Hepatitis A

Hepatitis A. of otherwise neutralizing antibodies, resulting in exacerbation of liver disease. Hepatitis A computer virus (HAV), a hepatotropic picornavirus (for a review, see reference 15), causes acute viral hepatitis (-)-Huperzine A in humans by an immunopathogenetic mechanism (41). The HAV contamination is usually characterized by a short, self-limited disease and does not lead to chronic cases. However, after initial improvement in symptoms and liver test values, one or more relapses of the disease are described for up to 20% of patients (14, 40). These relapses occur between 30 (-)-Huperzine A and 90 days after the primary episode, when high titers of neutralizing antibodies are already detectable (12). HAV is usually transmitted by the fecal-oral route, but the mechanism by which the virus first enters the bloodstream and reaches the liver as well as the pathogenetic mechanism leading to a relapsing disease remains unclear. Kaplan et al. (17) reported that a mucin-like class I integral membrane glycoprotein which was identified on African green monkey kidney cells acts as an attachment molecule for HAV. It was demonstrated that this human homolog is usually a binding receptor for HAV; it has been suggested that it is also a functional receptor (10). Although cell lines originating from tissues other than liver, such Gimap5 as fibroblasts and kidney cells, are also susceptible to HAV contamination (9, 11) and although HAV antigen and the putative receptor for HAV could be detected in different organs, such as kidney, spleen, and gastrointestinal tract (2, 6, 10, 18), no extrahepatic sites of HAV replication have been clearly identified. The data around the ubiquitous expression of a receptor for HAV and the ability of HAV to replicate in a number of nonliver cells in (-)-Huperzine A cell cultures, but obviously not in the organism, suggest that HAV may be targeted to the liver by a particular mechanism. Data from several laboratories showed that HAV virions are partially associated with immunoglobulin A (IgA) molecules (19, 22) and other host organism-derived materials, such as fibronectin or 2-macroglobulin (21, 23, 24, 35, 43). As viruses may find entry into host cells via receptors specific for molecules of the host organism ligated to the virion (13, 16, 20, 26) and as the liver plays a central role in IgA metabolism by eliminating IgA as well as antigen-IgA complexes (4), we wondered if HAV-specific IgA ligated to HAV supports the targeting of HAV to the liver and is able to mediate the entry of HAV into hepatocytes via receptors specific for the IgA molecule and if such a carrier-mediated (-)-Huperzine A mechanism may result in viral contamination. This mechanism, by which a molecule normally designed to neutralize viral infectivity is usually recruited to arrange HAV contamination of the liver, can explain still-unanswered questions about HAV pathogenesis, such as the lack of extrahepatic sites of replication and the relapsing courses of HAV contamination in the presence of otherwise neutralizing antibodies (12, 14, 40). Therefore, our studies were designed to examine binding to and uptake into hepatocytes of HAVCanti-HAV IgA immunocomplexes and the following viral replication. We also investigated whether HAVCanti-HAV IgA complexes may play a role in the oral transmission of HAV. MATERIALS AND METHODS Cells. The murine hepatocellular cell line NCTC clone 1469 (ATCC CCL 9.1) was used to investigate the IgA-assisted entry of HAV into hepatocytes. The cells were maintained as continuous cultures in Dulbecco altered Eagle medium (DMEM) supplemented with 1% fetal calf serum. In order to split the cells weekly at a ratio of 1 1:2, they were detached from the tissue culture plate with Versene and cultivated with DMEMC10% FCS as the.