Betaretrovirus Linked To Liver and Biliary Disease

Andrew L. Mason MBBS MRCPI Professor of Medicine,  Senior Scholar, Alberta Heritage Foundation for Medical Research Director, The Applied Genomic Core, Division of Gastroenterology and Hepatology University of Alberta, EdmontonMedicalResearch.com Interview with:
Andrew L. Mason MBBS MRCPI
Professor of Medicine,
Senior Scholar, Alberta Heritage Foundation for Medical Research
Director, The Applied Genomic Core,
Division of Gastroenterology and Hepatology
University of Alberta, Edmonton

Medical Research: What is the background for this study? What are the main findings?

Response: The study of viruses resembling mouse mammmary tumour virus (MMTV) dates back to the 1970s when virus like particles were discovered in breast milk of breast cancer patients. The virus was detected at low levels and ultimately researchers met a stalemate by the 1980s because no one could prove the existence of this agent. Interest waned in the study of betaretroviruses in humans when HIV was discovered in the 1980s.

We first found a similar agent in patients with primary biliary cirrhosis, an autoimmune liver disease in 2003. History repeated itself in as much as others could not find the virus and challenged us to show that a significant amount of patients had evidence of proviral integrations into the human genome, the gold standard for providing proof of retroviral infection. This we achieved by isolating biliary epithelium from patients undergoing liver transplantation and then investigating the presence of betaretrovirus proviral integrations in DNA extracted from liver, lymph nodes and biliary epithelial cells using a ligation mediated PCR technique coupled with next generation sequencing. The majority of patients with primary biliary cirrhosis had viral integration and RNA detected in their biliary epithelium, the site of disease and lymph nodes; however, the virus was difficult to detect in whole liver, reflecting the problem with prior studies.

Medical Research: What should clinicians and patients take away from your report?

Response: We have shown that a human betaretrovirus resembling MMTV can infect humans with liver disease. These data do not provide a causal association between virus and disease in this study. However, the role of the human betaretrovirus should be revisited using similar techniques to provide more convincing data in other diseases previously linked with the agent, such as lymphoma and breast cancer, and possibly other autoimmune disorders.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: Our current investigations focus on mechanisms of how viral infection triggers liver disease by:

(i)       determining the prevalence of betaretrovirus infection in patients with primary biliary cirrhosis using serology and by identifying viral genome in patients samples;

(ii)      studying how infection with the closely related agent, mouse mammary tumor virus triggers autoimmune biliary disease in several mouse models of PBC;

(iii)     investigating how the virus mediates a disease-specific phenotype in vitro by triggering the expression of sequestered autoantigens on the cell surface to break tolerance to self-mitochondrial proteins;

(iv)     translational studies studying whether anti-retroviral therapy leads to histological, biochemical and clinical improvements in mouse models of PBC

(v)      randomized controlled trial using combination Truvada and Kaletra antiretroviral therapy in patients with primary biliary cirrhosis

Citation:

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

Wang W1, Indik S, Wasilenko ST, Faschinger A, Carpenter EJ, Tian Z, Zhang Y, Wong GK, Mason AL.

Aliment Pharmacol Ther. 2015 Feb;41(4):393-405. doi: 10.1111/apt.13054.
Epub 2014 Dec 18.

MedicalResearch.com Interview with: Andrew L. Mason MBBS MRCPI (2015). Betaretrovirus Linked To Liver and Biliary Disease