ABSTRACT
The pathogenesis of hepatitis A virus (HAV) infection was studied in owl monkeys following oral administration of the wild-type HM-175 strain of HAV. Stools were collected daily and blood and pharyngeal swabs twice weekly for viral isolation, and animals were necropsied at various intervals after inoculation. Organs were examined for the presence of virus by isolation in cell culture and for viral antigens by immunofluorescence. Monkeys excreted HAV in the stools for 1-4 days after inoculation, presumably due to the residual unabsorbed inoculum. No virus was found in stools for the next 2-3 days. HAV re-appeared on days 4-7 and then persisted through day 39. Viremia occurred on the 10th day and continued until day 35. Virus was isolated occasionally from throat swabs 1 or 2 weeks after it was detected in stools and blood, and there was no evidence that HAV replicated in the pharyngeal tissues. Animals acquired anti-HAV antibody by the 4th week, and alanine aminotransferase (ALT) was elevated 5-5.5 weeks after inoculation. HAV was isolated from liver 5 days after inoculation; however, viral antigens were first detected in Kupffer cells of the liver at 14 days and in hepatocytes at 21 days. HAV antigen was detected in epithelial cells of the intestinal crypts and in the cells of the lamina propria of the small intestine 3 days postinoculation and thereafter until the 5th week, suggesting that these cells might represent an additional site of HAV replication.
Subject(s)
Hepatitis A/virology , Administration, Oral , Animals , Antigens, Viral/analysis , Aotidae , Disease Models, Animal , Feces/virology , Fluorescent Antibody Technique , Hepatitis A/immunology , Hepatitis A/pathology , Hepatitis A Antigens , Hepatovirus/isolation & purification , Humans , Liver/pathology , Pharynx/virologySubject(s)
Hepatovirus/immunology , Immunity, Cellular , Animals , Aotus trivirgatus , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Hepatitis A/etiology , Hepatitis A/immunology , Hepatitis A/pathology , Immunoglobulin G/biosynthesis , Immunoglobulin M/biosynthesis , Immunohistochemistry , Interleukin-6/biosynthesis , Liver/immunology , Liver/pathology , Plasma Cells/immunology , Plasma Cells/pathology , T-Lymphocytes/immunology , T-Lymphocytes/pathologyABSTRACT
Cytokines IL-1-beta, IL-2, and TNF alpha were detected in occasional cells within portal inflammatory infiltrates beginning 3 weeks after oral inoculation of monkeys with HAV. The number of cells secreting those cytokines did not increase, and they were not of importance in the pathogenesis. Production of cytokines IL-6 and IL-4 by T lymphocytes infiltrating portal areas started 4 weeks after inoculation, stimulating local expansion of B cells, probably secreting antibodies to HAV. IL-6 and IL-4 may also stimulate cytotoxic activity of a few CD8+ lymphocytes.
