TY - JOUR
T1 - Mechanistic interplay among the M184I HIV-1 reverse transcriptase mutant, the central polypurine tract, cellular dNTP concentrations and drug sensitivity
AU - Van Cor-Hosmer, Sarah K.
AU - Daddacha, Waaqo
AU - Kim, Baek
N1 - Funding Information:
This research was supported by AI049781 (BK), NIH T-32AI049815 (SKVCH) and R25 GM064133 (WD).
PY - 2010/10
Y1 - 2010/10
N2 - 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.
AB - 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.
KW - CPPT
KW - HIV-1
KW - RT inhibitor sensitivity
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U2 - 10.1016/j.virol.2010.07.028
DO - 10.1016/j.virol.2010.07.028
M3 - Article
C2 - 20701944
AN - SCOPUS:84755161158
SN - 0042-6822
VL - 406
SP - 253
EP - 260
JO - Virology
JF - Virology
IS - 2
ER -