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Generation and analysis of drug resistant isolates.
Boltz VF; Buckheit R; Southern Research Institute-Frederick Research
December 30, 1995
Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;:133.

Virus isolates resistant to several nonnucleoside reverse transcriptase inhibitors have been obtained by in vitro culture. The agents used in the selection of these isolates include TIBO, thiazolobenzimidazole, diphenyl sulfone, calanolide A, oxathiin carboxanilide and HEPT. Each of these compounds is HIV-1 specific and each, with the exception of calanolide A, is inactive against the pyridinone-resistant strain A17. Each of these resistant virus strains exhibits high level resistance (greater than 10-20-fold) to the selecting agent without any change in sensitivity to AZT. Cross-resistance patterns were analyzed to determine if resistance to the selecting agent would necessarily result in the generation of resistance to all members of this structurally diverse class of inhibitors. The results of these studies suggest that the compounds may be grouped into four classes. (1) The most common class of inhibitor includes the compounds TIBO, thiazolobenzimidazole, and oxathiin carboxanilide. The virus isolates resistant to these compounds are cross-resistant to all members of the nonnucleoside class of compounds. The calanolide A, HEPT, and diphenyl sulfone-resistant viruses, however, each have distinct patterns of cross-resistance. (2) Calanolide A- resistant virus is inhibited by all of the compounds except for calanolide A. (3) The diphenyl sulfone resistant virus is cross-resistant to all of the compounds except for calanolide A. The diphenyl sulfone-resistant virus is ten- fold more sensitive to calanolide A than to wild type virus. (4) The HEPT resistant virus is not cross-resistant to any of the compounds studied and exhibits increased sensitivity to thiazolobenzimidazole (5-fold). Analysis of the mutations responsible for these phenotypes and the in vitro selection of multiple drug resistant virus strains are in progress.

Cell Line Chronic Disease Didanosine/PHARMACOLOGY Gene Products, tat/ANTAGONISTS & INHIB Human HIV Core Protein p24/METABOLISM HIV Infections/*PATHOLOGY HIV Protease Inhibitors/PHARMACOLOGY HIV-1/DRUG EFFECTS/ISOLATION & PURIF Tumor Necrosis Factor/BIOSYNTHESIS Zidovudine/PHARMACOLOGY ABSTRACT