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

SUBGROUPS OF HIV-1-SPECIFIC INHIBITOR-RESISTANT ISOLATES ARE DEFINED BY THEIR RESPECTIVE RESISTANCE-ENGENDERING MUTATIONS

Int Wkshop HIV Drug Res 1994 Aug 2-5;3:40 (abstract no. 39)

R W. Buckheit Jr. and V. Fliakas-Boltz
Southern Research Institute-Frederick Research Center, Frederick, MD, USA

We have been investigating the possibility that specific combinations of nonnucleoside RT inhibitors may be therapeutically useful due to the generation of incompatible mutations. A variety of nonnucleoside RT inhibitors obtained by the National Cancer Institute and National Institute of Allergy and Infectious Diseases were used to generate drug-resistant virus isolates in cell culture. These agents include TIBO, thiazolobenzimidazole, diphenylsulfone, calanolide A, oxathiin carboxanilide and HEPT. These drug resistant virus isolates, as well as isolates obtained from other laboratories, were tested for cross-resistance to a variety of nonnucleoside RT inhibitors. These assays resulted in the identification of four distinct subgroups of nonnucleoside RT inhibitor. The subgroups were defined based on the amino acid substitution present in the reverse transcriptase of the drug resistant virus isolate. Subgroup I is comprised of virus isolates with mutations A98G, L100I, and V1081, which result in cross-resistance to all of the compounds tested. Subgroup II is comprised of the calanolide A-resistant virus which is not cross-resistant to any of the other nonnucleoside compounds tested. This virus exhibits a mutation which has not been observed to date. Subgroup III . includes viruses which exhibit the well-defined Y181C mutation. These virus isolates were cross-resistant to all of the compounds tested with the exception of calanolide A; enhanced sensitivity to calanolide A was detected. Subgroup IV includes a drug-resistant isolate with the P236L mutation. This isolate is sensitive to all of the compounds evaluated. In addItion to defining cross-resistance phenotypes, these studies have also determined that virus isolates with a specific mutation (i.e., Y181C) are not necessarily cross-resistant to each of the panel of compounds to the same degree. For example the N119 and the diphenylsulfone-resistant isolates both possess only the Y181C mutation but yield distinct cross-resistance profiles. We have also determined that a given class of compounds (i.e., HEPT) generate mutations which yield isolates belonging to different subgroups. Finally, phenotypic cross-resistance data served to identify specific combinations of compounds which might be therapeutically useful. The results of ongoing studies with selected drug combinations will be presented.

This work was supported in part by contracts NOI-AI-05087 (NIAID) and NO1-CM-37818 (NCI).

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1994-08-02
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