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3rd International Workshop on HIV Drug Resistance2-5 August 1994, Kauai, Hawaii, USA |
SELECTION OF NOVEL RT MUTATIONS UPON CONTINUED EXPOSURE OF NNRTI-RESISTANT HIV-1 MUTANT STRAINS TO NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)
Int Wkshop HIV Drug Res 1994 Aug 2-5;3:39 (abstract no. 38)
J. Balzarini1 , A. Karlsson2, V.V. Sardana3, E.A. Emini3 and E. De Clercq1
1Rega Institute, K.U.Leuven, B-3000 Leuven, Belgium; 2Karolinska Institute, S-104 01 Stockholm, Sweden; 3Merck Research Laboratories, West Point, PA, U.S.A.
OBJECTIVE: Investigation of the outcome of NNRTI-resistant HIV-1 mutant strains when further exposed to high concentrations of the NNRTI’s.
METHODS: The selection procedures and characterization of the mutated amino acids in the reverse transcriptase (RT) of the resistant HIV-1 strains was performed as previously described [Balzarini et al., Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):6952-6].
RESULTS AND DISCUSSION: Cells infected with a virus mutant containing the Tyr → Cys substitution at position 181 of its RT were temporarily protected by BHAP. The HIV-1 strain that finally emerged under the selective pressure of BHAP contained a novel amino acid substitution (Cys → Ile) at RT position 181. This virus mutant proved highly resistant to all HIV-1-specific RT inhibitors (i.e. TIBO R82913, nevirapine, pyridinone L697,661, BHAP U-88204E and TSAO-m3T), except for several HEPT derivatives. Recombinant HIV-1 RT containing the Ile-181 mutation proved also resistant to all HIV-1-specific inhibitors, except for the HEPT derivatives. Since a Phe-181 mutant virus strain was detected in one of the cell cultures, we postulate that the Ile codon (ATT) originated from the Cys codon (TGT) by a double transversion mutation, the Phe codon (TTT) being the intermediate.
CONCLUSION: Our data indicate that continued exposure of HIV-1 mutants containing the 181 Tyr → Cys mutation in their RT to high concentrations of NNRTIs result in the emergence of highly resistant HIV-1 mutants that contain novel mutations in the same codon (181 Cys → Ile).
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1994-08-02
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