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.
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 [IC(50)] of approximately 0.5 microM), whereas removal of AZTMP is much less sensitive to this inhibition (IC(50) of >100 microM). This could explain the lack of cross-resistance by AZT-resistant HIV-1 to d4T in phenotypic drug susceptibility assays.
Meyer
P R
PR
Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida 33101-6129, USA.
Matsuura
S E
SE
Schinazi
R F
RF
So
A G
AG
Scott
W A
WA
D000255:Adenosine Triphosphate / Q000378:metabolism; D017931:DNA Primers / Q000378:metabolism*; D054306:Dideoxynucleotides; D054303:HIV Reverse Transcriptase / Q000187:drug effects / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D018119:Stavudine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D013698:Templates, Genetic; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives / Q000378:metabolism; D013942:Thymine Nucleotides / Q000378:metabolism / Q000494:pharmacology; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
C113124:2',3'-dideoxy-2',3'-didehydrothymidine monophosphate; D017931:DNA Primers; D054306:Dideoxynucleotides; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; C057287:3'-azido-3'-deoxythymidine 5'phosphate; D013938:Thymidine Monophosphate; D015215:Zidovudine; D000255:Adenosine Triphosphate; D018119:Stavudine; D054303:HIV Reverse Transcriptase