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Linking human beta retrovirus infection with primary biliary cirrhosis

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Summary

Several environmental agents have been linked with primary biliary cirrhosis (PBC) that include bacteria, xenobiotics and viruses. A human beta retrovirus (HBRV) related to mouse mammary tumor virus has been cloned and characterized from patients with PBC. This agent can be detected in the majority of patients’ perihepatic lymph nodes by immunochemistry and RT-PCR. The HBRV has recently been isolated in culture and integration sites have been identified in the genome of patients to provide convincing evidence of beta retrovirus infection in patients. Three lines of evidence support a role for the virus in PBC. First, the beta retrovirus is linked with aberrant expression of mitochondrial protein(s) on the biliary epithelium cell (BEC) surface, a disease specific phenotype. Second, the related agent, mouse mammary tumor virus has been linked with autoimmune biliary disease in the NOD.c3c4 mouse model for PBC. In this mouse model, the virus is localized to diseased biliary epithelium that also display aberrant expression of the mitochondrial autoantigens. In translational studies, both patients with PBC and NOD.c3c4 mice demonstrate significant improvement in biliary disease with combination antiviral therapy. An overview of the biological relevance of the beta retrovirus infection in PBC will be discussed in this review.

Section snippets

Discovery of the human betaretrovirus in patients with primary biliary cirrhosis

Several complementary approaches were used to identify a retrovirus as a candidate agent associated with PBC. After finding no evidence of bacterial 16s ribosomal DNA in PBC liver samples, representational difference analysis studies were performed using liver and skin from a PBC patient, as the technique had recently been employed to discover the human herpes virus 8 associated with Kaposi's sarcoma [2], [8], [9]. Retroviral sequences were found and follow up Western blot studies using a

Prevalence of betaretrovirus infection in patients with primary biliary cirrhosis

Two studies have shown that the viremia can be detected in serum of approximately one in four patients with PBC as compared to 5% of control subjects [7], [38]. RT-PCR and immunochemistry investigations found that the HBRV was predominantly distributed in lymphoid tissue rather than the liver in patients with PBC as 75% of lymph node samples from PBC patients were positive for viral protein and RNA but only a third of patients had viral RNA in the liver (Fig. 1). As virus has been visualized in

Linking betaretrovirus infection with the mitochondrial phenotype of primary biliary cirrhosis

Koch's postulates are not applicable to chronic complex disorders with a strong genetic component. However, recapitulating a disease phenotype with viral infection in an animal model or in vitro can provide the necessary proof for a causal association. The aberrant expression of the mitochondrial antigens on the cell surface of biliary epithelium is both a disease specific phenotype and probably directly related to the development of the autoimmune response [1]. However, it is unknown why

Translational studies using antiretroviral therapy in patients with primary biliary cirrhosis

Pilot studies and randomized-controlled trials with antiretroviral therapy have been conducted to address the hypothesis that the human betaretrovirus causes cholangitis in patients with PBC. At the time the pilot studies were conducted, lamivudine therapy had proven to be an effective and safe treatment for patients with hepatitis B virus infection. Yet, PBC patients treated with lamivudine monotherapy derived little demonstrable biochemical or histological benefit [50]. The pilot study using

Prospectus

There are accumulating data linking HBRV with PBC (Table 1) and a strong suggestion that antiviral may be of benefit in PBC. Indeed, lead investigators in the treatment of PBC have suggested that antiviral trials are warranted in patients with PBC to address the viral hypothesis and find better therapies for patients with PBC [59]. The NOD.c3c4 mouse model has provided a relevant resource for investigating HAART regimens, such as Truvada and Kaletra that have reversed biliary disease without

Conflict of interest statement

The authors declare no other conflicts of interest.

Acknowledgements

The research was supported by Alberta Heritage Foundation for Medical Research, Canadian Association of Gastroenterology, Canadian Institutes for Health Research and the Canadian Liver Foundation. The clinical trials were supported by GlaxoSmithKline and Axcan Pharma. Andrew Mason was principal investigator on the antiviral clinical trials that were supported by GlaxoSmithKline and Axcan Pharma. The authors express their gratitude to Gina Mason for assistance with manuscript review and

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      Furthermore, the majority of PBC patients had viral RNA and proteins detected in lymph nodes, which other groups have not studied [4]. Subsequently, betaretrovirus integration sites have been indentified in PBC biliary epithelium using linker mediated-PCR, the gold standard for confirming retroviral infection, and case control studies are being conducted to determine whether viral infection can be localized to the site of disease [2,5]. The finding of increased MMTV gene expression and protein production in the AMA producing mice suggests that these models may be suitable for studying viral induction of autoimmunity [6].

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