Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors

J. Gerardo García-Lerma, Wutyi Aung, Mian Er Cong, Qi Zheng, Ae S. Youngpairoj, James Mitchell, Angela Holder, Amy Martin, Susan Kuklenyik, Wei Luo, Carol Yen Chin Lin, Debra L. Hanson, Ellen Kersh, Chou Pong Pau, Adrian S. Ray, James F. Rooney, William A. Lee, Walid Heneine

Research output: Contribution to journalArticle

Abstract

Preexposure prophylaxis (PrEP) with antiretroviral drugs is a novel human immunodeficiency virus (HIV) prevention strategy. It is generally thought that high systemic and mucosal drug levels are sufficient for protection. We investigated whether GS7340, a next-generation tenofovir (TFV) prodrug that effectively delivers tenofovir diphosphate (TFV-DP) to lymphoid cells and tissues, could protect macaques against repeated weekly rectal simian-human immunodeficiency virus (SHIV) exposures. Macaques received prophylactic GS7340 treatment 3 days prior to each virus exposure. At 3 days postdosing, TFV-DP concentrations in peripheral blood mononuclear cells (PBMCs) were about 50-fold higher than those seen with TFV disoproxil fumarate (TDF), and they remained above 1,000 fmol/106 cells for as long as 7 days. TFV-DP accumulated in lymphoid and rectal tissues, with concentrations at 3 days exceeding 500 fmol/106 mononuclear cells. Despite high mucosal and systemic TFV levels, GS7340 was not protective. Since TFV-DP blocks reverse transcription by competing with the natural dATP substrate, we measured dATP contents in peripheral lymphocytes, lymphoid tissue, and rectal mononuclear cells. Compared to those in circulating lymphocytes and lymphoid tissue, rectal lymphocytes had 100-fold higher dATP concentrations and dATP/TFV-DP ratios, likely reflecting the activated status of the cells and suggesting that TFV-DP may be less active at the rectal mucosa. Our results identify dATP/TFV-DP ratios as a possible correlate of protection by TFV and suggest that natural substrate concentrations at the mucosa will likely modulate the prophylactic efficacy of nucleotide reverse transcriptase inhibitors.

Original languageEnglish (US)
Pages (from-to)6610-6617
Number of pages8
JournalJournal of virology
Volume85
Issue number13
DOIs
StatePublished - Jul 1 2011

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ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

García-Lerma, J. G., Aung, W., Cong, M. E., Zheng, Q., Youngpairoj, A. S., Mitchell, J., Holder, A., Martin, A., Kuklenyik, S., Luo, W., Lin, C. Y. C., Hanson, D. L., Kersh, E., Pau, C. P., Ray, A. S., Rooney, J. F., Lee, W. A., & Heneine, W. (2011). Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors. Journal of virology, 85(13), 6610-6617. https://doi.org/10.1128/JVI.00311-11