Primary biliary cirrhosis (PBC) is an idiopathic multisystem autoimmune disorder that primarily effects women. Patients with PBC have a pluriglandular syndrome resulting in cirrhosis and sicca syndrome, and a demonstrable autoimmune response to specific mitochondrial oxo-acid dehydrogenase E2 proteins. PBC patients are also prone to develop other autoimmune diseases such as Sjogren's syndrome, thyroiditis, and systemic lupus erythematosus. These autoimmune disorders have all been linked to rettroviral infection as by Western blot studies 30 to 35 percent of patients have indeterminate serum reactivity to HIV proteins and 85 to 05 percent have serum reactivity to human intracisternal A type particle (HIAP-I) which was isolated from salivary glands of patients with Sjogren's syndrome and also visualized by electron microscopy. Likewise, 15 percent of PBC patients have been reported to have false positive HIV ELISA reactivity and in preliminary studies, retrovirus particles have been observed by electron microscopy in the biliary epithelial cells of PBC patients but not controls. Using representational difference analysis, we have isolated and cloned novel retroviral nucleic acid sequences from the liver of a PBC patients. These clones have been used to screen a cDNA library made from bilary epithelium cells isolated from three transplant recipients with PBC. We have now identified more than ten qunique cDNA clones with sequence homology to HIV, SIV, HTLV-1, and IAP as well as the E2 mitochondrial autoantigens. To date, our RTPCR studies have revealed that all the RDA and 3 of 3 novel clones tested to data are not unique to PBC patients, suggesting that they may be derived from endogenous retroviruses. Also, we have conducted Western blot studies which reveal that approximately 74 percent of PBC patients sera have indeterminate reactivity to HIAP proteins and 35 percent of patients react to HIV p24 gag, compared to less than 5 percent of liver disease controls. This suggests that the putative PBC retrovirus shares antigenic determinants with HIV-I and HIAP-I but is a separate virus. In order to further characterize the agent associated with PBC, we plan to identify specific retroviral proteins and nucleic sequences with the ultimate goal of investigating the role this virus plays in the eitology of PBC.
Our specific aims are to (1) Clone full length PBC retrovirus from hepatic tissue and PBC cDNA libraries; (2) Isolate the PBC retrovirus in lymphoblastoid and hepatic cell lines by co-culture with infected hepatic tissue; (3) Assess the prevalence of retroviral infection in PBC patients and controls by nucleic acid hybridization techniques and western blot experiments of recombinant or purified viral proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI001467-05
Application #
6488659
Study Section
Special Emphasis Panel (ZAI1-PSS-A (M1))
Program Officer
Podskalny, Judith M
Project Start
1997-09-30
Project End
2002-07-31
Budget Start
2002-01-01
Budget End
2002-07-31
Support Year
5
Fiscal Year
2002
Total Cost
$82,530
Indirect Cost
Name
Ochsner Clinic Foundation
Department
Type
DUNS #
077900207
City
New Orleans
State
LA
Country
United States
Zip Code
70121
Mason, Andrew L; Farr, Gist H; Xu, Lizhe et al. (2004) Pilot studies of single and combination antiretroviral therapy in patients with primary biliary cirrhosis. Am J Gastroenterol 99:2348-55
Xu, Lizhe; Sakalian, Michael; Shen, Zhiwei et al. (2004) Cloning the human betaretrovirus proviral genome from patients with primary biliary cirrhosis. Hepatology 39:151-6
Xu, Lizhe; Shen, Zhiwei; Guo, Linsheng et al. (2003) Does a betaretrovirus infection trigger primary biliary cirrhosis? Proc Natl Acad Sci U S A 100:8454-9
Mason, Andrew; Nair, Sateesh (2002) Primary biliary cirrhosis: new thoughts on pathophysiology and treatment. Curr Gastroenterol Rep 4:45-51
Gish, R G; Mason, A (2001) Autoimmune liver disease. Current standards, future directions. Clin Liver Dis 5:287-314
Mason, A L; Xu, L; Guo, L et al. (1999) Retroviruses in autoimmune liver disease: genetic or environmental agents? Arch Immunol Ther Exp (Warsz) 47:289-97
Mason, A L (1999) TT virus: will work for food? Am J Gastroenterol 94:3398-401