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Antimicrobial Agents and Chemotherapy, December 2000, p. 3465-3472, Vol. 44, No. 12
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Differential Removal of Thymidine Nucleotide Analogues from Blocked DNA Chains by Human Immunodeficiency Virus Reverse Transcriptase in the Presence of Physiological Concentrations of 2'-Deoxynucleoside Triphosphates

Peter R. Meyer,1 Suzanne E. Matsuura,1 Raymond F. Schinazi,2 Antero G. So,3 and Walter A. Scott1,*

Department of Biochemistry and Molecular Biology1 and Department of Medicine,3 University of Miami, Miami, Florida, and Department of Pediatrics, Emory University/Veterans Affairs Medical Center, Decatur, Georgia2

Received 4 April 2000/Returned for modification 22 June 2000/Accepted 25 August 2000

Removal of 2',3'-didehydro-3'-deoxythymidine-5'-monophosphate (d4TMP) from a blocked DNA chain can occur through transfer of the chain-terminating residue to a nucleotide acceptor by human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). ATP-dependent removal of either d4TMP or 3'-azido-3'-deoxythymidine-5'-monophosphate (AZTMP) is increased in AZT resistant HIV-1 RT (containing D67N/K70R/T215F/K219Q mutations). Removal of d4TMP is strongly inhibited by the next complementary deoxynucleoside triphosphate (50% inhibitory concentration [IC50] of ~0.5 µM), whereas removal of AZTMP is much less sensitive to this inhibition (IC50 of >100 µM). This could explain the lack of cross-resistance by AZT-resistant HIV-1 to d4T in phenotypic drug susceptibility assays.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, P.O. Box 016129, Miami, FL 33101-6129. Phone: (305) 243-6359. Fax: (305) 243-3342. E-mail: wscott{at}miami.edu.

Antimicrobial Agents and Chemotherapy, December 2000, p. 3465-3472, Vol. 44, No. 12
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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