Latest on the beta-retrovirus cause of PBC hypothesis

[Guest guest]

Dear All;

You may remember that earlier this year there was a report from

Mason's group about the cloning of a betaretrovirus from lymph nodes

of primary biliary cirrhosis (PBC) patients. This retrovirus (very

similar to the mouse mammary tumor virus) was implicated in PBC

because it was capable of inducing the characteristic anti-pyruvate

dehydrogenase complex antibodies of PBC in normal biliary epithelia

cells. Since then, there have been a couple of new devlopments.

1. Gershwin and co-workers were unable to find evidence for such a

virus in sera and liver samples from PBC patients [however, they did

not look in lymph nodes]:

Gastroenterology. 2004 Aug;127(2):493-501.

Lack of immunological or molecular evidence for a role of mouse

mammary tumor retrovirus in primary biliary cirrhosis.

Selmi C, Ross SR, Ansari AA, Invernizzi P, Podda M, Coppel RL,

Gershwin ME.

Division of Rheumatology, Allergy, and Clinical Immunology,

University of California at , 95616, USA.

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.

PMID: 15300582

2. In a paper shortly to be published in the American Journal of

Gastroenterolgy (not yet in the PubMed database) Mason reports

promising effects of antiretoviral therapy in PBC patients,

particularly with the lamivudine and zidovudine combination

(Combivir) antiretroviral agents:

Am. J. Gastroenterol. 99: (In Press) (2004)

Pilot studies of single and combination antiretroviral therapy in

patients with primary biliary cirrhosis.

Mason AL, Farr GH, Xu L, Hubscher SG, Neuberger JM

Section of Gastroenterology and Hepatology; and Department of

Pathology, Ochsner Clinic Foundation, New Orleans, Louisiana; and

Department of Pathology and Liver Unit, Queen Hospital,

University of Birmingham, UK

OBJECTIVE: Preliminary reports suggest that patients with primary

biliary cirrhosis (PBC) have evidence of human betaretrovirus

infection. The aim of this study was to determine whether antiviral

therapy impacts on the disease process.

METHODS: We conducted two consecutive open-labeled, nonrandomized, 1-

yr pilot studies; the first with lamivudine 150 mg/day and the

second with Combivir combination therapy using lamivudine 150 mg and

zidovudine 300 mg twice a day. Eleven PBC patients enrolled in each

study, seven patients were entered into both studies, and one

patient was withdrawn from each study due to side effects.

RESULTS: Evaluation of liver biopsies before and after lamivudine

therapy showed a 4–5 increase in necroinflammatory score, a 1–1.5

elevation in bile duct injury, with little change in the percentage

of portal tracts with bile ducts (50–52%). None of the patients in

the lamivudine study normalized alkaline phosphatase. Histological

assessment following Combivir therapy revealed a 6 to 4 improvement

in necroinflammatory score (p < 0.03, 95% CI: 0.53–2.33), a 3 to 1

reduction in bile duct injury (p < 0.02, 95% CI: 1.08–2.07), and a

45–75% increase in portal tracts with bile ducts (p < 0.05, 95% CI:

0.02–0.29). In the Combivir cohort, five patients normalized

alkaline phosphatase and four developed normal AST, ALT, and

alkaline phosphatase.

CONCLUSIONS: Histological and biochemical endpoints were achieved in

the Combivir pilot study suggesting a larger placebo-controlled

trial is required as a proof of principle to assess whether

antiviral therapy impacts the PBC disease process.

____________________________

Best regards,

(father of (19); PSC 07/03; UC 08/03)