The mechanism of chronic coxsackievirus B hepatitis in rabbits

The pathophysiology of chronic hepatitis in rabbits infected with coxsackie virus B5 (CVB5), (strain Mitchell) was investigated. Three-week-old male Ne w Zealand White rabbits were inoculated intraperitoneally with 1 x 10(5) pl aque forming units of virus. Every 3 months for 15 months postinoculation ( p.i.) groups of animals were sacrificed for the following tests: interleuki n (IL)-6, tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1 be ta cytokine levels by enzyme-linked immunosorbent assay (ELISA); splenic na tural killer (NK) cell function; sequence of a 154-bp section of the 5 ' no ncoding region; antihepatocyte autoantibodies; histologic examination; in s itu polymerase chain reaction (ISPCR) of the liver; neutralizing antibody r esponse to CVB5; and viral cultures of liver, spleen, blood, brain, heart, skeletal muscle, and pancreas samples. Histologic evidence of hepatocyte ne crosis was evident at each time point, although few inflammatory cells were seen. Liver samples were positive at each time by ISPCR, with viral nuclei c acid localized to hepatocyte cytoplasm. Other cells in the liver did not stain. No hepatocyte autoantibodies were detected, and there was no elevati on of intrahepatic cytokine levels compared to uninfected controls. There w ere no mutations in the virus over time. A vigorous neutralizing antibody r esponse to CVB5, Mitchell was generated, but splenic natural killer (NK) fu nction and numbers of splenic NK cells were significantly decreased. Virus culture was positive at 3 months, but negative at further time points. Cult ures were negative at 3 months for the other tissues tested. Thus, CVB5, Mi tchell causes a chronic hepatitis in rabbits, with virus limited to hepatoc yte cytoplasm and no evidence of autoimmunity.