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압타머를 이용한 C형 간염 바이러스 감염의 진단 및 저해

Title
압타머를 이용한 C형 간염 바이러스 감염의 진단 및 저해
Authors
박지훈
Date Issued
2013
Publisher
포항공과대학교
Abstract
Hepatitis C virus (HCV) was identified as the major etiologic agent causing NANBH in 1989. HCV is classified as a member of the Flaviviridae family, which includes Yellow Fever virus, Dengue virus and West Nile virus, and is the sole Member of the genus Hepaciviridae. HCV has been divided into six different genotypes (1 to 6) and numerous subtypes (a,b,c etc). Various forms of hepatitis C virus (HCV)-related particles are produced from HCV-infected cells. Measuring infectivity of a HCV sample with the conventional ‘foci counting method’ is laborious and time-consuming. Moreover, the infectivity of a HCV sample does not correlate with the amount of viral RNA that can be measured by real-time RT-PCR. Here I report a new assay suitable for quantifying infectious HCV particles using aptamers against HCV E2, which is named ‘Enzyme Linked Apto-Sorbent Assay (ELASA)’. The readout value of HCV ELASA linearly correlates with the infectious dose of an HCV sample, but not with the amount of HCV RNA. I also demonstrated that the activities of anti-HCV drugs can be monitored by HCV ELASA. Therefore, HCV ELASA is a quick-and-easy method to quantify infectious units of HCV stocks and to monitor efficacies of potential anti-HCV drugs. Currently, there are an estimated 170 million worldwide chronically infected individuals with HCV. Patients with HCV are usually asymptomatic during acute infection, but 70% of those infected will develop chronic hepatitis with the risk of developing liver cirrhosis and liver cancer. Although much research has been focused on the development of anti-HCV agents, no vaccine is available to date and there is no effective therapy for all genotypes of HCV. The current anti-HCV standard of care is a combination of pegylated interferon (Peg-IFN), ribavirin (RBV), and boceprevir or telaprevir, two recently approved antiviral agents targeting the viral NS3/4A protease. The response of the patients to the combination therapy with Peg IFN-α and RBV varies depending on both viral and host characteristics. Many patients, especially those with 1b genotype, don’t achieve a sustained virologic response. The need for a more efficient and safe therapy against HCV infection has initiated major research efforts. These have aimed at both inhibiting specific steps in the viral life cycle and finding way to modulate the host’s immune response. Here I discovered anti-viral aptamers against HCV envelope protein E2, and HCV cellular receptor CD81, Claudin-1. Successful viral infection requires intimate communication between virus and host cells, a process that absolutely requires various host proteins. However, current efforts to discover novel host proteins as therapeutic targets for viral infection are difficult. Here, I developed an integrative-genomics approach to predict human genes involved in the early steps of hepatitis C virus (HCV) infection. By integrating HCV and human protein associations, co-expression data, and tight junction-tetraspanin web specific networks, I identified host proteins required for the early steps in HCV infection. Moreover, I validated the roles of newly identified proteins in HCV infection by knocking down their expression using small interfering RNAs. I further demonstrated that CD63 may serve as a new therapeutic target for HCV-related diseases. The candidate gene list provides a source for identification of new therapeutic targets.
URI
http://postech.dcollection.net/jsp/common/DcLoOrgPer.jsp?sItemId=000001573746
http://oasis.postech.ac.kr/handle/2014.oak/1923
Article Type
Thesis
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