Title
Resistance and cross-resistance profile of the diaryltriazine NNRTI and candidate microbicide UAMC01398 Resistance and cross-resistance profile of the diaryltriazine NNRTI and candidate microbicide UAMC01398
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
London ,
Subject
Biology
Pharmacology. Therapy
Human medicine
Source (journal)
The journal of antimicrobial chemotherapy. - London, 1975, currens
Volume/pages
71(2016) :5 , p. 1159-1168
ISSN
0305-7453
ISI
000376291300004
Carrier
E
Target language
Dutch (dut)
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
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.
E-info
https://repository.uantwerpen.be/docman/iruaauth/b3026c/132829.pdf
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