Natural Substrate Concentrations Can Modulate the Prophylactic Efficacy of Nucleotide HIV Reverse Transcriptase Inhibitors
| Autor: | Wei Luo, Susan Kuklenyik, William A. Lee, Ellen N. Kersh, Chou Pong Pau, Walid Heneine, Adrian S. Ray, James F. Rooney, Qi Zheng, Wutyi Aung, Angela Holder, J. Gerardo García-Lerma, James Mitchell, Amy Martin, Ae S. Youngpairoj, Carol Yen Chin Lin, Debra L. Hanson, Mian Er Cong |
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| Rok vydání: | 2011 |
| Předmět: |
Anti-HIV Agents
Lymphoid Tissue Immunology Organophosphonates Simian Acquired Immunodeficiency Syndrome HIV Infections Biology Chemoprevention Microbiology Peripheral blood mononuclear cell Virus Substrate Specificity Deoxyadenine Nucleotides Rectal mucosa Virology Vaccines and Antiviral Agents Animals Humans Prodrugs Nucleotide Lymphocytes Tenofovir chemistry.chemical_classification Adenine Rectum Substrate (chemistry) Prodrug HIV Reverse Transcriptase Reverse transcriptase Lymphatic system chemistry Insect Science HIV-1 Macaca Reverse Transcriptase Inhibitors Simian Immunodeficiency Virus |
| Zdroj: | Journal of Virology. 85:6610-6617 |
| ISSN: | 1098-5514 0022-538X |
| Popis: | 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/10 6 cells for as long as 7 days. TFV-DP accumulated in lymphoid and rectal tissues, with concentrations at 3 days exceeding 500 fmol/10 6 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. |
| Databáze: | OpenAIRE |
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