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- Title
Variable antiviral activity of islatravir against M184I/V mutant HIV-1 selected during antiretroviral therapy.
- Authors
Aulicino, Paula C; Sharma, Suman; Truong, Khanghy; Kukunoor, Vindhya; Ghei, Karm; Arazi-Caillaud, Solange; Taicz, Moira; Bologna, Rosa; Mangano, Andrea; Kimata, Jason T
- Abstract
Background Islatravir is a new antiretroviral drug that inhibits the reverse transcriptase (RT) of HIV-1 through multiple mechanisms. It is proposed to be used in combination with doravirine, a new NNRTI. M184V/I mutations have been shown to reduce the in vitro antiviral activity of islatravir, but their effect when pre-selected during ART has not been investigated. Methods HIV-1 rt sequences were obtained from four individuals of the Garrahan HIV cohort prior to, or during virological failure to ART. HIV-1 infectious molecular clones were constructed on an NL4-3 backbone, and infectious viruses were produced by transfection of 293T cells. Fold-changes in IC50 were calculated for each mutant versus the NL4-3 WT. HIV-1 phenotypic drug resistance was tested in vitro against NRTIs and NNRTIs. Results In all the cases, M184I/V, either alone or in the presence of other mutations, was associated with reduced susceptibility to islatravir, abacavir and lamivudine. Viruses carrying M184V/I showed variable levels of resistance to islatravir (4.8 to 33.8-fold). The greatest reduction in susceptibility was observed for viruses carrying the mutations M184V + V106I (33.8-fold resistance) or M184V + I142V (25.2-fold resistance). For NNRTIs, the presence of V106I alone did not affect susceptibility to doravirine or etravirine, but showed a modest reduction in susceptibility to efavirenz (6-fold). Susceptibility to doravirine was slightly reduced only for one of the mutants carrying V106I in combination with Y181C and M184V. Conclusions Mutations and polymorphisms selected in vivo together with M184V/I depend on the viral genetic context and on ART history, and could affect the efficacy of islatravir once available for use in the clinic.
- Subjects
EFAVIRENZ; ANTIRETROVIRAL agents; ANTIVIRAL agents; HIV; NON-nucleoside reverse transcriptase inhibitors; REVERSE transcriptase; NUCLEOSIDE reverse transcriptase inhibitors
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2024, Vol 79, Issue 2, p370
- ISSN
0305-7453
- Publication type
Article
- DOI
10.1093/jac/dkad390