Impact of Hepatitis C and HIV coinfection on biological aging and hepatocellular carcinoma risk

摘要 本申请是为了回应一份题为“催化研究”的补充公告而提交的。 关于艾滋病毒对艾滋病毒感染者整个生命周期的老龄化影响的培训”， Fogarty International Center HIV Programs（HIV-Aging2023S）。 申请人的父母补助金（R21 TW 012390）的标题是，免疫分析检测病毒性肝炎相关的肝脏 HIV感染患者的癌症（PI Jose D. Debes，明尼苏达大学）。父母补助金的目的是 评估外周血中的标志物以区分患有和不患有肝细胞癌的个体， a拉丁美洲艾滋病毒感染者和病毒性肝炎合并感染者。对于此补充， 科学重点与家长补助金的目标一致，因为我们建议评估丙型肝炎的影响 通过表观遗传学估计生物学年龄， 外周血中DNA的改变。 肝细胞癌（HCC）是最常见的肝脏恶性肿瘤， 全球癌症相关死亡的原因。感染艾滋病毒的人患肝细胞癌的风险增加， 经常合并感染B或C型肝炎（HBV、HCV）。研究一致表明，艾滋病毒阳性者 HCV感染者发生HCC的年龄比HIV阴性者要小， 参与这种早期癌症发展的机制以及对风险人群的识别在很大程度上是 未知通过评估CpG甲基化模式（表观遗传时钟）来估计生物学年龄， 成为了解感染对年龄加速的影响的有力工具， 生理年龄和生理年龄之间的区别事实上，已知艾滋病毒感染者的生物学年龄为5- 10岁。 比HIV阴性的同龄人大11岁。这一过程如何影响癌症的发展， 其他合并感染如HCV的情况目前尚不清楚。 在这个补充申请中，我们建议评估合并感染的个体中的表观遗传时钟。 生活在拉丁美洲的HIV和HCV感染者发生肝细胞癌， 这两种感染对生物衰老和癌症的影响。此外，该项目旨在了解，如果 HCV的治愈降低了与衰老和HCC风险相关的病毒合并感染的影响。 这项研究将产生独特的和创新的信息有关的风险，早期肝癌的艾滋病毒感染者， 并为一项更大规模的研究提供了基础，该研究涉及合并感染中的衰老和癌症。

ABSTRACT This application is being submitted in response to a supplement announcement titled: “Catalyzing research and training on the impact of HIV on Aging Across the Lifespan of Persons Living with HIV” through administrative supplements to existing Fogarty International Center HIV programs (HIV-Aging2023S). The applicant’s parent grant (R21TW012390) is titled, Immune profiling to detect viral hepatitis-related liver cancer in HIV-infected patients (PI Jose D. Debes, University of Minnesota). The aims of the parent grant are to evaluate markers in peripheral blood to differentiate individuals with and without hepatocellular carcinoma in a Latin American population living with HIV and co-infected with viral hepatitis. For this supplement, the scientific focus aligns with the aims of the parent grant, as we propose to evaluate the impact of hepatitis C and HIV co-infection in the development of early-age HCC by estimating biological age via epigenetic modifications in DNA from peripheral blood. Hepatocellular carcinoma (HCC) is the most frequent malignancy of the liver and the second most common cause of cancer-related death worldwide. The risk of HCC is heightened in those infected with HIV as they are frequently co-infected with hepatitis B or C (HBV, HCV). Studies have consistently shown that HIV-positive individuals living with HCV develop HCC at younger ages than their HIV-negative counterparts and the mechanisms involved in such early cancer development as well as identification of those at risk are largely unknown. Estimation of biological age through evaluation of CpG methylation patterns (epigenetic clock) is becoming a powerful tool to understand the impact of infections in age acceleration, which is the difference between chronological and biological age. Indeed, individuals with HIV are known to have a biological age of 5- 11 years older than their HIV-negative counterparts. How this process affects cancer development in the setting of other co-infections such as HCV is currently unknown. In this supplement application, we propose to evaluate the epigenetic clock in individuals co-infected with HIV and HCV living in Latin America who developed hepatocellular carcinoma to estimate the impact of both infections in biological aging and cancer. Moreover, this project aims at understanding if cure of HCV decreases the impact of viral co-infection related to aging and HCC risk. This study will generate unique and innovative information related to risk of early-age HCC in HIV-infected individuals and provide the basis for a larger study addressing aging and cancer in co-infection.