| Title | Impact of novel human immunodeficiency virus type 1 reverse transcriptase mutations P119S and T165A on 4'-ethynylthymidine analog resistance profile. |
| Publication Type | Journal Article |
| Year of Publication | 2009 |
| Authors | Yang, Guangwei, Elijah Paintsil, Ginger E. Dutschman, Susan P. Grill, Chuan-Jen Wang, Jimin Wang, Hiromichi Tanaka, Takayuki Hamasaki, Masanori Baba, and Yung-Chi Cheng |
| Journal | Antimicrobial agents and chemotherapy |
| Volume | 53 |
| Issue | 11 |
| Pagination | 4640-6 |
| Date Published | 2009 Nov |
| ISSN | 1098-6596 |
| Keywords | Anti-HIV Agents, Computer Simulation, Drug Resistance, Viral, HIV Reverse Transcriptase, HIV-1, Humans, Microbial Sensitivity Tests, Mutation, Reverse Transcriptase Inhibitors, Stavudine |
| Abstract | 2',3'-Didehydro-3'-deoxy-4'-ethynylthymidine (4'-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'-Ed4T triphosphate was a better reverse transcriptase (RT) inhibitor than d4T triphosphate, due to the additional binding of the 4'-ethynyl group at a presumed hydrophobic pocket in the RT active site. Previous in vitro selection for 4'-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'-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'-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'-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'-Ed4TTP with 8- to 13-fold less efficiency than wild-type RT. M184V may be the primary resistance-associated mutation of 4'-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'-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'-Ed4T may be partly due to mutations both in the RT sequence and outside the RT sequence. |
| DOI | 10.1007/s10461-009-9532-3 |
| Alternate Journal | Antimicrob. Agents Chemother. |
