Abstract

This is a competitive renewal to examine the biochemical and molecular determinants of variation in HIV. The experiments are organized into four specific aims.
The first aim i s to characterize mutations that arise in natural viral sequences rather than indicator sequences. The second is to determine whether vif, vpr, and nef affect mutation rate. The third is to assess the contribution of RT fidelity to mutation rate. The last aim is to determine the contribution of RNA pol II to mutation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI034834-08
Application #
6532696
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Miller, Roger H
Project Start
1994-05-01
Project End
2003-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
8
Fiscal Year
2002
Total Cost
$300,764
Indirect Cost

  Institution

Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Smith, Robert A; Anderson, Donovan J; Pyrak, Crystal L et al. (2009) Antiretroviral drug resistance in HIV-2: three amino acid changes are sufficient for classwide nucleoside analogue resistance. J Infect Dis 199:1323-6
Smith, Robert A; Gottlieb, Geoffrey S; Anderson, Donovan J et al. (2008) Human immunodeficiency virus types 1 and 2 exhibit comparable sensitivities to Zidovudine and other nucleoside analog inhibitors in vitro. Antimicrob Agents Chemother 52:329-32
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
Klarmann, George J; Chen, Xin; North, Thomas W et al. (2003) Incorporation of uracil into minus strand DNA affects the specificity of plus strand synthesis initiation during lentiviral reverse transcription. J Biol Chem 278:7902-9
Klarmann, G J; Smith, R A; Schinazi, R F et al. (2000) Site-specific incorporation of nucleoside analogs by HIV-1 reverse transcriptase and the template grip mutant P157S. Template interactions influence substrate recognition at the polymerase active site. J Biol Chem 275:359-66
Smith, R A; Klarmann, G J; Stray, K M et al. (1999) A new point mutation (P157S) in the reverse transcriptase of human immunodeficiency virus type 1 confers low-level resistance to (-)-beta-2',3'-dideoxy-3'-thiacytidine. Antimicrob Agents Chemother 43:2077-80
Klarmann, G J; Yu, H; Chen, X et al. (1997) Discontinuous plus-strand DNA synthesis in human immunodeficiency virus type 1-infected cells and in a partially reconstituted cell-free system. J Virol 71:9259-69
Preston, B D; Dougherty, J P (1996) Mechanisms of retroviral mutation. Trends Microbiol 4:16-21
Ji, X; Klarmann, G J; Preston, B D (1996) Effect of human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein on HIV-1 reverse transcriptase activity in vitro. Biochemistry 35:132-43
Preston, B D (1996) Error-prone retrotransposition: rime of the ancient mutators. Proc Natl Acad Sci U S A 93:7427-31