Immunology

HCV evades host defenses and establishes a persistent infection in approximately 80% of infected individuals. Lynn B. Dustin leads our investigations into HCV interactions with the immune system and the response of the virus to other pressures, such as antiviral drugs. In chronically infected patients, HCV does not only avoid clearance, but may manipulate immune cells leading to additional pathologies. B cells may become abnormally activated, producing high levels of antibodies, which can accumulate causing mixed cryoglobulinemia; these B cells may also become cancerous. The possibility that B cells are polyclonally activated, or even infected, through their expression of an important HCV entry factor, CD81, has been proposed. In contrast, we have found that B cells in many HCV-infected individuals have a naïve phenotype, whereas those in some patients with mixed cryoglobulinemia are clonally activated. These findings suggest that HCV-related immune pathologies result from the specific activation of certain B cells, rather than a polyclonal expansion. The antigen responsible for this activation is not known, but may be related to components involved in autoimmune disease. We have also found no evidence that primary or cultured B cells can be productively infected with HCV. The finding that a second essential co-receptor, claudin-1, is absent from immune cells supported the hypothesis that B cells are resistant to HCV infection. We have shown that B cells engineered to display this entry factor are still refractory to virus entry and replication, suggesting their infection is stringently prevented.

Rapid evolution of the HCV genome through its error-prone replication strategy helps the virus to evade the immune response, and to overcome antiviral drugs. We are investigating the mechanisms by which HCV develops resistance to specific antiviral compounds, and the cost that these adaptations have on the virus when the drug is removed. An understanding of how HCV evades and manipulates the immune system, as well as knowledge of virus behavior in the face of inhibitors will be essential in devising treatments for HCV and in developing an effective vaccine.