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Author Notes:

Address correspondence to Raymond F. Schinazi, rschina@emory.edu.

R. F. Schinazi is the founder and a major shareholder of RFS Pharma, LLC, a clinical company that is developing [(−)-β-d-2,6-diaminopurine dioxolane, DAPD, AMDX]/DXG for the treatment of HIV.


Research Funding:

This work was supported in part by NIH grants 8R01OD011094 and 5P30-AI-50409 (CFAR) and by the Department of Veterans Affairs.

Cellular Pharmacology and Potency of HIV-1 Nucleoside Analogs in Primary Human Macrophages


Journal Title:

Antimicrobial Agents and Chemotherapy


Volume 57, Number 3


, Pages 1262-1269

Type of Work:

Article | Final Publisher PDF


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 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.

Copyright information:

© 2013, American Society for Microbiology. All Rights Reserved.

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