Extrahepatic Replication and Viral Evolution of HCV During HCV/HIV Co-infection

描述(由申请人提供)：2004年，估计有1900万美国人目前是非法吸毒者。重要的是，少数族裔人口继续深受伴随的吸毒、艾滋病毒/艾滋病和其他传染病的影响。此外，令人关切的是，主要来自白人男性人口的数据可能不能表明妇女和(或)种族/族裔少数群体中的艾滋病毒疾病。因此，艾滋病毒流行病学研究(HER)研究成立于1993年，旨在前瞻性地确定艾滋病毒感染对美国妇女健康的生物、心理和社会影响。由于HER研究招募了大量静脉注射吸毒者，丙型肝炎病毒(丙型肝炎病毒)的总体流行率为56.5%，因此提供了独特的机会来比较样本人群中随时间推移的丙型肝炎病毒单一感染和丙型肝炎病毒/艾滋病毒混合感染。虽然确切的机制(S)仍不清楚，但很明显，艾滋病毒合并感染会导致丙型肝炎病毒复制增加，因为与丙型肝炎病毒/艾滋病毒单一感染者相比，丙型肝炎病毒/艾滋病毒混合感染者的丙型肝炎病毒RNA水平显著升高。虽然肝细胞是主要的感染部位，但有证据表明外周血单个核细胞(PBMC)中存在丙型肝炎病毒的肝外复制。一些研究表明，丙型肝炎病毒在PBMC内的复制可能允许病毒重新激活和在停用丙型肝炎治疗后病毒反弹。然而，免疫抑制在促进丙型肝炎病毒肝外复制中可能发挥的作用还没有很好的确定。此外，丙型肝炎病毒的演变和分区可能导致感染的慢性化、肝病进展和丙型肝炎治疗结果，尽管这些现象在丙型肝炎病毒/艾滋病毒合并感染的背景下或以纵向方式尚未得到充分解决。因此，一位在丙型肝炎病毒和艾滋病毒方面都有临床和实验室经验的新研究员提出了R21。这项应用的目标是利用一种新的链特异性实时聚合酶链式反应分析和严格的生物信息学-系统发育学方法，确定女性静脉注射吸毒者之间丙型肝炎病毒单一感染和丙型肝炎病毒/艾滋病毒混合感染的重要质量差异，这是通过丙型肝炎病毒的肝外复制和进化动态来衡量的。这项建议将提供有关病毒传播的共同因素的重要数据，并确定丙型肝炎病毒疾病进展和治疗失败的潜在标记物。

DESCRIPTION (provided by applicant): In 2004, an estimated 19 million Americans were current illicit drug users. Importantly, racial and ethnic minority populations continue to be deeply impacted by concomitant drug use, HIV/AIDS, and other infectious diseases. Moreover, there is concern that data from predominantly white male populations may not be indicative of HIV disease in women and/or racial/ethnic minorities. Therefore, the HIV Epidemiologic Research (HER) Study was established in 1993 to prospectively define the biological, psychological, and social effects of HIV infection on the health of US women. Because the HER Study enrolled a large number of IVDUs, the overall prevalence of hepatitis C virus (HCV) was 56.5%, thus providing the unique opportunity to compare HCV mono-infection and HCV/HIV co-infection within the sample population over time. Although the precise mechanism(s) remain unclear, it is clear that HIV co-infection leads to increased HCV replication as HCV RNA levels are significantly elevated in HCV/HIV co-infected persons compared to HCV mono-infected persons. While hepatocytes are the major site of infection, there is evidence for extrahepatic replication of HCV in peripheral blood mononuclear cells (PBMCs). Several studies have suggested that HCV replication within PBMCs may allow for viral reactivation and viral rebound upon removal of HCV treatment. Nonetheless, the role that immunosuppression may play in boosting extrahepatic replication of HCV has not been well defined. Moreover, HCV evolution and compartmentalization may contribute to the chronicity of infection, liver disease progression, and HCV treatment outcome, although these phenomena have not been adequately addressed in the context of HCV/HIV co-infection or in a longitudinal manner. Thus, a new investigator with clinical and laboratory experience in both HCV and HIV is proposing this R21. The goals of this application are to define important qualitative differences in HCV mono-infection versus HCV/HIV co-infection, as measured by extrahepatic replication and evolutionary dynamics of HCV, among female IVDUs using a novel strand-specific real-time PCR assay and a rigorous bioinformatics- phylogenetics approach. This proposal will provide important data on co-factors of virus transmission and identify potential markers of HCV disease progression and treatment failure.