The major limitation to the sustainable suppression of HIV-1 infection is the emergence of drug-resistant mutants during the course of therapy. The emergence of resistant variants in response to drug selection is attributed to the extensive genomic variability of HIV-1. The overall purpose of this research is to understand the fundamental mechanisms of HIV-1 mutation. We are specifically interested in determining the alterations in the molecular mechanisms of mutation associated with the acquisition of drug resistance.
The specific aims are: 1) to isolate novel drug-resistant mutants of HIV-1 reverse transcriptase with altered fidelity of DNA synthesis; 2) to compare the fidelities of wild-type and drug-resistant mutator RTs; and 3) to assess the contribution of changes in RT fidelity to changes in the overall mutation rate of HIV-1. Strategies for the treatment of HIV-1 infection must take into account the high genetic variability of the virus and any perturbations to the rate of variation resulting from therapeutic pressure. The proposed studies should provide valuable insights into the basic mechanisms of HIV-1 mutation and guide the development of more effective therapeutic strategies to control HIV-I infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI010139-02
Application #
2886319
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Program Officer
Sager, Polly R
Project Start
1998-08-01
Project End
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Utah
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
El-Manzalawy, Yasser; Munoz, Elyse E; Lindner, Scott E et al. (2016) PlasmoSEP: Predicting surface-exposed proteins on the malaria parasite using semisupervised self-training and expert-annotated data. Proteomics 16:2967-2976
Smith, Robert A; Anderson, Donovan J; Preston, Bradley D (2006) Hypersusceptibility to substrate analogs conferred by mutations in human immunodeficiency virus type 1 reverse transcriptase. J Virol 80:7169-78
Smith, Robert A; Anderson, Donovan J; Preston, Bradley D (2004) Purifying selection masks the mutational flexibility of HIV-1 reverse transcriptase. J Biol Chem 279:26726-34