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药物使用者。重要的是，少数种族和少数民族人口继续受到伴随药物使用、艾滋病毒/艾滋病和其他传染病的严重影响。此外，令人关切的是，主要来自白色男性人口的数据可能并不表明妇女和/或少数种族/族裔中的艾滋病毒疾病。因此，HIV流行病学研究（HER）研究于1993年成立，旨在前瞻性地确定HIV感染对美国女性健康的生物，心理和社会影响。由于HER研究入组了大量IVDU，丙型肝炎病毒（HCV）的总体患病率为56.5%，因此提供了一个独特的机会，可以在样本人群中随时间推移比较HCV单一感染和HCV/HIV合并感染。尽管确切的机制尚不清楚，但很明显，HIV合并感染导致HCV复制增加，因为与HCV单一感染者相比，HCV/HIV合并感染者中的HCV RNA水平显著升高。虽然肝细胞是感染的主要部位，但有证据表明HCV在外周血单核细胞（PBMC）中进行肝外复制。几项研究表明，PBMC内的HCV复制可能会导致病毒再激活和在停止HCV治疗后病毒反弹。尽管如此，免疫抑制可能在促进HCV肝外复制中发挥的作用尚未得到很好的界定。此外，HCV的演变和区室化可能有助于感染的慢性化、肝病进展和HCV治疗结果，尽管这些现象在HCV/HIV合并感染的背景下或以纵向方式尚未得到充分解决。因此，一位具有HCV和HIV临床和实验室经验的新研究者提出了这一R21。本申请的目的是使用新型链特异性实时PCR检测和严格的生物信息学-遗传学方法，在女性IVDU中通过HCV的肝外复制和进化动力学测量，确定HCV单一感染与HCV/HIV合并感染的重要定性差异。该提案将提供有关病毒传播辅助因子的重要数据，并确定HCV疾病进展和治疗失败的潜在标志物。

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.