We have studied the pathogenesis of viral hepatitis and the molecular basis for virulence and attenuation of these important pathogens. We have shown previously that virulence and attenuation of hepatitis A virus (HAV) are controlled principally by two genes: VP1/2A and 2C. However, attenuating mutations are strongly selected against in vivo, resulting in the emergence of virulent variants. This has important implications for the development of live attenuated hepatitis A vaccines. The pathogenesis of hepatitis A is also being studied in the chimpanzee model by microarray analysis. Both innate and adaptive responses have been recorded. Interestingly, HAV does not trigger the up-regulation of certain interferon stimulated genes that are highly upregulated in HCV and HDV infections. This is surprising because HAV and HCV are both single-stranded RNA viruses with a double-stranded replicative form and HDV is a single-stranded virus with extensive base pairing that is perceived as double-stranded RNA. Thus, the PKR and RIG-I/MDA-5 pathways that sense double-stranded RNA intracellularly would be expected to trigger an innate immune response similarly in the three viruses. It will be important to search for viral mechanisms of control that may block these systems.? Although rare in the United States, hepatitis E is the single most important cause of acute hepatitis among adults throughout Asia, the Middle East and North Africa. Like most of the hepatitis viruses, it replicates poorly or not at all in cell culture and cannot be transmitted to small laboratory animals. We have developed replicons for the study of HEV in vitro; these tools are permitting a detailed molecular analysis of viral replication that can be confirmed in vivo with molecularly engineered infectious cDNA clones of the virus. In addition, with colleagues, we are developing small animal models (swine HEV in swine, avian HEV in chickens) that, with nonhuman primate models of HEV, provide an unprecedented opportunity for studying the comparative pathogenesis of hepatitis E viruses. Finally, hepatitis E has also been studied by microarray and a brisk innate but weak adaptive immune response has been seen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000915-07
Application #
7732577
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2008
Total Cost
$988,057
Indirect Cost
City
State
Country
United States
Zip Code
Graff, Judith; Zhou, Yi-Hua; Torian, Udana et al. (2008) Mutations within potential glycosylation sites in the capsid protein of hepatitis E virus prevent the formation of infectious virus particles. J Virol 82:1185-94
Emerson, Suzanne U; Purcell, Robert H (2007) Hepatitis E. Pediatr Infect Dis J 26:1147-8
Takikawa, Shingo; Engle, Ronald E; Emerson, Suzanne U et al. (2006) Functional analyses of GB virus B p13 protein: development of a recombinant GB virus B hepatitis virus with a p7 protein. Proc Natl Acad Sci U S A 103:3345-50
Sidney, John; Asabe, Shinichi; Peters, Bjoern et al. (2006) Detailed characterization of the peptide binding specificity of five common Patr class I MHC molecules. Immunogenetics 58:559-70
Bukh, Jens; Purcell, Robert H (2006) A milestone for hepatitis C virus research: a virus generated in cell culture is fully viable in vivo. Proc Natl Acad Sci U S A 103:3500-1
Graff, Judith; Nguyen, Hanh; Yu, Claro et al. (2005) The open reading frame 3 gene of hepatitis E virus contains a cis-reactive element and encodes a protein required for infection of macaques. J Virol 79:6680-9
Graff, Judith; Nguyen, Hanh; Kasorndorkbua, Chaiyan et al. (2005) In vitro and in vivo mutational analysis of the 3'-terminal regions of hepatitis e virus genomes and replicons. J Virol 79:1017-26
Wieland, Stefan; Thimme, Robert; Purcell, Robert H et al. (2004) Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A 101:6669-74
Wieland, Stefan F; Spangenberg, Hans Christian; Thimme, Robert et al. (2004) Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees. Proc Natl Acad Sci U S A 101:2129-34
Farci, Patrizia; Roskams, Tania; Chessa, Luchino et al. (2004) Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology 126:1740-9

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