Experimental inoculation of naive ducks with duck hepatitis B virus (DHBV) can lead to one of three outcomes, namely, persistent viremia, transient infection with or without viremia, or no evidence of infection. The ability of individual ducks to resolve DHBV infection was found to be linked to the age of the duck at the time of inoculation and the dose of inoculated virus. (1) In recently hatched ducks inoculated intravenously (i.v.) with 4 x 10(4) DHBV DNA genomes, a switch from persistent viremia to transient antibody appearance was seen at an age of inoculation between 7 and 14 days. A 25-fold increase in the dose of virus (1 x 10(6) DHBV genomes) delayed this switch by 7 days. (2) When 4-month-old ducks were inoculated i.v. with different doses of virus, only those receiving the highest dose (2 x 10(11) DHBV genomes) showed viremia and extensive viral replication and histological changes in the liver; 2/3 ducks in this group had a transient infection, while the third duck had viral replication and histological changes in the liver that were still present at day 120 postinoculation (p.i.). In all ducks receiving lower doses (1 x 10(3), 1 x 10(6), 1 x 10(9) DHBV genomes) antibodies to viral surface and core antigens developed without detectable viral replication in the liver on days 6, 9, or 12 p.i. (3) When 10- to 16-month-old ducks were inoculated i.v. with 2 x 10(11) DHBV genomes, all showed extensive viral replication in hepatocytes and mild to moderate histological changes in the liver on days 4 or 6 p.i. In 4/5 ducks viremia was not detected, anti-surface antibodies were first detected on day 8 p.i., and viral DNA and antigen were cleared from the liver by days 35-47 p.i. The remaining duck became viremic with persistence of virus in the liver until at least day 46 p.i. The findings of the study are consistent with a model for noncytopathic viruses (R. M. Zinkernagel (1996) Science 271, 173-178).

We cured a strain of Salmonella typhimurium of its cryptic plasmid and confirmed that orally administered cured strains lost virulence for mice. Loss of the cryptic plasmid rendered the S. typhimurium strain sensitive to the bactericidal action of normal human serum. However, loss of the plasmid did not change the ability of the strain to associate with HeLa cells in tissue culture. Furthermore, when administered orally to mice, both the plasmid-containing and plasmid-free strains invaded the Peyer's patches of the small intestine to the same extent, and both were capable of inducing resistance to oral challenge with virulent S. typhimurium. When injected intraperitoneally, the cured strain was eliminated rapidly, whereas the parental strain persisted. We also showed that the cured strain did not contain a plasmid copy in the chromosome. We propose that although the plasmid-cured strain of S. typhimurium is able to colonize Peyer's patches, it cannot survive when administered intraperitoneally because it is susceptible to elimination by macrophages.

This study was designed to test the efficacy of antiviral treatment with entecavir (ETV) in combination with DNA vaccines expressing duck hepatitis B virus (DHBV) antigens as a therapy for persistent DHBV infection in ducks. Ducks were inoculated with 109 DHBV genomes at 7 days of age, leading to widespread infection of the liver and viremia within 7 days, and were then treated orally with either ETV (0.1 mg/kg of body weight/day) or distilled water from 21 days posthatch for 244 days. Treatment with ETV caused a 4-log drop in serum DHBV DNA levels within 80 days and a slower 2-to 3-log drop in serum DHBV surface antigen (DHBsAg) levels within 120 days. Following withdrawal of ETV, levels of serum DHBV DNA and DHBsAg rebounded to match those in the water-treated animals within 40 days. Sequential liver biopsy samples collected throughout the study showed that ETV treatment reduced DHBV DNA replicative intermediates 70-fold in the liver, while the level of the stable, template form, covalently closed circular DNA decreased only 4-fold. ETV treatment reduced both the intensity of antigen staining and the percentage of antigen-positive hepatocytes in the liver, but the intensity of antigen staining in bile duct cells appeared not to be effected. Intramuscular administration of five doses of a DNA vaccine expressing the DHBV presurface, surface, precore, and core antigens, both alone and concurrently with ETV treatment, on days 50, 64, 78, 127, and 141 did not result in any significant effect on viral markers.Hepatitis B virus (HBV) is a noncytopathic virus that replicates primarily in hepatocytes. HBV infection of humans can result in either a transient infection with development of neutralizing antibodies and immunity to reinfection or a persistence of viral infection for many years. Patients with either acute or persistent HBV infection often have extensive infection of the liver with high titers of infectious virus and noninfectious surface antigen particles circulating in the bloodstream. Immune responses to HBV are responsible for clearance of virus-infected cells from the liver and for the liver damage seen in both acute and persistent infection. Models of hepadnavirus pathogenesis usually propose that effective humoral and cell-mediated immune responses lead to recovery from infection with elimination of virally infected cells or replicative intermediates, while ineffective immune responses allow extensive viral replication with or without hepatocyte damage (reviewed in references 2 and 3). Thus, in individuals destined to become persistently infected, the high viral load may overwhelm the capacity of the immune system or favor the induction of ineffective antibody responses.Persistent HBV infection occurs in 5 to 10% of adults with acute infections and in Ͼ90% of neonates. Current approaches to treatment for persistent HBV infection include long-term alpha interferon administration and antiviral drug therapy aimed at inhibiting viral replication. Partial suppression of levels of circulating virus can be ach...

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