Current Research and Scholarly Interests
The Foung laboratory is focused on the early events of hepatitis C virus infection- virus attachment and entry to susceptible cells. The approach is through the generation of human monoclonal antibodies (HMAbs) to the virus envelope proteins with an emphasis on antibodies to conformational epitopes. A large panel of HMAbs has been produced with many broadly reactive to different HCV isolates common in the US and elsewhere. Functional studies showed that the HCV envelope E2 glycoprotein is organized in distinct immunological and functional clusters with epitopes within each cluster or domain sharing similar functional and structural properties. At least three domains mediate virus neutralization and antibodies to epitopes within two domains inhibit virus binding to the virus receptor, CD81. Interestingly, some of these antibodies also block a second step in virus entry by inhibiting the low pH induced virus envelope conformational rearrangement that is necessary to trigger virus fusion with the endosomal membrane. These findings support the view that virus entry is mediated by only specific determinants on the virus surface and appear to be restricted to distinct immunogenic domains. This is in contrast for other viruses where the convention is that neutralization is the result of a critical number of any binding sites being occupied and preventing virus entry through steric hindrance. Studies are underway on expanding this model of the virus envelope glycoproteins, which will be important in linking structure and function.