Abstract
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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphate / metabolism
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DNA Primers / metabolism*
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Dideoxynucleotides
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HIV Reverse Transcriptase / drug effects
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HIV Reverse Transcriptase / metabolism*
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Reverse Transcriptase Inhibitors / pharmacology
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Stavudine / analogs & derivatives*
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Stavudine / metabolism*
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Stavudine / pharmacology
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Templates, Genetic
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Thymidine Monophosphate / analogs & derivatives
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Thymidine Monophosphate / metabolism
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Thymine Nucleotides / metabolism
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Thymine Nucleotides / pharmacology
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Zidovudine / analogs & derivatives*
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Zidovudine / metabolism
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Zidovudine / pharmacology
Substances
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2',3'-dideoxy-2',3'-didehydrothymidine monophosphate
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DNA Primers
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Dideoxynucleotides
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Reverse Transcriptase Inhibitors
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Thymine Nucleotides
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3'-azido-3'-deoxythymidine 5'phosphate
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Thymidine Monophosphate
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Zidovudine
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Adenosine Triphosphate
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Stavudine
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HIV Reverse Transcriptase