University of Miami >> Miller School of Medicine >> Office of Graduate Studies >> Faculty Research >> Faculty Research Detail

Walter A. Scott, Ph.D.

Professor, Department of Biochemistry & Molecular Biology, and Professor, Department of Microbiology & Immunology

(305) 243-6359 (office)

(305) 243-3342 (fax)

Room 216, Gautier Building

wscott@med.miami.edu


Curriculum Vitae
Ph.D. (1970) University of Wisconsin
 
Honors and Professional Activities

Director, Human Retrovirus Laboratory for the IMPAACT Clinical Trials Program
Member, Virology Technical Advisory Committee for the Division of AIDS, NIH
Full member, NIH Review Panel, AIDS Discovery and Development of Therapeutics
Member, American Society for Biochemistry and Molecular Biology
Member, American Society for Microbiology
 

Research Interests
Dr. Scott's laboratory has studied the biochemistry of HIV replication since the early 1990's. Replication is carried out by a virus-encoded protein, reverse transcriptase (RT). Since HIV RT is one of the simplest DNA polymerases, the study of this enzyme allows us to investigate some of the most basic mechanisms of DNA synthesis such as nucleotide recognition, enzyme translocation, and internal conformational changes that occur during DNA synthesis.
 
RT is the target for many drugs that are used to treat HIV-infected patients including drugs that work by chain termination. These compounds (including AZT, 3TC, d4T, etc.) are incorporated into growing DNA chains by RT and block further DNA synthesis. We discovered that HIV RT has a novel activity that allows it to remove the chain-terminating nucleotides after they have been incorporated and that a common intracellular molecule such as ATP can serve as acceptor for this unblocking reaction. Therapy with AZT selects virus mutants that are highly resistant to AZT because they encode RT with enhanced ATP-dependent unblocking activity.
 
Further research will focus on what determines sensitivity of HIV to various drugs that target RT and the mechanisms of resistance due to mutations that are selected by these drugs. We are also actively studying other steps in HIV replication in hopes of identifying new targets for drug development. Future development of anti-HIV drugs will depend on basic research that advances our understanding of the HIV life cycle.
 
Major Discoveries:
 
  • Primer unblocking activity of HIV-1 RT is enhanced by AZT-resistant mutants of HIV.
  • Identification of intracellular molecules that can serve as acceptors for primer-unblocking reaction of HIV RT.
  • Ligands that bind to HIV-1 RT and form stable complexes with the enzyme locked at distinct positions on the primer template.
 

Recent Publications
Meyer, P.R., Matsuura, S.E., Mian, A.M., So, A.G., and Scott, W.A. (1999) A mechanism of AZT-resistance: An increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Molecular Cell 4: 35-43.
 
Smith, A.J., and Scott, W.A. (2006) The influence of natural substrates and inhibitors on the nucleotide-dependent excision activity of HIV-1 reverse transcriptase in the infected cell. Curr. Pharm. Des. 12: 1827-1841.
 
Meyer, P.R, Smith, A.J., Matsuura, S.E., and Scott, W.A. (2006) Chain-terminating dinucleoside tetraphosphates are substrates for DNA polymerization by human immunodeficiency virus type 1 reverse transcriptase with increased activity against thymidine analogue-resistant mutants. Antimicrob. Agents Chemother. 50: 3607-3614.
 
Meyer, P.R., Rutvisuttinunt, W., Matsuura, S.E., So, A.G., and Scott, W.A. (2007) Stable complexes formed by HIV-1 reverse transcriptase at distinct positions on the primer-template controlled by binding deoxynucleoside triphosphates or foscarnet. J. Mol. Biol. 369: 41-54.
 
Rutvisuttinunt, W., Meyer, P.R., and Scott, W.A. (2008) Interactions between HIV-1 reverse transcriptase and the downstream template strand in stable complexes with primer-template. PLoS ONE 3(10): e3561.
 
 


 
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