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

COMBINATION THERAPY WITH TWO PROTEASE INHIBITORS AS AN APPROACH TO ANTIVIRAL THERAPY

Int Wkshop HIV Drug Res 1994 Aug 2-5;3:17 (abstract no. 16)

B. Rose, J. Greytok, C. Bechtold, M. Alam, B. Terry, Y.-F. Gong, K. DeVore, A. Patick, R. Colonno and P.-F. Lin
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT

Treatment of AIDS patients with nucleoside analogs has resulted in the appearance of resistant HIV variants. The protease of HIV is an essential viral enzyme and has been the target of several new antivirals in development. A novel class of HIV protease inhibitors, BMS aminodiols, has been recently described and shown to be potent and selective inhibitors of HIV infection. Similar to other HIV protease inhibitors, resistant variants (8 to 15-fold) can be generated following passage of HIV-1 RF in the presence of increasing concentrations of the aminodiols. Resistance maps to A71T and V82A changes within the protease gene. Drug susceptibility assays on HIV-1 variants resistant to the aminodiols indicated that they remain susceptible to several other protease inhibitors tested, suggesting a distinct resistance profile. These studies were supported by analyzing the resistance profile of several recombinant HIV-1 proteases. Attempts to generate recombinant NL4-3 viruses containing the A71T/V82A mutations and 1 or 2 additional mutations reported to encode resistance to other protease inhibitors have resulted in proteases with significantly reduced activity and either non-viable viruses or viruses with severely impaired growth properties. In contrast to the results obtained with the recombinant NL4-3 viruses, prolonged passage of a RF variant containing the A71T and V82A mutations in the presence of other protease inhibitors results in viable variants resistant to a second protease inhibitor. While these multiple-resistant viruses are also growth impaired, they grow significantly better than the NL4-3 multiple-resistant viruses. Genotypic analysis of the RF resistant variants identified several new mutations within the protease gene. The significance of these mutations are currently under study using HIV-1 recombinant viruses. These initial experiments investigating the viability of HIV-1 variants containing more than 2 protease mutations are quite encouraging. They suggest that treatment with 2 protease inhibitors having distinct resistance profiles may be an effective approach to antiviral therapy.

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1994-08-02
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