Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis

Abstract

Background & Aims: Recent observations, including a pilot clinical trial, have suggested that a human mouse mammary tumor virus (MMTV) causes primary biliary cirrhosis (PBC). We attempted to confirm such data. Methods: We obtained sera from 101 patients (53 with PBC and 48 controls), fixed liver sections from 10 patients (8 PBC and 2 controls), fresh liver specimens (6 PBC and 6 controls), and fresh peripheral blood lymphocytes (PBLs) (10 PBC and 10 controls). We studied sera for reactivities against 3 different strains of MMTV virions, MMTV(C3H), MMTV(FM), and MMTV(LA), including goat polyclonal antibodies against MMTV virions, gp52, and p27 as positive controls. We stained liver specimens using polyclonal antibodies against MMTV and gp52 and further examined tissue samples and PBLs for specific MMTV genome sequences. Results: By Western blot analysis, no detectable reactivity in any of the PBC sera against any of the 3 MMTV strains or MMTV gp52 or p27 was observed. However, viral proteins were recognized by our control positive polyclonal antibodies. We note that 13%–60% of PBC sera presented low reactivity against 2 proteins of approximately 57 and 74 kilodaltons. Such reactivity is related to the trace amounts of mitochondrial antigens in the virus preparations derived from murine mammary tumor tissue. No detectable immunohistochemical or molecular evidence for MMTV was found in the liver specimens or PBLs. Conclusions: We were unable to recapitulate the data on this specific retroviral etiology of PBC and suggest that such data could be the result of contamination.