Approximately there are 160 million people infected by the hepatis C virus (HCV) worldwide. There is a treatment against this infection based in the coadministration of pegylated interferon (IFN) alpha and ribavirin, but only 50% of the patients respond to the treatment. The HCV infection leads to progresive liver disease that ranges from mild inflammation to severe fibrosis, as well as cancer. Therefore it is very important to develop new antiviral strategies against this virus.

Analysis of HCV mechanisms to evade the immune response
Our group is focused in developing new therapeutical strategies against HCV and for this purpose we are analyzing the molecular mechanisms used by HCV to escape natural defenses against a viral infection: the interferon and immune systems.
Several years ago it was observed in our laboratory that the interferon alpha subtype (IFN-alpha5)  present in a healthy human liver was different to the interferon alpha subtype (IFN-alpha2) that is used in the HCV infection treatment and that the amount of IFN-alpha5 present in the liver of HCV infected patients is reduced (Patent: “Utilization of interferon alpha 5 in the treatment of viral hepatopathies”, Nº EP1077068B9).
We have found that HCV replication interferes with IFN-alpha induced signalling pathway inhibiting its antiviral activity. Consequently we looked for new approaches to potentiate IFN-alpha activity and we found that the use of IFN-alpha in combination with the IL-6 family cytokines increases its antiviral activity (Patent: “Use of a cytokine from the IL-6 family in the preparation of a composition for combined administration with Interferon-alpha”. Nº WO 2006/134195 A2).
In addition we have observed that HCV infection generates an immunosupresive environment in the liver, inducing an increase of IDO and other molecules that may dampen T-cell reactivity to viral antigens in chronic HCV infection. Thus we are analyzing the effects of several molecules that are differentially expressed in HCV infected cells and that can contribute to the chronicity of HCV infection.

Generation of “humanized” mice (in collaboration with Dr JI Riezu)
Nowdays there is a deficiency of animal models that can be used for analyzing HCV infection because this virus replicates eficiently only in human and chimpanzee hepatocytes. Therefore we want to generate mice with human hepatocytes in their liver, that it has been proven as a good host for HCV replication. Before human hepatocyte transplantation we are inducing a chronic liver damage to mice that are highly immunosupressed for generating a niche for human hepatocyte growth in the murine liver. We want to use these mice as an animal model for HBV infection and for testing the infectivity of several human hepatic vectors that are being developed in the department.

Characterization of the aminoterminal acetyltransferase NatB
Protein aminoterminal acetylation is a widely protein modification, being present in more than 80% of cytosolic mammalian proteins. In our laboratory we have observed that aminoterminal acetyltransferase NatB catalytic subunit (NAT5) is overexpressed in human hepatocarcinoma and in the hepatic tumors generated in a murine model. Furthermore, NAT5 expression inhibition in human cells induces cell growth arrest, indicating that this enzyme, NatB, can be a new target for the antitumoral therapy. Therefore we are seeking compounds that can inhibit NatB activity  and meanwhile we are analyzing the biological mechanisms that can be regulated by this postranslational modification.