Mechanistic interplay among the M184I HIV-1 reverse transcriptase mutant, the central polypurine tract, cellular dNTP concentrations and drug sensitivity.
We recently reported that the M184I 3TC resistant mutation reduces RT binding affinity to dNTP substrates. First, the HIV-1 M184I mutant vector displays reduced transduction efficiency compared to wild type (WT) RT vector, which could be rescued by both elevating the cellular dNTP concentration and incorporating WT RT molecules into the M184I vector particles. Second, the central polypurine tract (cPPT) mutation and M184I mutation additively reduced the vector transduction to almost undetectable levels, particularly in nondividing cells. Third, the M184I (-) cPPT vector became significantly more sensitive to 3TC than the M184I (+) cPPT vector, but not to AZT or Nevirapine in the dividing cells. Finally, this 3TC sensitizing effect of the cPPT inactivation of the M184I vector was reversed by elevating the dCTP level, but not by the other three dNTPs. These data support a mechanistic interaction between cPPT and M184I RT with respect to viral replication and sensitivity to 3TC.
Van Cor-Hosmer
Sarah K
SK
Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Daddacha
Waaqo
W
Kim
Baek
B
D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology; D002460:Cell Line; D003854:Deoxyribonucleotides / Q000378:metabolism*; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid; D014779:Virus Replication
D019380:Anti-HIV Agents; D003854:Deoxyribonucleotides; D019259:Lamivudine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase