Chow YK, Hirsch MS, Merrill DP, Bechtel LJ, Eron JJ, Kaplan JC, D'Aquila RT; International Conference on AIDS.
Int Conf AIDS. 1992 Jul 19-24; 8: A78 (article no. PoA 2450).
Dept. of Medicine, Harvard Med. Sch., Charlestown, MA.
OBJECTIVE: We have studied three types of interactions among drug resistance reverse transcriptase (RT) mutations to analyze the structure-function relationships of HIV-1 RT. Interactions among these RT mutations may compromise either the drug resistance or the replication capacity of HIV-1. Some interactions may even be incompatible with virus replication. METHODS & RESULTS: HIV-1 provirus clones were constructed which contain multiple RT mutations encoding resistance to AZT, ddI, foscarnet, and pyridinone, a non-nucleoside HIV-1 specific RT inhibitor. A group of mutant viruses from COS-7 transfected cells exhibited undetectable RT activity, but produced normal levels of supernatant p24 antigen. When used to infect 3 day PHA-stimulated peripheral blood mononuclear cells and SupT1 cells, these mutant viruses were replication incompetent as assessed by RT, p24 antigen, cytopathic effect, Western blots, and quantitative PCR assays. CONCLUSIONS: This combination mutant approach was used to determine resistance profiles of different proviruses, define tolerable interactions among various mutations, document compromising and incompatible combinations of mutations, and permit genetic analyses of the interactions of various regions of the RT. The demonstration of incompatible combinations of drug resistance mutations in the HIV-1 RT suggests that residues that were altered by the mutations were interacting in the native enzyme, and has clinical implications. We propose that there may be significant advantages to convergent combination therapy, that is, targeting multiple drugs simultaneously against the same HIV-1 gene product, such as the RT. In vitro and clinical trials are currently being planned to test this hypothesis.
Publication Types:
Keywords:
- DNA Primers
- Didanosine
- Drug Resistance
- Drug Resistance, Microbial
- Drug Resistance, Viral
- Foscarnet
- HIV-1
- In Vitro
- Mutation
- RNA-Directed DNA Polymerase
- Virus Replication
- Zidovudine
- genetics
- virology
Other ID:
UI: 102198483
From Meeting Abstracts