Studies on transmission and immune responses of the human hepaciviruses

Abstract

The hepatitis C virus (HCV) and GB virus C/hepatitis G virus (GBV-C/HGV) are the most recently identified hepaciviruses in the family of Flaviviridae. Although these viruses are transmitted mainly through parenteral routes a significant proportion of infected individuals lack identified transmission routes. The chronic HCV infection is associated with chronic liver diseases which may progress to cirrhosis and hepatocellular carcinoma. Coexistence of HCV and immune responses is usually found in chronically HCV infected patients. In contrast, infection with GBV-C/HGV has not been conclusively associated to a known disease and GBV-C/HGV antibodies are most often not detectable in chronically infected patients.

The aim of this study was to investigate the viral transmission through non parenteral routes and to characterize the immune responses to the viral proteins. The presence of these viruses in serum and saliva was determined by reverse transcription polymerase chain reaction (RT-PCR) amplification of the viral RNA genomes. The viral RNA was detected in the saliva obtained from HCV and HGV infected patients at the frequency of 18% and 33%. respectively. Mother-to-infant transmission of HGV was identified and was confirmed by the high genetic homology between the virus of the mother and the infected child. HGV RNA was detected in saliva from the infected mother and child raising the possibility that HGV may be transmitted by close social contacts. Salivary HCV was detected in the cell-fraction of whole saliva, but not in the submaxillary saliva, suggesting that the virus might be derived from the circulation. The transient presence of HCV in the saliva during and alter oral surgely may help to explain the high seroprevalence of HCV found in oral surgeons. The acute HCV infection was shown to be characterized by poor IgM production of limited diagnostic value. However an increasing number of linear antibody reactivities to the HCV core protein was observed as the infection progressed to the chronic phase. Antibodies responses to most HCV proteins, including the non-structural 3 (NS3), were restricted to the IgGI isotype. Other IgG isotypes were mainly produced at low levels. The immunogenicity of HCV NS3 was therefore further characterized in mice which demonstrated that HCV NS3 is not an intrinsically poor immunogen. These data suggest that HCV infection elicits comparatively weak immune responses which in combination with the high degree of genetic variability is likely to be a mechanism for viral persistence. In conclusion, HCV and HGV/GBV are present in the extravascular compartment which may serve as a route of transmission for these viruses. The characteristics of the weak HCV induced immune responses may be important for viral persistence. These findings will have an impact on the prevention and diagnosis of hepacivirus infections.