek.kim@emory.edu.
authors: Baek
authors: B
authors: Kim
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral; D015870:Gene Expression; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D008826:Microbial Sensitivity Tests; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D054334:Viral Regulatory and Accessory Proteins
keywords: Antiretrovirals; HIV-1; RT-SHIV; SAMHD1; SIV; Vpx