title: Cellular pharmacology and potency of HIV-1 nucleoside analogs in primary human macrophages.
abstract: Understanding the cellular pharmacology of antiretroviral agents in macrophages and subsequent correlation with antiviral potency provides a sentinel foundation for definition of the dynamics between antiretroviral agents and viral reservoirs across multiple cell types, with the goal of eradication of HIV-1 from these cells. Various clinically relevant nucleoside antiviral agents, and the integrase inhibitor raltegravir, were selected for this study. The intracellular concentrations of the active metabolites of the nucleoside analogs were found to be 5- to 140-fold lower in macrophages than in lymphocytes, and their antiviral potency was significantly lower in macrophages constitutively activated with macrophage colony-stimulating factor (M-CSF) during acute infection than in resting macrophages (EC(50), 0.4 to 9.42 μM versus 0.03 to 0.4 μM, respectively). Although tenofovir-treated cells displayed significantly lower intracellular drug levels than cells treated with its prodrug, tenofovir disoproxil fumarate, the levels of tenofovir-diphosphate for tenofovir-treated cells were similar in lymphocytes and macrophages. Raltegravir also displayed significantly lower intracellular concentrations in macrophages than in lymphocytes, independent of the activation state, but had similar potencies in resting and activated macrophages. These data underscore the importance of delivering adequate levels of drug to macrophages to reduce and eradicate HIV-1 infection.
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Gavegnano
authors.forename: Mervi A
authors.initials: MA
authors.lastname: Detorio
authors.forename: Leda
authors.initials: L
authors.lastname: Bassit
authors.forename: Selwyn J
authors.initials: SJ
authors.lastname: Hurwitz
authors.forename: Thomas W
authors.initials: TW
authors.lastname: North
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001692:Biological Transport; D019428:HIV Integrase Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000821:virology; D008262:Macrophage Activation / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000821:virology; D009928:Organ Specificity; D063065:Organophosphonates / Q000494:pharmacology*; D061251:Primary Cell Culture; D011760:Pyrrolidinones / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D063065:Organophosphonates; D011760:Pyrrolidinones; D018894:Reverse Transcriptase Inhibitors; D000068898:Raltegravir Potassium; D016173:Macrophage Colony-Stimulating Factor; D000068698:Tenofovir; D000225:Adenine