The retroviral myth of primary biliary cirrhosis: Is this (finally) the end of the story?
Authors: Carlo Selmi, M. Eric Gershwin
Journal: Journal of Hepatology (2009)

The retroviral story of primary biliary cirrhosis (PBC) has been enriched by a new episode in the March issue of this Journal. In their article, Johal and colleagues report their study of a large number of liver samples taken from patients affected by chronic liver diseases of all etiologies (including 26 PBC cases), at different stages, with or without hepatocellular carcinoma [[1]Johal H. Marie Scott G. Jones R. Camaris C. Riordan S. Rawlinson W.D. Mouse mammary tumour virus-like virus (MMTV-LV) is present within the liver in a wide range of hepatic disorders and unrelated to nuclear p53 expression or hepatocarcinogenesis.J Hepatol. 2009; 50: 548-554Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. In all these samples, molecular methods were utilized to determine the presence of the mouse mammary tumor virus-like virus (coined MMTV-LV). There was no evidence of MMTV-LV env protein in healthy liver tissues while a variable proportion of samples with different chronic diseases manifested the presence of the virus. This proportion (namely 3/26 for PBC) did not differ among different etiologies, between early and advanced stages, or between neoplastic and non neoplastic tissues. While we welcome a new group in the dichotomy which has characterized the retroviral hypothesis of PBC, we feel the necessity to raise some concerns on the data and their interpretation. The involvement of a retrovirus in the etiology of PBC was first proposed 11 years ago by Andrew Mason's group [[2]Mason A.L. Xu L. Guo L. Munoz S. Jaspan J.B. Bryer-Ash M. et al.Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic biliary disorders.Lancet. 1998; 351: 1620-1624Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar] and has since been supported by publications coming only from that group. This work has more recently culminated in a pilot trial for antiretroviral therapies in patients with PBC in which putative non validated endpoints (such as upper abdominal pain) were included [[3]Mason A.L. Lindor K.D. Bacon B.R. Vincent C. Neuberger J.M. Wasilenko S.T. Clinical trial: randomized controlled trial of zidovudine and lamivudine for patients with primary biliary cirrhosis stabilized on ursodiol.Aliment Pharmacol Ther. 2008; (Jul 9 [Epub ahead of print])Google Scholar]. In 2004, we undertook an unbiased and blinded effort to determine the presence of multiple MMTV molecular and tissue markers in a large number of fresh liver and peripheral blood cells from patients with PBC. We failed to identify any proof of MMTV [[4]Selmi C. Ross S.R. Ansari A.A. Invernizzi P. Podda M. Coppel R.L. et al.Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis.Gastroenterology. 2004; 127: 493-501Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar]; we note that Johal et al. failed to cite subsequent editorials. Furthermore, we submit that the work by Johal and colleagues has fatal and naive flaws and does not address crucial questions arising from their results. First, while stating that contaminations were carefully avoided, the authors utilized both paraffin-embedded and fresh liver tissues for DNA extraction, thus including an obvious source of potential contamination. Second, it is not established that the molecular methods used have adequate sensitivity for MMTV detection and sufficient specificity since sequencing was performed in a minor group of positive cases. Third, the number of healthy controls is clearly too limited to allow powerful comparisons given the rarity of the virus in PBC samples. Fourth, the authors have not attempted to explain the basis for the discrepancies between the findings from the three groups, including ours. Fifth and most importantly, the lack of association between etiology, stage, or cancer fails to identify any possible working theory behind the reported experimental observation. There is still no biologic or immunologic plausibility. The involvement of MMTV appears to be common to all chronic liver diseases in minor percentages and this clearly does not allow to formulate a rational hypothesis to recapitulate the observation, as suggested by experts in the field of autoimmunity [[5]Mackay I.R. Leskovsek N.V. Rose N.R. Cell damage and autoimmunity: a critical appraisal.J Autoimmun. 2008; 30: 5-11Crossref PubMed Scopus (123) Google Scholar]. For all the aforementioned reasons, we conclude this letter with the same conclusion we arrived at in 2004 [[6]Gershwin M.E. Selmi C. Apocalypsal versus apocryphal: the role of retroviruses in primary biliary cirrhosis.Am J Gastroenterol. 2004; 99: 2356-2358Crossref PubMed Scopus (12) Google Scholar]. The retroviral story for PBC has been around for almost a decade and no group has reproduced the original data nor developed any biologic plausibility. We are all working together for the common goal of improved patient care. But let us remind the readership of a saying attributed to Confucious: "Learning without thought is labor lost. Thought without learning is perilous".