Byrnes V, Blahy O, Condra J, Gotlib L, Graham D, Long W, Quintero J, Rhodes A, Roth E, Sardana V; National Conference on Human Retroviruses and Related Infections.
Program Abstr First Natl Conf Hum Retrovir Relat Infect Natl Conf Hum Retrovir Relat Infect 1st 1993 Wash DC. 1993 Dec 12-16; 56.
Merck Research Laboratories, West Point, PA.
The reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1) is inhibited by the nucleoside analogs 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI) as well as by the nonnucleoside inhibitors (NNI) L-697,661 and BI-RG-587. Unfortunately, the usefulness of these inhibitors as single therapeutic agents is limited by the emergence, in treated infected persons, of resistant virus variants. The molecular basis for the loss of virus susceptibility has been attributed to substitutions at RT residues 41, 67, 70, 215 and 219 for AZT; 74 for ddI; and 98, 100, 101, 103, 106, 181 and 188 for the NNI's. Currently several clinical studies are underway to evaluate the efficacy of therapy combining nucleoside analogs with NNI's. The possibility exists of selecting virus that loses susceptibility to both classes of inhibitors. To directly address the question of functional interactions of RT residues that mediate sensitivity to AZT, ddI and NNI's we constructed a series of recombinants that contain combinations of substitutions mediating sensitivity to both classes of inhibitors and analyzed their effect on susceptibility in the RT enzymes and viruses. For instance, we found that substitutions at residues 74, 100, or 181 resensitized virus to AZT in the presence of AZT resistance engendering mutations. However, this effect of the residue 74 alteration was abrogated by co- expression of NNI specific substitutions at residues 103 or 106. The apparent phenotypic interactions that occur among co-expressed RT mutations reflect significant structural and functional flexibility by the enzyme which allows the virus to be resistant to various combinations of RT inhibitors.
Publication Types:
Keywords:
- Didanosine
- Disease Susceptibility
- HIV-1
- Humans
- Mutation
- Nevirapine
- Nucleosides
- RNA-Directed DNA Polymerase
- Zidovudine
- genetics
Other ID:
UI: 102213984
From Meeting Abstracts