โ Scribed by Tomasz I. Michalak; Ingrid U. Pardoe; Carla S. Coffin; Norma D. Churchill; Dion S. Freake; Paula Smith; Colleen L. Trelegan
No coin nor oath required. For personal study only.
Traces of hepatitis B virus (HBV) genome can persist for years following recovery from hepatitis B. To determine overall duration, molecular characteristics, and pathological implications of this serologically undetectable form of hepadnaviral carriage, we have analyzed the expression of transcriptionally active virus genomes, their infectivity, and examined liver alterations during the natural lifespan of woodchucks convalescent from acute infection with HBVrelated woodchuck hepatitis virus (WHV). In this study, we document lifelong persistence of scanty amounts of replicating virus both in the liver and lymphatic system after spontaneous resolution of an episode of experimental hepadnaviral hepatitis. Antibodies to virus nucleocapsid (core) were found to be the most reliable immunovirological marker coexisting with occult infection. In the majority of convalescent woodchucks, serial liver biopsies showed protracted minimal to mild necroinflammation with periods of normal morphology; however, hepatocellular carcinoma (HCC) ultimately developed in 2 of 9 animals studied. Inocula derived from lymphoid cells of convalescent animals induced classical acute hepatitis in virus-naive woodchucks that progressed to chronic hepatitis and HCC in 1 of the animals, demonstrating infectivity and pathogenic competence of the carried virus. Our results reveal that low levels of infectious WHV and residual hepatic inflammation usually continue for life after resolution of hepatitis and that this recovery does not avert HCC development. They also demonstrate that, in addition to the liver, the lymphatic system is the site of the occult lifelong maintenance of replicating hepadnavirus. (HEPATOLOGY 1999;29:928-938.)
Current evidence indicates that carriage of minute quantities of hepatitis B virus (HBV) genome can continue for years following complete clinical and serological recovery from acute hepatitis B. In these convalescent patients, HBV DNA have been detected both in serum and in circulating lymphomononuclear cells, often despite the presence of neutralizing antibodies to virus envelope (hepatitis B surface antigen) 2,3,5 and a vigorous polyclonal HBV-specific cytotoxic T-cell response. In addition, traces of hepatitis B surface antigen and HBV-DNA-reactive particles with physicochemical properties of intact virions have been detected in the circulation of some of the recovered individuals. 2 These findings imply that HBV eradication does not coincide with the rise of antivirusspecific humoral and cellular immune responses and with clinical resolution of acute hepatitis.
It is expected that this serologically undetectable persistence of HBV may have important epidemiological and pathogenic implications, whose range has yet to be established. This assumption is based on a growing number of observations indicating that HBV infection can appear in recipients of organs from HBV serologically negative donors, and that hepatocellular carcinoma (HCC) with integrated HBV genomic sequences can arise in HBVseronegative patients and animals. There is also the likelihood that some individuals who develop subclinical infection after exposure to HBV become serologically silent carriers of virus and a potential source of infection to nonimmune humans.
The main aims of this present study were to determine overall longevity and the sites of hidden hepadnavirus replication that continues after recovery from an episode of self-limited acute hepatitis (SLAH), to assess infectivity and pathogenic competence of the carried virus, and to recognize the long-term pathological consequences of this silent form of hepadnavirus infection. To circumvent practical and ethical difficulties associated with long-term study of individuals considered to be completely healthy, in particular with obtaining multiple liver biopsy samples, we have followed, for up to 6 years, woodchucks inoculated with woodchuck hepatitis virus (WHV), which is the closest relative of HBV among hepadnaviruses. All animals investigated in this study had developed classical acute hepatitis and demonstrated recovery from the disease, as judged by serological and histological criteria. Our work shows that such naturally Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; SLAH, self-limited acute hepatitis; WHV, woodchuck hepatitis virus; anti-WHc, woodchuck hepatitis core antibody; PBMC, peripheral blood mononuclear cells; WHsAg, WHV surface antigen; anti-WHs, woodchuck hepatitis surface antigen antibody; PBS, phosphate-buffered saline; HBSS, Hanks' balanced salt solution; PCR, polymerase chain reaction; RT, reverse transcriptase; dpi, days postinoculation.
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