乙型肝炎病毒药物持久性的复杂遗传编码

StephenW

Complex genetic encoding of the hepatitis B virus on-drug persistence
Hong Thai  1 , James Lara  2 , Xiaojun Xu  2   3 , Kathryn Kitrinos  4   5 , Anuj Gaggar  4 , Henry Lik Yuen Chan  6 , Guo-Liang Xia  2 , Lilia Ganova-Raeva  2 , Yury Khudyakov  2
Affiliations
Affiliations

    1
    Division of Viral Hepatitis, Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA, 30329, USA. [email protected].
    2
    Division of Viral Hepatitis, Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA, 30329, USA.
    3
    Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA.
    4
    Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
    5
    ViiV Healthcare, Research Triangle Park, NC, 27709, USA.
    6
    The Chinese University of Hong Kong, Hong Kong, China.

    PMID: 32968103 DOI: 10.1038/s41598-020-72467-9

Abstract

Tenofovir disoproxil fumarate (TDF) is one of the nucleotide analogs capable of inhibiting the reverse transcriptase (RT) activity of HIV and hepatitis B virus (HBV). There is no known HBV resistance to TDF. However, detectable variation in duration of HBV persistence in patients on TDF therapy suggests the existence of genetic mechanisms of on-drug persistence that reduce TDF efficacy for some HBV strains without affording actual resistance. Here, the whole genome of intra-host HBV variants (N = 1,288) was sequenced from patients with rapid (RR, N = 5) and slow response (SR, N = 5) to TDF. Association of HBV genomic and protein polymorphic sites to RR and SR was assessed using phylogenetic analysis and Bayesian network methods. We show that, in difference to resistance to nucleotide analogs, which is mainly associated with few specific mutations in RT, the HBV on-TDF persistence is defined by genetic variations across the entire HBV genome. Analysis of the inferred 3D-structures indicates no difference in affinity of TDF binding by RT encoded by intra-host HBV variants that rapidly decline or persist in presence of TDF. This finding suggests that effectiveness of TDF recognition and binding does not contribute significantly to on-drug persistence. Differences in patterns of genetic associations to TDF response between HBV genotypes B and C and lack of a single pattern of mutations among intra-host variants sensitive to TDF indicate a complex genetic encoding of the trait. We hypothesize that there are many genetic mechanisms of on-drug persistence, which are differentially available to HBV strains. These pervasive mechanisms are insufficient to prevent viral inhibition completely but may contribute significantly to robustness of actual resistance. On-drug persistence may reduce the overall effectiveness of therapy and should be considered for development of more potent drugs.

StephenW

乙型肝炎病毒药物持久性的复杂遗传编码
Hong Thai 1，James Lara 2，Xiaojun Xu 2 3，Kathryn Kitrinos 4 5，Anuj Gaggar 4，Henry Lik Yuen Chan 6，夏国良2，Lilia Ganova-Raeva 2，Yury Khudyakov 2
隶属关系
隶属关系

    1个
    30329美国佐治亚州亚特兰大市疾病预防控制中心病毒性肝炎科。 [email protected]。
    2
    30329美国佐治亚州亚特兰大市疾病预防控制中心病毒性肝炎科。
    3
    加利福尼亚大学圣地亚哥分校Moores癌症中心，加利福尼亚州拉霍亚，美国92037。
    4
    吉利德科学公司（Gilead Sciences Inc.），美国加利福尼亚州福斯特市湖滨大道333号，美国94404。
    5
    ViiV Healthcare，美国北卡罗来纳州研究三角公园，27709。
    6
    香港中文大学，中国香港。

    PMID：32968103 DOI：10.1038 / s41598-020-72467-9

抽象

替诺福韦富马酸替索罗非酯（TDF）是一种核苷酸类似物，能够抑制HIV和乙肝病毒（HBV）的逆转录酶（RT）活性。没有已知的HBV对TDF的抗性。但是，在使用TDF治疗的患者中HBV持续时间的可检测变化表明存在药物持续性遗传机制，这些遗传机制降低了某些HBV株的TDF疗效而又没有实际抵抗力。在这里，从对TDF有快速反应（RR，N = 5）和慢反应（SR，N = 5）的患者中对宿主内HBV变异体的整个基因组（N = 1,288）进行测序。使用系统发育分析和贝叶斯网络方法评估了HBV基因组和蛋白质多态性位点与RR和SR的关联。我们显示，在对核苷酸类似物的抗性不同（主要与RT中的几个特定突变相关）方面，HBV在TDF上的持久性是由整个HBV基因组中的遗传变异定义的。对推断的3D结构的分析表明，由宿主内HBV变体编码的RT编码的TDF与TDF结合的亲和力没有差异，该宿主体内HBV变体在TDF存在下迅速下降或持续存在。这一发现表明，TDF识别和结合的有效性对药物持久性没有显着贡献。 HBV基因型B和C之间对TDF反应的遗传关联模式的差异以及对TDF敏感的宿主内部变体之间缺乏单一突变模式表明该特征的复杂遗传编码。我们假设存在许多药物持久性的遗传机制，这些遗传机制可用于HBV菌株。这些普遍的机制不足以完全防止病毒抑制，但可能对实际耐药性的稳健性有很大贡献。药物持久性可能会降低治疗的总体效果，应考虑开发更有效的药物。

StephenW

https://www.nature.com/articles/s41598-020-72467-9.pdf