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Supplement

Viral Induction of Type 2 Diabetes and Autoimmune Liver Disease¹

Richard Freeman Research Institute, Alton Ochsner Medical Institutions, New Orleans, LA 70121

²To whom correspondence should be addressed. E-mail: amason{at}ochsner.org.

Cross-sectional studies performed worldwide have shown that hepatitis C virus (HCV) infection is linked with type 2 diabetes, but these endocrine and liver diseases have an insidious onset, and it has been difficult to establish that patients acquire HCV infection before the development of diabetes. It is likely that investigations in small animal models or in vitro systems will be required to determine whether a causal relationship of HCV infection and the development of diabetes can be established. We have developed an in vitro model to study the viral induction of primary biliary cirrhosis (PBC) based on the phenotype of the diseased biliary epithelial cells. PBC patients make antimitochondrial antibodies and also express proteins reactive to these antibodies on their biliary epithelium. In coculture studies we have found that normal biliary epithelial cells develop the phenotypic manifestation of PBC in vitro specifically when cultivated with lymph nodes from PBC patients and not with relevant liver disease control subjects. We have also cloned a novel human retrovirus from a PBC biliary epithelium cDNA library and confirmed that the development of the PBC phenotype in vitro coincides with the presence of this virus. In clinical trials using antiretroviral therapy, we have observed a reversal of ductopenia as well as improvements in histology and hepatic biochemistry in patients with PBC. As Koch’s postulates are not readily applicable to chronic diseases, we have used cocultivation viral transmission model in vitro and antimicrobial clinical studies in vivo to help establish a causal relationship with a retrovirus infection and the phenotypic manifestation of disease.

KEY WORDS: • diabetes • hepatitis • infection • liver • cirrhosis