3rd International Workshop on HIV Drug Resistance


2-5 August 1994, Kauai, Hawaii, USA


DEFINED MUTATIONS IN THE HIV PROTEASE GENE CONFER REDUCED SUSCEPTIBILITY TO STRUCTURALLY DISSIMILAR HIV PROTEASE INHIBITORS

Int Wkshop HIV Drug Res 1994 Aug 2-5;3:5 (abstract no. 4)

D.L. Winslow, E.D. Anton, R.A. Horlick, R.J. Zagursky, R.J. Tritch, H. Scarnati, K. Ackerman, R. Buckery, and L.T. Bacheler
DuPont Merck Pharmaceutical Company, Glenolden, Pennsylvania and Wilmington, Delaware (USA)

HIV protease inhibitors are a new class of antiretroviral agents that have recently entered clinical trials. Otto et al. AIDS. 1994 Jun;8(6):753-6 and others have reported several amino acid alterations in the protease gene which may result in reduced susceptibility to various protease inhibitors.

Recombinant viruses containing protease genes altered by site-directed mutagenesis were constructed in the background of pHxB2. Infectious recombinant virus was recovered after transfection into MT-2 cells. In vitro susceptibility testing of recombinant viruses containing variations in protease to a panel of 4 structurally dissimilar HIV protease inhibitors was performed using an RNA hybridization assay (in MT-2 cells) and using the ACTG/DoD PBMC consensus assay. Data shown are from the PBMC assay.

  XM323
IC50 µM		 P9941
IC50 µM		 A80987
IC50 µM		 R031-8959
IC50 µM
HxB2 0.02 0.13 0.04 0.006
V82A 0.04 0.78 0.18 0.006
V82F 0.11 0.82 – 0.009
V821 0.03 0.35 – 0.006
V321 0.03 0.35 0.4 0.004
G48V 0.05 1.8 – 0.045
L90M 0.02 0.69 – 0.004
G48V+L90M 0.04 3.4 – 0.12

These data show potentially significant cross-resistance between cyclic urea, linear diol, asymmetric mono-ol, and hydroxyethylene isostere protease inhibitors.

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1994-08-02
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