@article {3072,
	title = {Impact of novel human immunodeficiency virus type 1 reverse transcriptase mutations P119S and T165A on 4{\textquoteright}-ethynylthymidine analog resistance profile.},
	journal = {Antimicrobial agents and chemotherapy},
	volume = {53},
	year = {2009},
	month = {2009 Nov},
	pages = {4640-6},
	abstract = {2{\textquoteright},3{\textquoteright}-Didehydro-3{\textquoteright}-deoxy-4{\textquoteright}-ethynylthymidine (4{\textquoteright}-Ed4T), a derivative of stavudine (d4T), has potent activity against human immunodeficiency virus and is much less inhibitory to mitochondrial DNA synthesis and cell growth than its progenitor, d4T. 4{\textquoteright}-Ed4T triphosphate was a better reverse transcriptase (RT) inhibitor than d4T triphosphate, due to the additional binding of the 4{\textquoteright}-ethynyl group at a presumed hydrophobic pocket in the RT active site. Previous in vitro selection for 4{\textquoteright}-Ed4T-resistant viral strains revealed M184V and P119S/T165A/M184V mutations on days 26 and 81, respectively; M184V and P119S/T165A/M184V conferred 3- and 130-fold resistance to 4{\textquoteright}-Ed4T, respectively. We investigated the relative contributions of these mutations, engineered into the strain NL4-3 background, to drug resistance, RT activity, and viral growth. Viral variants with single RT mutations (P119S or T165A) did not show resistance to 4{\textquoteright}-Ed4T; however, M184V and P119S/T165A/M184V conferred three- and fivefold resistance, respectively, compared with that of the wild-type virus. The P119S/M184V and T165A/M184V variants showed about fourfold resistance to 4{\textquoteright}-Ed4T. The differences in the growth kinetics of the variants were not more than threefold. The purified RT of mutants with the P119S/M184V and T165A/M184V mutations were inhibited by 4{\textquoteright}-Ed4TTP with 8- to 13-fold less efficiency than wild-type RT. M184V may be the primary resistance-associated mutation of 4{\textquoteright}-Ed4T, and P119S and T165A are secondary mutations. On the basis of our findings and the results of structural modeling, a virus with a high degree of resistance to 4{\textquoteright}-Ed4T (e.g., more than 50-fold resistance) will be difficult to develop. The previously observed 130-fold resistance of the virus with P119S/T165A/M184V to 4{\textquoteright}-Ed4T may be partly due to mutations both in the RT sequence and outside the RT sequence.},
	keywords = {Anti-HIV Agents, Computer Simulation, Drug Resistance, Viral, HIV Reverse Transcriptase, HIV-1, Humans, Microbial Sensitivity Tests, Mutation, Reverse Transcriptase Inhibitors, Stavudine},
	issn = {1098-6596},
	doi = {10.1007/s10461-009-9532-3},
	author = {Yang, Guangwei and Paintsil, Elijah and Dutschman, Ginger E and Grill, Susan P and Wang, Chuan-Jen and Wang, Jimin and Tanaka, Hiromichi and Hamasaki, Takayuki and Baba, Masanori and Cheng, Yung-Chi}
}
