MRC Notes continued
This series is based on notes that I took when I attended the Medical Research Council (MRC) HCV Conference in Ottawa on January 15 &16, 1999. While every attempt has been made to maintain accuracy, you must keep in mind that these are only my personal notes.
Darlene
What are the Gaps in Our Knowledge?
By Ramon Tellier, MD
Hospital for Sick Children,
550 University Avenue,
Toronto, Ontario, M5G 1X8
Tel: 416.813.1500 Fax: 416.813.5993
The Biology and Pathology of Hepatitis C
HCV is very similar to yellow fever. We have found that the is not capped but rather has an internal ribosomal entry site (IRES). This site may be key as it is unique to hepatitis C and does not occur in humans.
Genotypes 1 and 2 are very different in genetic analysis compared to the other genotypes . If we compare this to other systems, this genetic variance would be classified as separate species. The quasispecies development shows the error prone nature of the RNA virus and its ability to mutate which may be responsible for the chronicity of infection.
At present we know that there is no HCV replication in Kupffer cells. HCV in liver cells is sufficient to cause disease. HCV can grow in transformed T cells. This as been shown to be real in vitro culture as we can be inoculate chimps which then get acute HCV which becomes chronic.
We have also seen extra hepatic replication in peripheral blood cells (PBMC) in patients. The detection is very difficult because of lower limits of the PCR. Instead we have to look for the negative strand HCV RNA and then it is possible to detect. We can see that the virus multiplies in PBMC through RT -PCR specific for negative strand.
The E2 portion of HCV binds to CD 81. Neutralizing antibodies will prevent this. It is possible for patients to clear HCV. If we infect with another strain it is possible that chronicity will develop. Challenging with the same strain can also lead to chronicity. Therefor previous infection does not lead to immunological protection. Yet there are antibodies that will neutralize the virus. Chronic infected individuals exposed to another strain can show antibody neutralization. We believe that HCV if escapes immune detection through the E2 generation of mutants.
Chronic HCV with ALT Normalized
We see many patients with low histopathology but we also see high. We cannot correlate a normal ALT with a histological index. ALT is not good marker of histopathology. There are other pathways of clearance that do not lead to the increase in ALT.
Interferon Resistance
In genotype 1b NS5A sequence binds PKR ( in the pathway of interferon binding) and this prevents the utilization of the interferon. If this mutant protein NS5A can also block apotosis we can see Hepatocellular Carcinoma. HCV itself does not carry the oncogene We feel that it accelerates the development of Hepatocellular Carcinoma due to a shortened telomere length.
HCV and non Hodgkins Lymphomas
HCV has been linked to both non Hodgkins Lymphomas and cryoglobulinemia. It has not been positively proven. Is it possible for HCV to cause this or is it due to increased immune responses? We are not sure.