Cellular pharmacology and potency of HIV-1 nucleoside analogs in primary human macrophages

Christina Gavegnano, Mervi A. Detorio, Leda Bassit, Selwyn J. Hurwitz, Thomas W. North, Raymond F. Schinazi

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 (EC50, 0.4 to 9.42 μM versus 0.03 to 0.4 μM, respectively). Although tenofovirtreated 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.

Original languageEnglish (US)
Pages (from-to)1262-1269
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume57
Issue number3
DOIs
StatePublished - Mar 2013
Externally publishedYes

Fingerprint

Nucleosides
HIV-1
Macrophages
Pharmacology
Tenofovir
Anti-Retroviral Agents
Antiviral Agents
Integrase Inhibitors
Lymphocytes
Macrophage Colony-Stimulating Factor
Prodrugs
Lymphocyte Activation
Pharmaceutical Preparations
HIV Infections
Infection

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Gavegnano, C., Detorio, M. A., Bassit, L., Hurwitz, S. J., North, T. W., & Schinazi, R. F. (2013). Cellular pharmacology and potency of HIV-1 nucleoside analogs in primary human macrophages. Antimicrobial Agents and Chemotherapy, 57(3), 1262-1269. https://doi.org/10.1128/AAC.02012-12

Cellular pharmacology and potency of HIV-1 nucleoside analogs in primary human macrophages. / Gavegnano, Christina; Detorio, Mervi A.; Bassit, Leda; Hurwitz, Selwyn J.; North, Thomas W.; Schinazi, Raymond F.

In: Antimicrobial Agents and Chemotherapy, Vol. 57, No. 3, 03.2013, p. 1262-1269.

Research output: Contribution to journalArticle

Gavegnano, C, Detorio, MA, Bassit, L, Hurwitz, SJ, North, TW & Schinazi, RF 2013, 'Cellular pharmacology and potency of HIV-1 nucleoside analogs in primary human macrophages', Antimicrobial Agents and Chemotherapy, vol. 57, no. 3, pp. 1262-1269. https://doi.org/10.1128/AAC.02012-12
Gavegnano, Christina ; Detorio, Mervi A. ; Bassit, Leda ; Hurwitz, Selwyn J. ; North, Thomas W. ; Schinazi, Raymond F. / Cellular pharmacology and potency of HIV-1 nucleoside analogs in primary human macrophages. In: Antimicrobial Agents and Chemotherapy. 2013 ; Vol. 57, No. 3. pp. 1262-1269.
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