This is a application to investigate the role of HIV RT fidelity in the genomic hypervariablity of HIV in response to selective pressures such as drug therapy. Presumably, it is the hypervariablity of HIV which leads to the emergence of drug-resistant strains. This genetic diversity has been hypothesized to result from error-prone replication by the viral polymerase. However, direct in vivo evidence relating the infidelity of HIV RT to genomic diversity is lacking. The investigator plans to pursue his investigation by three major objectives: First, the investigator will use random mutagenesis of the Beta-9/Beta 10 palm region of the HIV RT followed by genetic selection in a bacterial-based genetic complimentation assay to isolate HIV RT fidelity mutants. The selected mutants, and a mutant of interest already generated from his preliminary work, will then be characterized to determine the extent to which replicational accuracy has changed. Mutants which exhibit a 5-fold change in fidelity will be considered for further study. Second, the investigator will construct proviral clones containing the HIV RTs with mutations of interest and determine the degree of genetic variability in the genome of the HIV species carrying these altered RTs. Third, the investigator plans to measure the capability of HIV with mutant RT genes characterized from the previous aims to escape from the selective pressure of HIV protease inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29GM055500-04
Application #
6180675
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Program Officer
Wolfe, Paul B
Project Start
1997-07-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
4
Fiscal Year
2000
Total Cost
$111,226
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627