Inhibition of Viral Replication Reduces Transcriptionally Active Distinct Hepatitis B Virus Integrations With Implications on Host Gene Dysregulation

病毒血症 病毒载量 病毒复制 病毒学 乙型肝炎病毒 生物 病毒释放 病毒 病毒进入 病毒性肝炎
作者
Yao‐Chun Hsu,Vithika Suri,Mindie H. Nguyen,Yen‐Tsung Huang,Chi-Yi Chen,I‐Wei Chang,Cheng‐Hao Tseng,Chun–Ying Wu,Jaw‐Town Lin,David Z. Pan,Anuj Gaggar,Ondřej Podlaha
出处
期刊:Gastroenterology [Elsevier]
卷期号:162 (4): 1160-1170.e1 被引量:40
标识
DOI:10.1053/j.gastro.2021.12.286
摘要

Background & aims Hepatocellular carcinogenesis of hepatitis B virus (HBV) infection may arise from integration of viral DNA into the host genome. We aimed to gauge the effect of viral inhibition on transcriptionally active HBV-host integration events and explore the correlation of viral integrations with host gene dysregulation. Methods We leveraged data and biospecimens from an interventional trial, in which patients with HBV viremia above 2000 IU/mL and minimally raised serum liver enzyme were randomized to receive tenofovir disoproxil fumarate (TDF) or placebo for 3 years. Total RNA-sequencing was performed on paired liver biopsies taken before and after the 3-year intervention in 119 patients. Virus-host chimeric reads were captured to quantify the number of distinct viral integrations. Dysregulation of a host gene disrupted by viral integration was defined by aberrant expression >2 standard deviations away from samples without viral integration. Results The TDF (n = 64) and placebo groups (n = 55) were comparable at baseline. Expressed viral integrations were detected in all pre- and posttreatment samples. The number of distinct viral integrations significantly correlated with circulatory biomarkers indicative of viral activities including HBV DNA, RNA, and viral antigens (P < .0003 for all correlations). Moreover, TDF vs placebo achieved a significantly greater reduction in distinct viral integrations, with 3.28-fold and 1.81-fold decreases in the expressed integrations per million reads, respectively (analysis of covariance, P = .037). Besides, viral integrations significantly correlated with host gene dysregulation. Conclusion Inhibition of viral replication reduces the number of transcriptionally active distinct HBV-host DNA integrations in patients with substantial viremia. Given the mutagenic potentials of viral integrations, such treatment effects should be considered in patient management. Hepatocellular carcinogenesis of hepatitis B virus (HBV) infection may arise from integration of viral DNA into the host genome. We aimed to gauge the effect of viral inhibition on transcriptionally active HBV-host integration events and explore the correlation of viral integrations with host gene dysregulation. We leveraged data and biospecimens from an interventional trial, in which patients with HBV viremia above 2000 IU/mL and minimally raised serum liver enzyme were randomized to receive tenofovir disoproxil fumarate (TDF) or placebo for 3 years. Total RNA-sequencing was performed on paired liver biopsies taken before and after the 3-year intervention in 119 patients. Virus-host chimeric reads were captured to quantify the number of distinct viral integrations. Dysregulation of a host gene disrupted by viral integration was defined by aberrant expression >2 standard deviations away from samples without viral integration. The TDF (n = 64) and placebo groups (n = 55) were comparable at baseline. Expressed viral integrations were detected in all pre- and posttreatment samples. The number of distinct viral integrations significantly correlated with circulatory biomarkers indicative of viral activities including HBV DNA, RNA, and viral antigens (P < .0003 for all correlations). Moreover, TDF vs placebo achieved a significantly greater reduction in distinct viral integrations, with 3.28-fold and 1.81-fold decreases in the expressed integrations per million reads, respectively (analysis of covariance, P = .037). Besides, viral integrations significantly correlated with host gene dysregulation. Inhibition of viral replication reduces the number of transcriptionally active distinct HBV-host DNA integrations in patients with substantial viremia. Given the mutagenic potentials of viral integrations, such treatment effects should be considered in patient management.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
失眠惊蛰发布了新的文献求助10
刚刚
刚刚
Dream7完成签到,获得积分10
1秒前
慕青应助沉默的早晨采纳,获得10
1秒前
夏侯德东发布了新的文献求助10
2秒前
2秒前
超帅新之发布了新的文献求助10
2秒前
稳重秋寒完成签到,获得积分10
2秒前
丫妹发布了新的文献求助10
3秒前
ced完成签到,获得积分10
3秒前
科研通AI5应助淡然白安采纳,获得10
3秒前
阿嚏发布了新的文献求助10
4秒前
4秒前
SciGPT应助沫沫采纳,获得10
4秒前
5秒前
安然僧发布了新的文献求助10
5秒前
rui关闭了rui文献求助
6秒前
在学一会完成签到,获得积分10
6秒前
细腻小笼包完成签到,获得积分10
7秒前
8秒前
菠萝菠萝哒应助General采纳,获得30
9秒前
爆米花应助悦悦采纳,获得10
10秒前
何时到达关注了科研通微信公众号
10秒前
10秒前
盘尼西林发布了新的文献求助30
11秒前
丫妹完成签到,获得积分10
11秒前
11秒前
烟花应助三木采纳,获得10
11秒前
科目三应助李星翰采纳,获得10
12秒前
13秒前
14秒前
噜噜噜噜完成签到,获得积分10
14秒前
14秒前
不学无墅完成签到,获得积分10
16秒前
caibuyaobing完成签到,获得积分10
16秒前
whisper发布了新的文献求助10
17秒前
科研通AI5应助虚心青采纳,获得10
17秒前
17秒前
Hezhiwu777发布了新的文献求助10
18秒前
YY完成签到 ,获得积分10
18秒前
高分求助中
Continuum Thermodynamics and Material Modelling 3000
Production Logging: Theoretical and Interpretive Elements 2700
Mechanistic Modeling of Gas-Liquid Two-Phase Flow in Pipes 2500
Kelsen’s Legacy: Legal Normativity, International Law and Democracy 1000
Conference Record, IAS Annual Meeting 1977 610
Interest Rate Modeling. Volume 3: Products and Risk Management 600
Interest Rate Modeling. Volume 2: Term Structure Models 600
热门求助领域 (近24小时)
化学 材料科学 生物 医学 工程类 有机化学 生物化学 物理 纳米技术 计算机科学 内科学 化学工程 复合材料 基因 遗传学 物理化学 催化作用 量子力学 光电子学 冶金
热门帖子
关注 科研通微信公众号,转发送积分 3543718
求助须知:如何正确求助?哪些是违规求助? 3121033
关于积分的说明 9345352
捐赠科研通 2819128
什么是DOI,文献DOI怎么找? 1549968
邀请新用户注册赠送积分活动 722341
科研通“疑难数据库(出版商)”最低求助积分说明 713153