Convergence and coevolution of Hepatitis B virus drug resistance

被引：40

作者：

Hong Thai ^{[1
]}

Campo, David S. ^{[1
]}

Lara, James ^{[1
]}

Dimitrova, Zoya ^{[1
]}

Ramachandran, Sumathi ^{[1
]}

Xia, Guoliang ^{[1
]}

Ganova-Raeva, Lilia ^{[1
]}

Teo, Chong-Gee ^{[1
]}

Lok, Anna ^{[2
]}

Khudyakov, Yury ^{[1
]}

机构：

[1] Ctr Dis Control & Prevent, Mol Epidemiol & Bioinformat Lab, Div Viral Hepatitis, Atlanta, GA 30329 USA

[2] Univ Michigan Hlth Syst, Div Gastroenterol & Hepatol, Dept Internal Med, Ann Arbor, MI 48109 USA

来源：

NATURE COMMUNICATIONS | 2012年 / 3卷

关键词：

NAIVE PATIENTS; NUCLEOSIDE; POLYMERASE; SELECTION; THERAPY; ANALOGS; TREES;

D O I：

10.1038/ncomms1794

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Treatment with lamivudine of patients infected with hepatitis B virus (HBV) results in a high rate of drug resistance, which is primarily associated with the rtM204I/V substitution in the HBV reverse transcriptase domain. Here we show that the rtM204I/V substitution, although essential, is insufficient for establishing resistance against lamivudine. The analysis of 639 HBV whole-genome sequences obtained from 11 patients shows that rtM204I/V is independently acquired by more than one intra-host HBV variant, indicating the convergent nature of lamivudine resistance. The differential capacity of HBV variants to develop drug resistance suggests that fitness effects of drug-resistance mutations depend on the genetic structure of the HBV genome. An analysis of Bayesian networks that connect rtM204I/V to many sites of HBV proteins confirms that lamivudine resistance is a complex trait encoded by the entire HBV genome rather than by a single mutation. These findings have implications for public health and offer a more general framework for understanding drug resistance.

引用

页数：8

共 27 条

[1] Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase [J].