The laboratory of Robert Lanford is involved in three research programs involving hepatitis B virus (HBV), hepatitis C virus (HCV) and GBV-B, a surrogate model for HCV.
One of the primary focuses of Lanford’s research program is to better understand the interactions of the hepatitis virus with the host, and how it influences either viral clearance or persistence and disease progression. The chimpanzee is the only animal other than man susceptible to infection with HCV, thus Lanford has studied this animal model extensively. Using DNA microarray technology, his team currently examines liver tissue from HCV-infected chimpanzees for changes in expression due to viral replication of 47,000 genes and the immune response to viral infection. Within days of infection, hundreds of interferon response genes are increased in expression in the liver. Although the virus manages to persist in the liver, the host limits the spread of the virus such that only a minor fraction of hepatocytes are infected. The data suggest that the mechanism of viral clearance during a successful immune response is dependent on both the innate and adaptive T cell response. In a multi-institute collaboration, Lanford recently compared the immune response to HCV and hepatitis A virus (HAV), a virus with many similarities to HCV, but differs in that it never induces chronic infection. Remarkably, they discovered that during HAV infections little to no induction of interferon response genes occurs in the liver (Fig). Thus, the virus that evades the innate immune response is always cleared and the one that induces a robust innate immune response often causes chronic infection. These studies highlight the limitations of our understanding of how HCV persist in the liver, and the need for research on persistent viral infections to aid in vaccine development.
Another goal of his HCV program is to help bring new antiviral therapies to the clinic. During the past several years, Lanford’s group has tested dozens of new inhibitors of HCV, many of which have progressed to phase I and II clinical trials. Recent data demonstrate that new antiviral cocktails currently in clinic trials offer a cure of HCV chronic infection without the harsh side effects of interferon therapy. One of the antivirals examined by Lanford sequesters a liverspecific microRNA, miR-122, that is essential for HCV persistence. The drug SPC3649 (Miravirsen in the clinic) was developed by the Danish company Santaris Pharma and is an antisense oligonucleotide that targets miR122. This drug is the first example of a DNA-based therapy that is highly efficacious when administered systemically.