title: Colorectal microbicide design:  triple combinations of reverse transcriptase inhibitors are optimal against HIV-1 in tissue explants.
abstract: OBJECTIVE
  Receptive anal intercourse in both men and women is associated with the highest probability for sexual acquisition of HIV infection. As part of a strategy to develop an effective rectal microbicide, we performed an ex-vivo preclinical evaluation to determine the efficacy and limitation of multiple combinations of reverse transcriptase inhibitors (RTIs).
  
  
  METHODS
  A nucleotide, PMPA (tenofovir), a nucleoside, FTC (emtricitabine), RTIs and two nonnucleoside RTIs, UC781 and TMC120 (dapivirine), were used in double, triple and quadruple combinations against a panel of CCR5-uing and CXCR4-using clade B HIV-1 isolates and against RTI-escape variants.
  
  
  METHODS
  Indicator cells and colorectal tissue explants were used to assess antiviral activity of drug combinations.
  
  
  RESULTS
  All combinations inhibited the isolates tested in a cellular model and in colorectal explants and produced, for at least one of the compounds, a change in the dose-response curve. Double and triple combinations incrementally augmented activity, even against RTI-escape mutants, whereas quadruple combinations conferred little further advantage.
  
  
  CONCLUSIONS
  The colorectal explant model may be used to identify the best candidate molecules and their combinations at the preclinical stage. Furthermore, this study demonstrates that combinations based on RTIs with different HIV-1 inhibitory mechanisms have potential as colorectal microbicides.
authors.affiliation: Division of Clinical Sciences, Centre for Infection & Immunity, St George's University of London, UK.
authors.forename: Carolina
authors.initials: C
authors.lastname: Herrera
authors.forename: Martin
authors.initials: M
authors.lastname: Cranage
authors.forename: Ian
authors.initials: I
authors.lastname: McGowan
authors.forename: Peter
authors.initials: P
authors.lastname: Anton
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Shattock
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008297:Male; D009092:Mucous Membrane / Q000187:drug effects; D012007:Rectum / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012725:Sexual Behavior; D046509:Tissue Culture Techniques
chemical_list: D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D018894:Reverse Transcriptase Inhibitors