Faculty

Chiaho Shih, Ph.D.

Professor
cshih@utmb.edu
Keiller, Route 0609
Departments of Pathology and Microbiology & Immunology
Phone: (409)772-2563
Fax: (409)747-2429

Education:	Ph.D. | 1982 | Massachusetts Institue of Technology, Cambridge, MA
	B.S. | 1973 | National Taiwan University, Taipei, Taiwan

Overview

Molecular virology and pathogenesis of human hepatitis B virus and hepatoma; vaccine development for tropical infectious agents.

Research Interests

My research focuses on the mechanisms of chronicity of human hepatitis B virus (HBV) infection, which plays a major role in liver cancer. Specifically, I am studying HBV variants and their biological significance in persistent infection. Three major research projects are outlined below.

Immature Secretion Project (supported by NIH RO1 CA84217): The most frequent mutation of HBV core protein occurs at codon 97 in chronic carriers worldwide. My recent functional characterization of this variant uncovered a novel and strong phenotype, dubbed an "immature secretion" phenotype. Unlike wild type HBV, the secreted virion particles of the codon-97 mutant contain an immature form (lower molecular weight) of the HBV DNA genome. The "immature secretion" phenotype is a global phenomenon since it can be found in both a European strain (ayw) and an Asian strain (adr). Recently, we discovered a naturally occurring mutation, which can offset the immature secretion phenotype. In addition, I uncovered another new phenotype of low level virion secretion associated with naturally occurring mutations at HBcAg codons 5 and 60. Our findings of these predominant secretion-defective variants, including immature secretion and low secretion variants, in more than 80% of HBV replication-positive human hepatoma samples have important implications in liver pathogenesis in chronic hepatitis B patients. In addition, these secretion-defective capsid variants provide an important tool for studying the regulation of HBV virion assembly and morphogenesis.

DI Particle Project (supported by NIH RO1 CA70336): Since the original discovery of defective interfering (DI) variants of influenza virus in tissue culture in 1947, there have been no reports that DI variants of animal viruses can be found in natural infections. For the past half a century, DI research has been limited to laboratory settings (tissue culture and animal models), despite the fact that it is generally believed that DI particles are important for chronicity and pathogenesis in viral diseases.

Using a novel approach, I discovered the first DI variants in human natural infections. The results have renewed research interests in DI variants, which might be involved in a number of human chronic progressive viral diseases. This project is to test the hypothesis that HBV DI particles can influence liver pathogenesis as well as contribute to the establishment of chronic infection. In addition to investigating the mechanism of HBV defective interference, I am extending the HBV pathogenesis study to the woodchuck model.

Inducible Replication of Hepatitis B Virus in Trans-differentiated Pancreatic Hepatocytes: Despite the existence of a large number of hepatoma cell lines, only a very limited number of cell lines (HepG2, Huh7 and rat hepatoma 7777) are currently available to support the efficient replication of HBV. Recently, both pancreatic buds from mouse embryo and a rat pancreatic cell line was shown to transdifferentiate to liver-like cells upon induction with steroid and cytokines. To determine if the hepatotropic HBV can indeed replicate in transdifferentiated pancreatic hepatocytes, we stably transfected this pancreatic cell line with HBV DNA, and viral activities were characterized with or without induction. A full spectrum of HBV replicative intermediates, including covalently closed circular (ccc) DNA, can be detected in this system. HBcAg and HBsAg can be detected by ELISA, Western blot and immunofluorescence microscopy. Predominant nuclear localization of HBcAg was observed when the culture was aged. Interestingly, while the expression of HBsAg was inducer dependent, the expression of HBeAg was age dependent. Characteristic Dane particles and subviral particles were identified by electron microscopy. Since core specific RNA can be detected without induction by Northern and primer extension analysis, a post-transcriptional control of the expression of HBV core antigen is being investigated. In summary, HBV replication and gene expression can be induced synchronously and maintained by physiological inducers in a tissue culture model of transdifferentiation. This novel system offers an opportunity for drug screening and molecular dissection of virus-host interaction.

Recent Publications

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