Role of Type 1 Versus Type 2 Immune Responses in Liver During the Onset of Chronic Woodchuck Hepatitis Virus Infection

Correlation of Virus and Host Response Markers with Circulating Immune Complexes during Acute and Chronic Woodchuck Hepatitis Virus Infection

“…This assumption is supported by the results for the proliferation and apoptosis of hepatocytes (Table 3), with a much higher percentage of hepatocytes undergoing cell division than apoptosis at the peak of serum SDH activity. The above-described results indicate furthermore that the suppression of WHV replication in the liver is caused mainly by noncytotoxic rather than cytotoxic mechanisms as also described previously in other studies of resolving WHV infection in woodchucks (15,21,38,47,48). One possible explanation for the different course of acute, self-limited WHV infection in individual woodchucks may relate to the individual immune response genes leading to different antigen recognition on virus-infected hepatocytes and different regulation, level, and action of cytokine production.…”

“…The reduction in serum WHV DNA levels before liver injury suggests that noncytotoxic immune mechanisms are mainly responsible for the initial decrease of WHV replication. As demonstrated in HBV-transgenic mice and HBV-infected chimpanzees, a massive production of the cytokine gamma interferon by HBV-specific CD8 ϩ T cells followed by tumor necrosis factor alpha from macrophages and hepatic Kupffer cells is responsible for the initial reduction in levels of HBV DNA and was also described previously for the self-limited outcome of acute WHV infection in woodchucks (12,14,15,19,21,37,38,48). The inhibition of HBV replication by these cytokines is a result of destabilized HBV mRNA and HBV covalently closed circular DNA in infected hepatocytes (17,37) and, by analogy, in WHV-infected hepatocytes of woodchucks.…”

“…The age and status of the immune system of an individual woodchuck are host factors that determine the outcome and course of WHV infection (6,8,32,38,47,48). Studies of humans and woodchucks suggested that the fine balance between viral load and quality of the individual antiviral immune response is important for an efficient suppression of viral replication resulting in the eradication of the virus from the host (3,8,32,38,47,48). The quality of the antiviral immune response appears to be the main determining factor for the observed differences in the course of WHV infection in the present study, because all group 1 and group 2 adult woodchucks had been infected with the same inoculum and dose.…”

“…Clearance of WHV during the acute phase of infection is associated further with strong and frequently detectable Thcell responses to WHV antigens in the peripheral blood and also with strong Th1 cytokine expression in the liver (5, 8, 30-32, 38, 47, 48). In contrast, the persistence of WHV replication and the onset and subsequent progression to chronicity as an outcome of experimental neonatal WHV infection are associated with deficiencies in virus-specific B-and Th-cell responses in the periphery, deficiencies in Th1 cytokine expression in the liver, and reduced immune-mediated liver injury (5,8,30,32,38,47,48). These results indicate a crucial role of humoral and cellular immune responses in the outcome of WHV infection.…”

Infection of neonates with murine gammaherpesvirus 68 results in enhanced viral persistence in lungs and absence of infectious mononucleosis syndrome

“…Other infections that occur during childhood that are associated with chronic infection, such as hepatitis viruses (Cote et al, 2000) and cytomegalovirus (Tu et al, 2004) infections, are due to differences in the infant and adult immune systems. The woodchuck model of hepatitis virus has been used to demonstrate that neonatal infection leads to chronic persistence, due in part to a decrease in the T-cell response along with a decrease in Th1-associated cytokines (Menne et al, 2002;Nakamura et al, 2001;Wang et al, 2003). Similarly, children infected with cytomelagovirus, a betaherpesvirus, exhibit a decreased CD4 + T-cell response and decreased IFN-c production (Tu et al, 2004).…”