The relationship between hepatitis virus invasion and emergence of liv
er-specific autoantibodies against asialoglycoprotein receptor (anti-A
SGPR) and the occurrence patterns, prognostic value, and specificity o
f these autoantibodies toward polypeptides of host ASGPR were investig
ated in experimental viral hepatitis in the woodchuck system. Sequenti
al sera (n = 231) obtained before and after inoculation with woodchuck
hepatitis virus (WHV) from animals which resolved acute infection (n
= 7) or developed chronic hepatitis (n = 6) were tested for anti-ASGPR
using radio and enzyme-immunodetection assays. In addition, the outco
me of WHV hepatitis was analyzed in 30 other woodchucks whose preinocu
lation sera were tested for anti-ASGPR. The receptor subunit specifici
ty of virus-induced anti-ASGPR was determined by Western blotting and
compared with that of anti-ASGPR raised in woodchucks challenged with
a heterologous (rabbit) receptor. The results revealed that WHV infect
ion triggered anti-ASGPR in all except one of the initially autoantibo
dy nonreactive animals (eight of nine; 89.9%). Once induced, anti-ASGP
R were detectable throughout the entire follow-up independent of histo
logical severity of liver damage or the outcome of hepatitis. In healt
hy WHV-naive woodchucks, anti-ASGPR occurred at low titers in approxim
ately one third of the animals. Importantly, woodchucks reactive for a
nti-ASGPR before WHV inoculation developed chronic hepatitis with a si
gnificantly greater frequency (55.5%) than those autoantibody negative
(15.6%; P < .05). In contrast to anti-ASGPR elicited by immunization
with a heterologous receptor, which initially recognized only the ASGP
R 40-kd polypeptide, anti-ASGPR emerging after virus invasion reacted
with both the ASGPR 40- and 47-kd subunits from the moment of their ap
pearance. This study provides the first direct evidence that hepatitis
virus in the natural host triggers autoantibodies against a unique he
patocyte antigen and shows that anti-ASGPR autoimmunity existing befor
e virus infection is associated with a high rate of progression to chr
onic disease in experimental hepadnaviral hepatitis.