Resistance and cross-resistance profile of the diaryltriazine NNRTI and candidate microbicide UAMC01398

Kevin K Ariën, Muthusamy Venkatraj, Johan Michiels, Jurgen Joossens, Katleen Vereecken, Pieter Van der Veken, Jan Heeres, Hans De Winter, Leo Heyndrickx, Koen Augustyns, Guido Vanham

Research output: Contribution to journalA1: Web of Science-article

Abstract

OBJECTIVES: 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.

Original languageEnglish
JournalJournal of Antimicrobial Chemotherapy
Volume71
Issue number5
Pages (from-to)1159-1168
ISSN0305-7453
DOIs
Publication statusPublished - 2016

Fingerprint Dive into the research topics of 'Resistance and cross-resistance profile of the diaryltriazine NNRTI and candidate microbicide UAMC01398'. Together they form a unique fingerprint.

Cite this