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Frequent proviral integration of the human betaretrovirus in biliary epithelium of patients with autoimmune and idiopathic liver disease

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University of Alberta researchers wind up a 40 year old debate on betaretrovirus infection in humans

In a new study published in Alimentary Pharmacology & Therapeutics, researchers at the University of Alberta’s Faculty of Medicine & Dentistry have shown that a betaretrovirus which resembles a mouse mammary tumor virus infects patients with the rare liver disease, primary biliary cirrhosis (PBC). Using next generation sequencing, the team of scientists at the University of Alberta along with colleagues at Beijing Genomics Institute, in Shenzhen, China, identified over 2,000 junction regions where the betaretrovirus DNA had inserted into the patient’s genome. The demonstration of integration sites is considered a gold standard for detection of retroviral infection and the missing piece of the puzzle in the ongoing dispute of whether humans are susceptible to betaretrovirus infection. The human betaretrovirus was first discovered in patients with primary biliary cirrhosis by the Andrew Mason laboratory in 2003. This rare form of autoimmune liver disease is found in one in 500 middle aged women and is also responsible for approximately 10 per cent of all liver transplant cases in Canada. PBC is currently considered autoimmune in nature because the majority of patients make antibodies to mitochondrial proteins. The demonstration of viral infection in the bile ducts of patients with PBC adds a new dimension to understanding what may cause the liver disease. Andrew Mason used ligation mediated PCR and next generation sequencing to find the miniscule amounts of viral genomic sequence. They extracted biliary epithelium cells from the liver and derived more than 1 million DNA sequences per sample. The intensive effort was required to prove viral infection in most patients at the site of disease. “At least we have shown pretty convincingly that a human betaretrovirus infects patients with primary biliary cirrhosis,” says Mason. “We had to do this because virologists don’t think this betaretrovirus can infect humans due to negative studies in the 1970’s when researchers tried to identify mouse mammary tumor virus in breast cancer patients.” Mason is currently performing patient studies using antiviral therapy to see if it improves clinical outcomes in patients with primary biliary cirrhosis. “We still have a long way to go to convince the medical community that our virus plays any role in triggering the liver disease process. Some of the anti-viral therapies useful for viral hepatitis and HIV have some effect in our patients with primary biliary cirrhosis but we need to show this in the proper setting of a randomized controlled trial.”

Frequent proviral integration of the human betaretrovirus in biliary epithelium of patients with autoimmune and idiopathic liver disease.-	. Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Wang W, Indik S, Wasilenko ST, Faschinger A, Carpenter EJ, Tian Z, Zhang Y, Wong GK, Mason AL.

Aliment Pharmacol Ther. 2015;41(4):393-405.

Center of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, AB, Canada.

Abstract

BACKGROUND:

A human betaretrovirus (HBRV) has been linked with primary biliary cirrhosis (PBC) following the detection of viral particles in biliaryepithelium by electron microscopy and cloning of the betaretrovirus genome from biliary epithelium and peri-hepatic lymph nodes. Evidence for viral infection was found in the majority of PBC patients’ peri-hepatic lymph node samples. However, less than a third of the liver samples had detectable HBRV, whereas others were unable to detect betaretrovirus infection or noted the presence of virus in the liver of patients with other diagnoses.

AIMS:

To address the hypothesis that the betaretrovirus may be below the limits of detection in the liver,  biliary epithelial cells (BEC) were investigated for the evidence of infection.

METHODS:

Ligation-mediated PCR and next generation sequencing were used to detect proviral integrations in liver, lymph nodes and BEC isolated from liver transplant recipients. Hybridisation-based assays were used to detect betaretroviral RNA in BEC.

RESULTS:

Unique HBRV integrations and betaretrovirus RNA were detected in the majority of biliary epithelia derived from patients with PBC,autoimmune hepatitis and cryptogenic liver disease but rarely in other liver transplant recipients with primary sclerosing cholangitis and other hepatic disorders. HBRV integrations were commonly found in PBC patients’ lymph nodes but rarely in whole liver samples.

CONCLUSIONS:

Human betaretrovirus infection is frequently observed at the site of disease in patients with primary biliary cirrhosis and also in biliary epithelium  of patients  with  autoimmune hepatitis and cryptogenic liver disease.

© 2014 The Authors. Alimentary Pharmacology & Therapeutics Published by John Wiley & Sons Ltd.

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