Adaptation of Hepatitis C to Host HLA-Restricted Immune Responses in Australian Populations

丙型肝炎在澳大利亚人群中适应 HLA 限制性免疫反应

• 批准号: nhmrc : 334603
• 负责人: Dr Silvana Gaudieri
• 金额: $ 32.06万
• 依托单位: Murdoch University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/adaptation-hepatitis-c-australian-populations/95626
• 关键词: Adaptation; Hepatitis; Host; HLA; Restricted

Over 200,000 Australians are infected with the Hepatitis C Virus (HCV) and about 11,000 new infections are diagnosed each year. Around 25% of people infected with HCV will clear the virus while for individuals with chronic infection 10 to 20% will develop cirrhosis of the liver within the next 20-40 years. Differences in host genetic factors and viral variants will, in large part, explain the observed heterogeneity in the clinical outcome and course of HCV infection. The basic theory underpinning this research is that the evolution of viruses such as HCV and HIV are influenced by the HLA type of the individual (hots), in combination with the ability of the virus to mutate (rid itself of deleterious mutations) to avoid the host's immune challenge (analogous to drug resistance) even at the lesser cost of impairing viral fitness or replication. We have shown that this is dependent on the immune environment that the virus encounters in relation to which HLA alleles are present in the host, therefore the escape is context specific. After transmission to a new host who lacks the same HLA type, the virus eliminates the previously advantageous mutations which could potentially impair viral fitness. The current study will carry out HCV sequencing and HLA typing on approximately 500 people with HCV from multiple Centres in Australia in order to characterise the interaction between the viral and host genetic factors. A customised software programme, Epipop, has been designed to perform sophisticated statistical analyses on the generated data, and has been successfully applied to HIV vaccine design. The results of this study could help explain why some infected individuals can spontaneously clear their infection while others go on to severe liver disease and allow clinicians to anticipate the course of infection in individuals and plan their management accordingly. Furthermore, the results may facilitate the search for optimal therapeutic and vaccination strategies.

超过 20 万澳大利亚人感染丙型肝炎病毒 (HCV)，每年诊断出约 11,000 例新感染病例。大约 25% 的 HCV 感染者会清除病毒，而对于慢性感染者，10% 到 20% 的人会在未来 20-40 年内发展为肝硬化。宿主遗传因素和病毒变异的差异在很大程度上解释了 HCV 感染临床结果和病程中观察到的异质性。支持这项研究的基本理论是，HCV 和 HIV 等病毒的进化受到个体 HLA 类型（热点）的影响，再加上病毒突变（消除有害突变）的能力，以避免宿主的免疫挑战（类似于耐药性），甚至以损害病毒适应性或复制的较小代价。我们已经证明，这取决于病毒遇到的免疫环境，以及宿主中存在的 HLA 等位基因，因此逃逸是特定于环境的。在传播到缺乏相同 HLA 类型的新宿主后，病毒消除了先前可能损害病毒适应性的有利突变。目前的研究将对来自澳大利亚多个中心的约 500 名 HCV 患者进行 HCV 测序和 HLA 分型，以表征病毒与宿主遗传因素之间的相互作用。 Epipop 定制软件程序旨在对生成的数据进行复杂的统计分析，并已成功应用于艾滋病毒疫苗设计。这项研究的结果可以帮助解释为什么一些感染者可以自发清除感染，而另一些人则继续发展为严重的肝病，并允许临床医生预测个体的感染过程并相应地制定治疗计划。此外，结果可能有助于寻找最佳治疗和疫苗接种策略。