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

HCV/HIV 共感染期间 HCV 的肝外复制和病毒进化

• 批准号: 7282702
• 负责人: JASON T BLACKARD
• 金额: $ 17.04万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7282702
• 关键词: Address; American; Bioinformatics; Biological; Biological Assay; Clinical; Communicable Diseases; Data; Development; Disease Progression; Drug usage; Drug user; Enrollment; Epidemic; Epidemiologic Studies; Evolution; Excision; Extrahepatic; Female; Fibrosis; Genetic Variation; Goals; HIV; HIV-1; Health; Hepatitis C; Hepatitis C virus; Hepatocyte; Illicit Drugs; Immunosuppression; Infection; Integration Host Factors; Knowledge; Laboratories; Liver diseases; Measures; Minority Groups; Molecular; Mono-S; Morbidity - disease rate; Numbers; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Persons; Phase; Phylogenetic Analysis; Play; Polymerase Chain Reaction; Polymerase Gene; Population; Prevalence; Research Personnel; Risk; Role; Sampling; Site; Testing; Therapeutic immunosuppression; Time; Treatment Failure; Treatment outcome; Viral; Virus; Virus Diseases; Virus Replication; Woman; Work; cohort; ethnic minority population; experience; innovation; intravenous drug user; male; mortality; novel; psychologic; racial and ethnic; research study; social; transmission process; viral RNA

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.

描述（由申请人提供）：2004年，估计有1900万美国人是目前的非法吸毒者。重要的是，种族和少数民族人口继续深受同时吸毒、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/族裔少数群体感染艾滋病毒。因此，1993年建立了艾滋病毒流行病学研究（HER）研究，以前瞻性地确定艾滋病毒感染对美国妇女健康的生物学、心理和社会影响。由于HER研究招募了大量的IVDUs，丙型肝炎病毒（HCV）的总体患病率为56.5%，因此提供了独特的机会来比较样本人群中HCV单一感染和HCV/HIV合并感染。虽然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（PBMCs）中的肝外复制。几项研究表明，HCV在pbmc内的复制可能允许病毒再激活和在去除HCV治疗后病毒反弹。尽管如此，免疫抑制在促进HCV肝外复制中的作用尚未得到很好的定义。此外，HCV的进化和分区化可能会导致感染的慢性性、肝脏疾病的进展和HCV治疗结果，尽管这些现象在HCV/HIV合并感染的背景下或在纵向上还没有得到充分的解决。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种R21。本应用的目的是通过一种新型链特异性实时PCR检测和严格的生物信息学-系统发育方法，在女性IVDUs中通过肝外复制和进化动力学来确定HCV单感染与HCV/HIV合并感染的重要定性差异。该建议将为病毒传播的辅助因素提供重要数据，并确定HCV疾病进展和治疗失败的潜在标志物。