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

AN HIV-1 (RF) VARIANT ENCODING A PROTEASE WITH V82F AND 184V MUTATIONS EXHIBITS RESISTANCE TO CYCLIC UREA AND C₂ LINEAR DIOl PROTEASE INHIBITORS

Int Wkshop HIV Drug Res 1994 Aug 2-5;3:12 (abstract no. 11)

Robert W. King, Sena Garber, Carol D. Reid and Michael J. Otto
The DuPont Merck Pharmaceutical Co., Glenolden, PA, USA 19036

Previously we have reported that the amino acid located at position 82 of the HIV-1 protease affects the susceptibility of HIV-1 to protease inhibitors of the C₂ symmetrical diol and cyclic urea classes. Likewise, it has been shown that an 184V change reduces the susceptibility of HIV-1 to a synthetic peptide analog. HIV-1 (RF) was serially passaged for 28 passages in increasing concentrations of XM323, a non-peptidyl, cyclic urea protease inhibitor. The surviving virus was plaque purified and individual isolates were expanded in MT-2 cells. Each isolate was tested for susceptibility to four different protease inhibitors, and its protease gene was sequenced. Sequence analysis of the protease gene of an isolate, designated HIV-1 (RF82F84V), showed that it contained two mutations. A transversion of G to T in the first base of the V82 codon and a transition of A to G in the first base of the 184 codon resulted in V82F and 184V changes, respectively. When this isolate was tested for its susceptibility to several protease inhibitors, it exhibited a >50-fold decrease in its susceptibility to XM323 as well as a 3-fold decrease in susceptibility to P9941, a C₂ symmetrical diol. These mutations did not alter the susceptibility of the variant to the Roche inhibitor, R031-8959, or to the Abbott inhibitor, A-8098.

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1994-08-02
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