DRUG RESISTANT HIV REVERSE TRANSCRIPTASES

Project: Research project

Project Details

Description

DESCRIPTION: (Adapted from applicant's abstract) The applicant proposes to
use an in vitro procedure that detects drug-resistant genetic variants of
HIV reverse transcriptase (RT) expressed in bacteria. Employing a recently
developed, novel in situ colony screening assay for HIV RT, substrate
analog inhibitor-resistant HIV RT enzymes will be isolated.
Cross-resistance of such mutant RTs to other drugs will be determined to
help plan combination therapy. Selected mutations will be rebuilt into an
infectious molecular clone of HIV and will be tested for replication
competence. This will be done in an attempt to test the in vivo relevance
of the mutant RTs with decreased sensitivity to substrate analog inhibitors
obtained by in situ colony screening. Furthermore, the investigator
proposes to characterize mutant RTs with respect to the site of mutation,
rates of misincorporation and other aspects of DNA polymerization. To gain
further insights into substrate-binding sites, residues in and around the
mutations will be further examined by specific mutagenesis. Resistance
detected biochemically may or may not reflect resistance during replication
in vivo. To ascertain the ability to anticipate mutations that arise in
vivo by utilizing this simple in vitro approach, viruses will be isolated
from patients who are under therapy in AIDS clinical trials and their RT
sequences will be tested for the presence of mutations that lead to
resistance.
StatusFinished
Effective start/end date9/1/917/31/92

Funding

  • National Institute of Allergy and Infectious Diseases

ASJC

  • Infectious Diseases

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