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

doi:10.1093/jac/dkv501

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

Virology

Research output: Contribution to journal › A1: Web of Science-article › peer-review

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 language	English
Journal	Journal of Antimicrobial Chemotherapy
Volume	71
Issue number	5
Pages (from-to)	1159-1168
ISSN	0305-7453
DOIs	https://doi.org/10.1093/jac/dkv501
Publication status	Published - 2016

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title = "Resistance and cross-resistance profile of the diaryltriazine NNRTI and candidate microbicide UAMC01398",

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.",

author = "Ari{\"e}n, {Kevin K} and Muthusamy Venkatraj and Johan Michiels and Jurgen Joossens and Katleen Vereecken and {Van der Veken}, Pieter and Jan Heeres and {De Winter}, Hans and Leo Heyndrickx and Koen Augustyns and Guido Vanham",

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year = "2016",

doi = "10.1093/jac/dkv501",

language = "English",

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pages = "1159--1168",

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TY - JOUR

T1 - Resistance and cross-resistance profile of the diaryltriazine NNRTI and candidate microbicide UAMC01398

AU - Ariën, Kevin K

AU - Venkatraj, Muthusamy

AU - Michiels, Johan

AU - Joossens, Jurgen

AU - Vereecken, Katleen

AU - Van der Veken, Pieter

AU - Heeres, Jan

AU - De Winter, Hans

AU - Heyndrickx, Leo

AU - Augustyns, Koen

AU - Vanham, Guido

N1 - FTX

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

U2 - 10.1093/jac/dkv501

DO - 10.1093/jac/dkv501

M3 - A1: Web of Science-article

C2 - 26850721

SN - 0305-7453

VL - 71

SP - 1159

EP - 1168

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

IS - 5

ER -

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

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