title: Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors.
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/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.
authors.affiliation: Division of HIV/AIDS Prevention, National Center for HIV, Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, USA. GGarcia-Lerma@cdc.gov
authors.forename: J Gerardo
authors.initials: JG
authors.lastname: García-Lerma
authors.forename: Wutyi
authors.initials: W
authors.lastname: Aung
authors.forename: Mian-er
authors.initials: ME
authors.lastname: Cong
authors.forename: Qi
authors.initials: Q
authors.lastname: Zheng
authors.forename: Ae S
authors.initials: AS
authors.lastname: Youngpairoj
authors.forename: James
authors.initials: J
authors.lastname: Mitchell
authors.forename: Angela
authors.initials: A
authors.lastname: Holder
authors.forename: Amy
authors.initials: A
authors.lastname: Martin
authors.forename: Susan
authors.initials: S
authors.lastname: Kuklenyik
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.forename: Carol Yen-Chin
authors.initials: CY
authors.lastname: Lin
authors.forename: Debra L
authors.initials: DL
authors.lastname: Hanson
authors.forename: Ellen
authors.initials: E
authors.lastname: Kersh
authors.forename: Chou-Pong
authors.initials: CP
authors.lastname: Pau
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.forename: James F
authors.initials: JF
authors.lastname: Rooney
authors.forename: William A
authors.initials: WA
authors.lastname: Lee
authors.forename: Walid
authors.initials: W
authors.lastname: Heneine
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018890:Chemoprevention; D003838:Deoxyadenine Nucleotides / Q000378:metabolism*; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008221:Lymphoid Tissue / Q000378:metabolism; D008251:Macaca; D063065:Organophosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012007:Rectum / Q000821:virology; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects; D013379:Substrate Specificity; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D003838:Deoxyadenine Nucleotides; D063065:Organophosphonates; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D000225:Adenine; C026600:2'-deoxyadenosine triphosphate