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

PATTERNS OF SPECIFIC MUTATIONS IN HIV-1 PROTEASE THAT CONFER RESISTANCE TO PROTEASE INHIBITORS IN CLINICAL DEVELOPMENT

Int Wkshop HIV Drug Res 1994 Aug 2-5;3:13 (abstract no. 12)

H. Mo*, M. Markowitz*, and D.D. Ho
Aaron Diamond AIDS Research Center and NYU School of Medicine, New York, NY, U.S.A.

We undertook this project to define specific mutations in the HIV-1 protease that would result in increased resistance to a panel of protease inhibitors in clinical development. Using in vitro selection in the presence of increasing concentrations of an inhibitor, variants with increased resistance were generated. The variant viruses were then sequenced, and the importance of each observed amino-acid change in conferring resistance was assessed by site-directed mutagenesis followed by drug sensitivity testing. We have previously reported that 8Q and 8K were important in conferring resistance to Abbott-77003 (Ho et al, J Virol. 1994 Mar;68(3):2016-20). We have also derived HIV-1 variants with increased resistance to Abbott-84538 (or ABT-538). In this case, 84V and 82F were found to be the critical mutations conferring greater resistance, although changes elsewhere were also observed (46I, 63P, and 71V). Similarly, resistant variants were selected in vitro using two inhibitors, MP-134 and MP-167, provided by J. Erickson of NCI; the important changes were found to be 84V and 48V, respectively. Using the information generated in experiments described above as well as those in published reports, a sizeable panel of single (8Q, 8K, lOF, 32I, 46I, 46L, 46F, 48V, 63P, 71V, 82A, 82F, 84V, and 90M), double (8Q/32I, 8Q/46I, 8Q/46F, 8Q/82A, 8K/46I, 8K/82I, 8K/82A, 10F/48V, lOF/84V, 32I/82A, 32I/82I, 32I/84V, 46F/82A, 461/84V, and 82F/84V), and triple (8Q/32I/82A, 8Q/46F/82A, 8K/321/82A, 8K/32I/82I, 8K/48V/82A, 63P/82F/84V, 71V/82F/84V, 46I/82F/84V, etc.) mutants were created. The viable mutants, along with selected HIV-1 variants from above, were individually tested using a panel of protease inhibitors that represent clinical candidates from a number of pharmaceutical companies (Roche, Merck, Abbott, Dupont Merck, Agouron, and Upjohn among others). Results from these studies as well as from additional in vitro selections will be described in detail. In conclusion, HIV-1 resistance was found for every protease inhibitor studied to date. Certain amino acids in protease seemed to be hot spots for conferring resistance, including but not limited to residues 8, 48, 82, and 84. Furthermore, our early findings suggest that the protease inhibitors currently under clinical development fall into several different groups based on their resistance patterns, raising the notion that specific combinations of these agents could be useful in combating the resistance problem.

* Contributed equally to these studies.

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1994-08-02
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