3rd International Workshop on HIV Drug Resistance 2-5 August 1994, Kauai, Hawaii, USA

PHENOTYPIC AND GENOTYPIC CHARACTERIZATION OF HIV-1 VARIANTS SELECTED DURING TREATMENT WITH THE PROTEASE INHIBITOR L-735,524

Int Wkshop HIV Drug Res 1994 Aug 2-5;3:15 (abstract no. 14)

E.A. Emini, W.A. Schleif, D. Graham, P. Deutsch, F. Massari, H. Teppler*, K. Squires# andJ.H. Condra
Merck Research Laboratories, West Point, PA, USA; *Thomas Jefferson University, Philadelphia, PA, USA; #University of Alabama, Birmingham, AL, USA

L-735,524 is a selective and potent inhibitor of the HIV-1 protease enzyme that exhibits acceptable pharmacokinetics and safety profiles. In an initial human antiviral activity study, L-735,524 was orally administered to HIV-1-infected patients. Activity was assessed by monitoring serum p24 antigen and viral RNA levels. Virus susceptibility was examined by systematic virus isolation and cell culture testing as well as by sequencing of the protease-coding region in the circulating viral RNA. Noted antiviral effects were seen in some patients, but the duration of the effect varied. Following 24 weeks or more of therapy, a number of patients yielded virus with reduced susceptibility to the inhibitor. In all cases, the reduction was approximately 4- to 8-fold and was accompanied by various protease-associated amino acid substitutions. The substitution patterns differed among isolates, with the exception of an ala, thr or phe substitution for val at residue 82. Alteration at this residue position was uniformly affiliated with the appearance of resistance. Substitutions at position 82 were introduced into the NL4-3 provirus. However, the derived mutant viruses were not resistant to L-735,524, suggesting that the context into which the substitutions are introduced influences the phenotypic expression of resistance. Studies to define the nature of this influence are in progress.

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1994-08-02
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