Short Communication: A Novel Mutation (F227L) Arises in the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 on Dose-Escalating Treatment of HIV Type 1-Infected Cell Cultures with the Nonnucleoside Reverse Transcriptase Inhibitor Thiocarboxanilide UC-781

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Abstract
Treatment of wild-type human immunodeficiency virus [HIV-l(IIIB)]-infected cell cultures with the thiocarboxanilide UC-781 under low selective pressure (i.e., 0.01 μg/ml) resulted in the emergence of V106A RT mutant virus. On increasing drug concentrations (stepwise up to 30 μg/ml) the virus retained the V106A RT mutation but acquired the novel F227L mutation in the RT genome in addition to the L100I, K101I, and Y181C mutations. This multiple-mutant virus proved highly resistant to virtually all nonnucleoside RT inhibitors (NNRTIs) (e.g., nevirapine, delavirdine, and loviride), but retained full sensitivity to nucleoside analogs such as AZT, ddI, (−)FTC, and 3TC. The F227 amino acid is highly conserved in HIV-1 strains and forms part of the NNRTI-binding pocket. Our model suggests a hydrophobic interaction between F227 and the chloro atom of UC-781.

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