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Session 88 Poster Abstracts
Mechanisms of Drug Resistance and Increased Susceptibility
Tuesday, 1:30 - 3:30 pm
Poster Hall


628
Effect of Interactions of HIV-1 Reverse Transcriptase Inhibitor Drug-resistance Mutations on Phenotypic Drug Sensitivity
X Han1, M Montes-Walters1, M Filizzola1, M B Goetz2, W A O'Brien*1, and M R Ferguson1
1Univ. of Texas Med. Branch at Galveston, USA and 2Univ. of California, Los Angeles/VA Greater Los Angeles Healthcare System, USA

Background:  Many mutations selected by RTI are well described, and have been shown to correlate with decreased virologic response to their corresponding drugs.  Although the 3TC/FTC/ABC mutation M184V can diminish the effect of thymidine analog mutations (TAM; 41, 67, 70, 210, 215, 219) 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 treated patients, and used to generate full-length proviral clones (NL4-3 chimeras) for analysis of phenotypic drug resistance (Phenosense, ViroLogic).  Specific modifications of key RT amino acids were performed by site-directed mutagenesis (Quik Change, Stratagene).

Results: The effect of TAM on sensitivity to ZDV, d4T, and TDF was diminished by coexpression of mutations 74V and in some cases 69D, as well as 184V.  In addition, the presence of multiple NNRTI mutations (98A, 101E and 190A) further reduced the IC50 fold change seen with TAM alone.  Addition of 69D, 74V, or 184V tended to increase the IC50 fold change for ddI and ABC when added to TAM.  For TDF, the combination of either 69D or 184V together with the NNRTI mutations resulted in IC50 values that were within 1.2-fold of wild type for viruses with 2 to 4 TAM, including the 41L, 210W, 215Y pattern associated with decreased virologic response to TDF observed in studies GS 902 and GS 907.

Conclusions: Interactions of RTI mutations can affect the phenotypic sensitivity of RTI.  In addition to M184V, 69D, and 74V also appear to ameliorate the decrease in sensitivity caused by TAM for ZDV, d4T, and TDF, whereas all 3 tend to further decrease sensitivity to ddI and ABC.  In the presence of multiple NNRTI mutations, diminished phenotypic sensitivity to TDF is uncommon, as seen in this study and in virus from GS903 patients with virologic failure.  The mechanism of mutational interaction effects and potential clinical implications warrant further exploration.

Keywords: NRTI resistance; tenofovir; phenotype