This lecture was about understanding the role of interferon stimulated gene (ISG) expression and the relationship to nHCV infection. We all have some degree of ISG expression; this is partly responsible for combating the virus. As you can see from the graphic above, these genes are upregulated by activation of the Jak/STAT pathway, among others. This is the pathway that HCV tries to disrupt with its non-structural proteins (NS5A, for example; also depicted on the image above).
It was discovered that non-responders to Peg-interferon + Ribavirin have higher basal levels of ISG activity. Hepatic Kupfer cells (resident macrophages) may play a role in the innate activation of ISG and interferon production. It is this continuous innate interferon exposure that renders hepatocytes refractory to subsequent Peg-interferon exposures.
Recall from a previous lecture that the IL28B ‘CC’ genotype is associated with a more successful virologic response to therapy. Perhaps it is not surprising, therefore, that patients with the CC genotype do not have very high basal levels of ISG. Recognition of such pre-treatment factors and the likelihood of response is another step in the direction of personalized medicine for HCV treatment.