AEGiS-15IAC: Effect of interactions of HIV-1 reverse transcriptase inhibitor (RTI) drug resistance mutations on phenotypic sensitivity to RTI.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

Effect of interactions of HIV-1 reverse transcriptase inhibitor (RTI) drug resistance mutations on phenotypic sensitivity to RTI.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. WeOrA1274)

Ferguson MR, Han X, Montes-Walters M, Filizzola M, Goetz MB, O'Brien WA
University of Texas Medical Branch, Galveston, United States

BACKGROUND: Many mutations selected by RTI are well described, and have been shown to correlate with decreased virologic response. Although the 3TC/FTC/ABC mutation M184V can diminish the effect of thymidine analog mutations (TAMs - 41L,67N,70R,210W,215Y,219E/Q) on phenotypic sensitivity to ZDV, d4T or TDF, other potential interactions between RTI mutations have not been rigorously explored.

METHODS: The RT gene (1.3 kb) was cloned from plasma HIV-1 RNA from treatment experienced patients, and used to generate full-length proviral clones (pNL4-3 chimeras) for analysis of phenotypic drug resistance (Phenosense, ViroLogic). Specific modifications of key RT amino acids were performed by site-directed mutagenesis.

RESULTS: HIV strains with multiple TAM combinations, L74V and three NNRTI mutations showed only modestly reduced IC50, with measured fold-change near the resistance break point for most NRTI, but showed full susceptibility to TDF and 3TC. When 184V was introduced there was an increase in IC50 fold change for ABC, ddI, and ddC, and a decrease for TDF, ZDV, and d4T. Overall, when we removed NNRTI (98S, 101E, and 190A), the viral clones became more sensitive to drugs. For TDF the TAM combination of 41L, 210W and 215Y, together with 74V, showed an IC50 fold change of 0.61, and all other TAM combinations resulted in fold change of 0.3-0.4.

CONCLUSIONS: Interactions of RTI mutations can affect the phenotypic sensitivity of RTI, best demonstrated by introduction of 184V into virus strains with multiple TAMS, 74V and multiple NNRTI. Removal of NNRTI mutations was associated with improved susceptibility to all NRTI, and full susceptibility to TDF and ZDV (IC50 fold change< 1.0). The effect of 74V on phenotypic susceptibility to TDF and ZDV, and the mechanism of mutational interactions and their potential clinical implications warrant further exploration.

Keywords: AEGIS, HIV-1 Reverse Transcriptase, Zidovudine, Stavudine, Lamivudine, Drug Resistance, Mutation, Didanosine, Thymidine, Acquired Immunodeficiency Syndrome, Drug Interactions, Humans, genetics

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