title: Resistance and cross-resistance profile of the diaryltriazine NNRTI and candidate microbicide UAMC01398.
abstract: OBJECTIVE
  The resistance development, cross-resistance to other NNRTIs and the impact of resistance on viral replicative fitness were studied for the new and potent NNRTI UAMC01398.
  
  
  METHODS
  Resistance was selected by dose escalation and by single high-dose selection against a comprehensive panel of NNRTIs used as therapeutics and NNRTIs under investigation for pre-exposure prophylaxis of sexual HIV transmission. A panel of 27 site-directed mutants with single mutations or combinations of mutations involved in reverse transcriptase (RT) inhibitor-mediated resistance was developed and used to confirm resistance to UAMC01398. Cross-resistance to other NNRTIs was assessed, as well as susceptibility of UAMC01398-resistant HIV to diarylpyrimidine-resistant viruses. Finally, the impact of UAMC01398 resistance on HIV replicative fitness was studied.
  
  
  RESULTS
  We showed that UAMC01398 has potent activity against dapivirine-resistant HIV, that at least four mutations in the RT are required in concert for resistance and that the resistance profile is similar to rilpivirine, both genotypically and phenotypically. Resistance development to UAMC01398 is associated with a severe fitness cost.
  
  
  CONCLUSIONS
  These data, together with the enhanced safety profile and good solubility in aqueous gels, make UAMC01398 an excellent candidate for HIV topical prevention.
authors: Department of Biomedical Sciences, Institute of Tropical Medicine, B-2000 Antwerp, Belgium karien@itg.be.
authors: Kevin K
authors: KK
authors: Ariën
authors: Laboratory of Medicinal Chemistry, University of Antwerp, B-2000 Antwerp, Belgium.
authors: Muthusamy
authors: M
authors: Venkatraj
authors: Department of Biomedical Sciences, Institute of Tropical Medicine, B-2000 Antwerp, Belgium.
authors: Johan
authors: J
authors: Michiels
authors: Laboratory of Medicinal Chemistry, University of Antwerp, B-2000 Antwerp, Belgium.
authors: Jurgen
authors: J
authors: Joossens
authors: Department of Biomedical Sciences, Institute of Tropical Medicine, B-2000 Antwerp, Belgium.
authors: Katleen
authors: K
authors: Vereecken
authors: Laboratory of Medicinal Chemistry, University of Antwerp, B-2000 Antwerp, Belgium.
authors: Pieter
authors: P
authors: Van der Veken
authors: Laboratory of Medicinal Chemistry, University of Antwerp, B-2000 Antwerp, Belgium.
authors: Jan
authors: J
authors: Heeres
authors: Laboratory of Medicinal Chemistry, University of Antwerp, B-2000 Antwerp, Belgium.
authors: Hans
authors: H
authors: De Winter
authors: Department of Biomedical Sciences, Institute of Tropical Medicine, B-2000 Antwerp, Belgium.
authors: Leo
authors: L
authors: Heyndrickx
authors: Laboratory of Medicinal Chemistry, University of Antwerp, B-2000 Antwerp, Belgium.
authors: Koen
authors: K
authors: Augustyns
authors: Department of Biomedical Sciences, Institute of Tropical Medicine, B-2000 Antwerp, Belgium Department of Biomedical Sciences, University of Antwerp, B-2000 Antwerp, Belgium.
authors: Guido
authors: G
authors: Vanham
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D006678:HIV / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D054303:HIV Reverse Transcriptase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009154:Mutation; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D054303:HIV Reverse Transcriptase