Occult Hepatitis B Infection in South African HIV Patients

南非艾滋病毒患者隐匿性乙型肝炎感染

• 批准号: 8265596
• 负责人: JASON T BLACKARD
• 金额: $ 19.02万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265596
• 关键词: Acquired Immunodeficiency Syndrome; African; Alanine Transaminase; Bioinformatics; Biological Assay; Characteristics; Chronic Hepatitis B; Cirrhosis; Clinical Management; Detection; Development; Diagnostic Sensitivity; Enzymes; Epidemiology; Flare; Future; Gene Mutation; Genes; Genome; HIV; HIV Infections; HIV Seropositivity; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Transmission; Hepatitis B Virus; Hepatocyte; High Prevalence; Highly Active Antiretroviral Therapy; Human; Immune; Immune response; In Vitro; Individual; Infection; Lamivudine; Lead; Length; Liver; Liver Fibrosis; Liver diseases; Methods; Morbidity - disease rate; Mutation; Mutation Analysis; Natural History; Open Reading Frames; Patients; Persons; Populations at Risk; Prevalence; Primary carcinoma of the liver cells; Primates; Publications; Resistance; Risk Factors; Screening procedure; Serum; South Africa; Surface; Surface Antigens; Testing; Time; Universities; Viral; Virus Diseases; Virus Replication; Withdrawal; anti-hepatitis B; assay development; cell mediated immune response; chronic liver disease; cohort; cost effective; expression vector; hepatitis B virus P protein; improved; in vitro Assay; in vivo; interest; interferon therapy; mortality; mutant; novel; reconstitution; resistance mutation; response; secondary infection; therapy development; transmission process; viral DNA

DESCRIPTION (provided by applicant): Globally, 350 million people are chronically infected with hepatitis B virus (HBV) - the world's leading cause of cirrhosis and hepatocellular carcinoma (HCC). Chronic HBV infection is characterized by the presence of hepatitis B surface antigen (HBsAg) in the serum. In contrast, occult HBV infection (O-HBV) is defined as low level HBV replication in the absence of detectable circulating HBsAg. The transmissibility of O-HBV and the subsequent establishment of chronic HBV infection are well documented in humans and in primates. Moreover, O-HBV is associated with advanced liver fibrosis, reduced response to interferon therapy, the development of HCC, and increased liver enzyme levels. In HIV-positive cohorts, the prevalence of O-HBV infection is significantly elevated. In South Africa, both HIV and HBV are endemic, and HIV co-infection is a major risk factor for O-HBV infection. Moreover, treatment resistance mutations in the HBV Polymerase (P) gene - which overlaps with the Surface (S) gene - are common in South Africa - even among treatment-naove individuals - and may also impact HBsAg expression. Only a small number of studies evaluated the potential mechanism(s) for this lack of HBsAg detection in vitro. Major limitations to characterizing O-HBV infection include 1) the lack of sensitive quantitative assays for HBV DNA, and 2) the limited ability to identify and characterize mutations that are associated with O-HBV in the context of full-length, replication-competent genomes. Fortunately, highly sensitive, cost effective real-time PCR assays for HBV DNA quantification - such as that developed within our lab - are now available. Moreover, a novel method for efficient amplification of whole HBV genomes that also permits rapid functional analysis has been developed. The aims of this application are to determine the effects of S and P gene mutations associated with O-HBV infection on HBsAg synthesis/retention/secretion and HBV replication in hepatocytes using full-length, replication-competent HBV expression vectors. The identification and characterization of O-HBV mutations in vivo that are not detected using current HBV screening assays and the development of in vitro assays to evaluate the mechanism(s) underlying the lack of HBsAg detection would improve future diagnostic sensitivity for O-HBV infection, limit secondary transmission of HBV, provide critical information on treatment options for O-HBV, and improve our understanding of how HBV replication contributes to the development of HCC.

描述（由申请人提供）：全球有3.5亿人慢性乙型肝炎病毒（HBV）感染，这是世界上导致肝硬化和肝细胞癌（HCC）的主要原因。慢性HBV感染的特点是血清中存在乙型肝炎表面抗原（HBsAg）。相比之下，隐匿性HBV感染（O-HBV）被定义为在没有可检测到的循环HBsAg的情况下低水平HBV复制。在人类和灵长类动物中，O-HBV的传播性和随后建立的慢性HBV感染得到了充分的证明。此外，O-HBV与晚期肝纤维化、干扰素治疗反应降低、HCC发展和肝酶水平升高相关。在hiv阳性队列中，O-HBV感染的流行率显著升高。在南非，艾滋病毒和乙型肝炎病毒都是地方性的，艾滋病毒合并感染是o型乙型肝炎病毒感染的主要危险因素。此外，HBV聚合酶(P)基因（与表面(S)基因重叠）的耐药突变在南非很常见，甚至在未接受治疗的个体中也很常见，并且可能影响HBsAg的表达。只有少数研究评估了这种缺乏HBsAg体外检测的潜在机制。表征O-HBV感染的主要限制包括：1)缺乏对HBV DNA的敏感定量分析；2)在全长、复制能力强的基因组背景下，识别和表征与O-HBV相关的突变的能力有限。幸运的是，用于HBV DNA定量的高灵敏度、高成本效益的实时PCR分析方法——例如我们实验室开发的方法——现在已经可用。此外，还开发了一种高效扩增HBV全基因组的新方法，该方法也允许快速功能分析。本应用程序的目的是利用全长、复制能力强的HBV表达载体，确定与O-HBV感染相关的S和P基因突变对肝细胞中HBsAg合成/保留/分泌和HBV复制的影响。目前的HBV筛查方法无法检测到的O-HBV体内突变的鉴定和表征，以及开发体外检测方法来评估缺乏HBsAg检测的机制，将提高未来对O-HBV感染的诊断敏感性，限制HBV的继发性传播，提供O-HBV治疗选择的关键信息，并提高我们对HBV复制如何促进HCC发展的理解。

项目成果

Hepatitis B virus infection in post-vaccination South Africa: occult HBV infection and circulating surface gene variants.

• DOI: 10.1016/j.jcv.2014.11.032
• 发表时间: 2015-02
• 期刊: Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
• 作者: Amponsah-Dacosta E;Lebelo RL;Rakgole JN;Selabe SG;Gededzha MP;Mayaphi SH;Powell EA;Blackard JT;Mphahlele MJ
• 通讯作者: Mphahlele MJ

Occult Hepatitis B Virus Infection in a Previously Vaccinated Injection Drug User.

• DOI: 10.5812/hepatmon.34758
• 发表时间: 2016-02
• 期刊: Hepatitis monthly
• 影响因子: 0.6
• 作者: Powell EA;Razeghi S;Zucker S;Blackard JT
• 通讯作者: Blackard JT

Functional analysis of 'a' determinant mutations associated with occult HBV in HIV-positive South Africans.

与 HIV 阳性南非人隐匿性 HBV 相关的“a”决定突变的功能分析。

• DOI: 10.1099/jgv.0.000469
• 发表时间: 2016
• 期刊: The Journal of general virology
• 作者: Powell,EleanorA;Boyce,CeejayL;Gededzha,MaemuP;Selabe,SelokelaG;Mphahlele,MJeffrey;Blackard,JasonT
• 通讯作者: Blackard,JasonT