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

超过20万澳大利亚人感染了丙型肝炎病毒(丙型肝炎病毒)，每年约有11000名新感染病例被诊断出来。大约25%的丙型肝炎病毒感染者会清除病毒，而对于慢性感染者，10%到20%的人会在未来20-40年内发展为肝硬变。宿主遗传因素和病毒变异的差异将在很大程度上解释观察到的丙型肝炎病毒感染临床结局和病程的异质性。支持这项研究的基本理论是，丙型肝炎病毒和艾滋病毒等病毒的进化受到个体的人类白细胞抗原类型(HOTS)的影响，再加上病毒变异(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)，即使以损害病毒适合性或复制的较低成本为代价。我们已经证明，这取决于病毒遇到的免疫环境，与宿主中存在的HLA等位基因有关，因此逃逸是上下文特定的。在传播给缺乏相同HLA型的新宿主后，病毒消除了以前有利的突变，这些突变可能会潜在地损害病毒的适合性。目前的研究将对来自澳大利亚多个中心的大约500名丙型肝炎病毒携带者进行丙型肝炎病毒测序和人类白细胞抗原分型，以表征病毒和宿主遗传因素之间的相互作用。一个定制的软件程序Epiop被设计用来对产生的数据进行复杂的统计分析，并已成功地应用于艾滋病毒疫苗的设计。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地清除感染，而另一些人则继续患上严重的肝病，并允许临床医生预测个人的感染过程，并相应地计划他们的治疗。此外，这些结果可能有助于寻找最佳的治疗和疫苗接种策略。

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.