HIV Tat and HBV HBx in HIV/HBV Coinfection-associated Liver Disease

HIV/HBV 合并感染相关性肝病中的 HIV Tat 和 HBV HBx

基本信息

批准号：
10375548
负责人：
Michael J Bouchard
金额：
$ 18.47万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-19 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375548
关键词：
Address Affect Antibodies Antiviral Therapy Apoptosis Apoptotic Area Blood Cell Culture Techniques Cell Surface Receptors Cells Chronic Chronic Disease Chronic Hepatitis B Coculture Techniques Development Diagnostic Disease Endocytosis Extracellular Protein Fibrosis Foundations Future Genetic Transcription Goals HBV Liver Disease HIV HIV Infections HIV-1 Heparan Sulfate Proteoglycan Hepatitis B Infection Hepatitis B Virus Hepatitis B X-Protein Hepatocyte Human Incidence Individual Infection Inflammatory Kupffer Cells LDL-Receptor Related Protein 1 Lead Link Liver Liver diseases Measurable Mediating Molecular Pathogenesis Pathologic Pathway interactions Persons Physiology Primary carcinoma of the liver cells Process Protein Biosynthesis Proteins Publishing Regulation Research Risk Risk Factors Role Severities Signal Pathway Signal Transduction System TLR4 gene Trans-Activators Transcription Regulatory Protein Transcriptional Activation Transgenic Mice Viral Load result Viral Proteins Viral reservoir Virus Virus Replication anti-hepatitis B cancer type carcinogenesis co-infection comorbidity cytokine extracellular global health high risk in vivo inflammatory milieu inhibitor macromolecule macrophage novel prevent receptor recombinant adenovirus small molecule small molecule inhibitor

项目摘要

SUMMARY Globally, an estimated 250 million people are chronically infected with hepatitis B virus (HBV) and an estimated 38 million people are infected with human immunodeficiency virus type 1 (HIV-1). 10-25% of HIV-infected individuals are co-infected with HBV. A chronic HBV infection is the most common risk factor for hepatocellular carcinoma (HCC). HIV infection also has pathological effects in the liver and increases the risk for HCC in HIV/HBV co-infection. The molecular mechanisms underlying liver disease in HIV/HBV co-infection are poorly understood. When treated with antiviral therapy (AT), either for mono- or co-infection, the viral load of HIV-1 and HBV can be undetectable. For HIV, this pushes the disease to a chronic state that is associated with increased comorbidities, including several types of cancer. Approved anti-HIV and anti-HBV AT do not block viral protein synthesis in HIV- or HBV-infected cells, and the HIV Tat and HBV HBx proteins are expressed even with AT. HBx is required for in vivo HBV replication, regulates cell signals, such as apoptotic signals, that influence carcinogenesis, and causes HCC in HBx-transgenic mice. Tat also has a role in chronic HIV disease, can alter apoptotic signals, and causes HCC in Tat-transgenic mice. HBV infects hepatocytes; however, whether HIV infects hepatocytes in a natural infection is unclear, and if so, studies indicate this is inefficient. In an HIV-infected individual, Tat is in the circulating blood even with AT, and in an HIV/HBV co-infection, circulating Tat could provide signals in the liver to enhance HBV-induced HCC. Kupffer cells (KCs) are liver-resident macrophages that can be infected by HIV and would be expected to secrete pro-inflammatory cytokines and Tat in the liver. We hypothesize that in an HIV/HBV co-infection, the effects of Tat, as an extracellular protein or in combination with other cellular macromolecules from HIV-infected KCs, enhance HBx-driven cellular signals that regulate HBV replication and/or hepatocyte apoptosis, leading to an elevated risk for liver disease, including HCC, as compared to mono-infection. The goal of this proposal is to determine whether cooperative HBx and Tat activities affect HBV replication and apoptosis in HBV-infected hepatocytes and define mechanisms underlying cooperative effects. We will: 1) Determine how Tat cooperates with HBx to affect HBV replication and hepatocyte apoptosis; and 2) Determine how HIV-infected KCs affect HBV replication and hepatocyte apoptosis and how this is linked to Tat activities. We will use HBV- or HBx-expressing recombinant adenovirus (AdHBx)-infected cultured primary human hepatocytes (PHHs). Tat will be provided as exogenous purified protein, as a component of conditioned cell culture medium from HIV-infected KCs, or from co-culture of HIV-infected KCs with HBV- or AdHBx-infected PHHs. We will assess how Tat, alone or in combination with factors produced in HIV-infected KCs, affects HBV replication and hepatocyte apoptosis. These studies should lead to translational opportunities, such as developing inhibitors for interacting Tat and HBx signals or diagnostics for increased HCC risk.

概括全球估计有 2.5 亿人慢性感染乙型肝炎病毒 (HBV)，并且估计 3800 万人感染 1 型人类免疫缺陷病毒 (HIV-1)。 10-25% 的 HIV 感染者个体同时感染 HBV。慢性乙型肝炎病毒感染是肝细胞癌最常见的危险因素癌（HCC）。 HIV 感染还会对肝脏产生病理影响，并增加患 HCC 的风险 HIV/HBV 双重感染。 HIV/HBV 合并感染引起肝病的分子机制尚不清楚明白了。当使用抗病毒疗法 (AT) 治疗时，无论是单一感染还是混合感染，HIV-1 和病毒载量都会降低。乙型肝炎病毒可能检测不到。对于艾滋病毒来说，这会将疾病推向慢性状态，这种状态与增加合并症，包括几种类型的癌症。批准的抗 HIV 和抗 HBV AT 不会阻断病毒蛋白 HIV 或 HBV 感染细胞中的合成，HIV Tat 和 HBV HBx 蛋白甚至可以与 AT 一起表达。 HBx 是体内 HBV 复制所必需的，调节细胞信号，例如细胞凋亡信号，从而影响致癌作用，并在 HBx 转基因小鼠中引起 HCC。 Tat 在慢性 HIV 疾病中也发挥作用，可以改变细胞凋亡信号，并在 Tat 转基因小鼠中引起 HCC。乙型肝炎病毒感染肝细胞；然而，无论是艾滋病毒在自然感染中感染肝细胞尚不清楚，如果是这样，研究表明这是低效的。在艾滋病毒感染者中对于个体，即使患有 AT，Tat 也存在于循环血液中，并且在 HIV/HBV 合并感染中，循环 Tat 可能在肝脏中提供信号以增强 HBV 诱发的 HCC。库普弗细胞 (KC) 是肝脏驻留的巨噬细胞可能被 HIV 感染，预计会在肝脏中分泌促炎细胞因子和 Tat。我们假设，在 HIV/HBV 合并感染中，Tat 作为细胞外蛋白或组合的作用与来自 HIV 感染的 KC 的其他细胞大分子一起，增强 HBx 驱动的细胞信号，从而调节 HBV 复制和/或肝细胞凋亡，导致肝病（包括 HCC）风险升高，如与单一感染相比。该提案的目标是确定 HBx 和 Tat 活动是否合作影响 HBV 感染的肝细胞中的 HBV 复制和凋亡并确定其潜在机制协同效应。我们将：1）确定Tat如何与HBx配合影响HBV复制和肝细胞细胞凋亡； 2) 确定 HIV 感染的 KC 如何影响 HBV 复制和肝细胞凋亡以及如何影响这与 Tat 活动有关。我们将使用表达 HBV 或 HBx 的重组腺病毒 (AdHBx) 感染培养的原代人肝细胞（PHH）。 Tat 将作为外源纯化蛋白作为组分提供来自 HIV 感染的 KC 的条件细胞培养基，或来自 HIV 感染的 KC 与 HBV- 或 AdHBx 感染的 PHH。我们将评估 Tat 单独或与 HIV 感染者结合产生的因素如何 KCs，影响 HBV 复制和肝细胞凋亡。这些研究应该带来转化机会，例如开发 Tat 和 HBx 信号相互作用的抑制剂或诊断 HCC 风险增加。