title: Synergy against drug-resistant HIV-1 with the microbicide antiretrovirals, dapivirine and tenofovir, in combination.
abstract: OBJECTIVE
  To evaluate the candidate antiretroviral microbicide compounds, dapivirine (DAP) and tenofovir (TFV), alone and in combination against the transmission of wild-type and nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 from different subtypes.
  
  
  METHODS
  We determined single-drug efficacy of the RTIs, DAP and TFV, against subtype B and non-B wild-type and NNRTI-resistant HIV-1 in vitro. To assess breadth of activity, compounds were tested alone and in combination against wild-type and NNRTI-resistant subtype C primary HIV-1 isolates and complimentary clonal HIV-1 from subtypes B, C and CRF02_AG to control for viral variation. Early infection was quantified by counting light units emitted from TZM-bl cells less than 48-h postinfection. Combination ratios were based on drug inhibitory concentrations (IC(50)s) and combined effects were determined by calculating combination indices.
  
  
  RESULTS
  Both candidate microbicide antiretrovirals demonstrated potent anti-NNRTI-resistant HIV-1 activity in vitro, albeit the combination protected better than the single-drug treatments. Of particular interest, the DAP with TFV combination exhibited synergy (50% combination index, CI(50) = 0.567) against subtype C NNRTI-resistant HIV-1, whereas additivity (CI(50) = 0.987) was observed against the wild-type counterpart from the same patient. The effect was not compounded by the presence of subdominant viral fractions, as experiments using complimentary clonal subtype C wild-type (CI(50) = 0.968) and NNRTI-resistant (CI(50) = 0.672) HIV-1, in lieu of the patient quasispecies, gave similar results.
  
  
  CONCLUSIONS
  This study supports the notion that antiretroviral drug combinations may retain antiviral activity against some drug-resistant HIV-1 despite subtype classification and quasispecies diversity.
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Schader
authors.forename: Susan P
authors.initials: SP
authors.lastname: Colby-Germinario
authors.forename: Jordana R
authors.initials: JR
authors.lastname: Schachter
authors.forename: Hongtao
authors.initials: H
authors.lastname: Xu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000187:drug effects*; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000235:genetics / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D063065:Organophosphonates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D000068698:Tenofovir
chemical_list: D063065:Organophosphonates; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000225:Adenine; C481671:Dapivirine