Dynamics of hepatitis B virus quasispecies in association with nucleos(t)ide analogue treatment determined by ultra-deep sequencing.
Dynamics of hepatitis B virus quasispecies in association with nucleos(t)ide analogue treatment determined by ultra-deep sequencing.
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DOI：
10.1371/journal.pone.0035052
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Chiba T
中科院分区：
文献类型：
--
作者：
Nishijima N;Marusawa H;Ueda Y;Takahashi K;Nasu A;Osaki Y;Kou T;Yazumi S;Fujiwara T;Tsuchiya S;Shimizu K;Uemoto S;Chiba T
尽管超深度测序技术的出现允许分析迄今为止无法检测到的微小病毒突变体，但目前关于B型肝炎病毒（HBV）基因组异质性的临床意义的信息有限。为了表征与抗病毒治疗相关的HBV遗传异质性，我们对19例慢性病毒感染患者的肝脏和血清中的全基因组HBV进行了超深度测序，其中包括14例未经治疗的患者和5例核苷（酸）类似物（NA）治疗的患者。在病毒变异体中观察到的大多数基因组变化是单碱基取代，并且广泛分布于整个HBV基因组中。8例慢性治疗初治HBeAg阴性患者中有4例（50%）显示肝组织中G1896 A前核心（pre-C）突变的患病率相对较低，表明其他突变参与了HBeAg血清转换。有趣的是，5例慢性NA治疗的抗HBe阳性病例中有4例（80%）的肝组织中G1896 A前C突变体的水平极低（0.0%，0.0%，0.1%和1.1%），表明G1896 A前C突变体对NA的高敏感性。此外，在未经治疗的患者的肝脏和血清中，对NA耐药的克隆的各种丰度是常见的，并且在35.7%（5/14）的患者的血清中，对拉米夫定和恩替卡韦耐药的M204 VI突变体的比例在恩替卡韦治疗后扩大，这表明了对NA产生耐药性的假定风险。我们的研究结果说明了病毒基因组深度测序作为剖析HBV感染病理生理学的工具的强大优势。
Although the advent of ultra-deep sequencing technology allows for the analysis of heretofore-undetectable minor viral mutants, a limited amount of information is currently available regarding the clinical implications of hepatitis B virus (HBV) genomic heterogeneity. To characterize the HBV genetic heterogeneity in association with anti-viral therapy, we performed ultra-deep sequencing of full-genome HBV in the liver and serum of 19 patients with chronic viral infection, including 14 therapy-naïve and 5 nucleos(t)ide analogue(NA)-treated cases. Most genomic changes observed in viral variants were single base substitutions and were widely distributed throughout the HBV genome. Four of eight (50%) chronic therapy-naïve HBeAg-negative patients showed a relatively low prevalence of the G1896A pre-core (pre-C) mutant in the liver tissues, suggesting that other mutations were involved in their HBeAg seroconversion. Interestingly, liver tissues in 4 of 5 (80%) of the chronic NA-treated anti-HBe-positive cases had extremely low levels of the G1896A pre-C mutant (0.0%, 0.0%, 0.1%, and 1.1%), suggesting the high sensitivity of the G1896A pre-C mutant to NA. Moreover, various abundances of clones resistant to NA were common in both the liver and serum of treatment-naïve patients, and the proportion of M204VI mutants resistant to lamivudine and entecavir expanded in response to entecavir treatment in the serum of 35.7% (5/14) of patients, suggesting the putative risk of developing drug resistance to NA. Our findings illustrate the strong advantage of deep sequencing on viral genome as a tool for dissecting the pathophysiology of HBV infection.
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影响因子：
2.5
作者：
Hollinger, F. B.
通讯作者：
Hollinger, F. B.
影响因子：
39.2
作者：
Ikeda, Kazuki;Marusawa, Hiroyuki;Chiba, Tsutomu
通讯作者：
Chiba, Tsutomu
影响因子：
3.7
作者：
Lataillade M;Chiarella J;Yang R;Schnittman S;Wirtz V;Uy J;Seekins D;Krystal M;Mancini M;McGrath D;Simen B;Egholm M;Kozal M
通讯作者：
Kozal M
DOI：
10.1086/597808
发表时间：
2009-05-01
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Margeridon-Thermet S;Shulman NS;Ahmed A;Shahriar R;Liu T;Wang C;Holmes SP;Babrzadeh F;Gharizadeh B;Hanczaruk B;Simen BB;Egholm M;Shafer RW
通讯作者：
Shafer RW
影响因子：
3.2
作者：
Fishman, Sarah L.;Branch, Andrea D.
通讯作者：
Branch, Andrea D.