Science

Betaretrovirus infection linked to primary biliary cirrhosis

Last Updated: 2003-06-23 17:00:25 -0400 (Reuters Health)

NEW YORK (Reuters Health) - A betaretrovirus related to murine mammary tumor virus (MMTV) may trigger the development of primary biliary cirrhosis (PBC), according to a report in the June 23rd PNAS Early Edition.

PBC is considered a classical autoimmune disease, as is Sjogren's syndrome, the authors explain, and Sjogren's syndrome was recently linked to a transmissible retrovirus known as human intracisternal A-type particle (HIAP).

Dr. Andrew Mason from Ochsner Clinic Foundation in New Orleans, Louisiana and colleagues identified viral particles in biliary epithelium by electron microscopy and investigated nucleotide segments in an effort to classify the agent.

The nucleotide sequences from particles isolated from PBC patients showed greater than 95% homology with multiple MMTV pol genes and with a retroviral pol gene cloned from human breast cancer tissue, the authors report. The highest match was with human reverse transcriptase gene.

The researchers named the putative agent human betaretrovirus because its sequence is nearly identical to that of MMTV.

Viral proteins were seen in 9 of 12 PBC patients in a pattern similar to that of PDC-E2 protein expression that characterizes PBC, the report indicates. In fact, viral proteins were seen only in cells with aberrant PDC-E2 expression.

Biliary endothelial cells cultured in the presence of lymph node tissue from PBC patients developed a PBC phenotype, the investigators note, and supernatant from these cultures contained particles whose morphology and RNA sequences were consistent with the human betaretrovirus.

"It is likely that betaretroviral infection is far more common than the development of PBC, which probably only manifests in genetically predisposed individuals," the researchers suggest. "Once infected the development of PBC may be related to the extent of viral replication and the ability of the virus to access the liver."

"The virus is associated with the development of a disease specific phenotype of aberrant autoantigen expression in vivo and in vitro and therefore may play a causal role in the disease process," Dr. Mason, now at the University of Alberta, Canada, told Reuters Health.

"We have pilot studies out now showing a 40% normalization of all liver tests in 10 PBC patients treated with Combivir," Dr. Mason said. "The randomized controlled trial will be completed in a couple of years."

"The detection of the human betaretrovirus in PBC patients lends credence to the association with human breast cancer," Dr. Mason added. "The study may be generative; retroviruses may cause other biliary or autoimmune diseases."

Proc Natl Acad Sci USA Early Edition 23 June 2003.

doi:10.1073/pnas.1433063100.