Microbiology, Immunology & Molecular Genetics Adjunct Faculty
Robert E. Lanford, Ph.D.
Keywords: Hepatitis B; Hepatitis C; HCV
Dr. Lanford's laboratory is involved in 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 his 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 they have studied this animal model extensively using DNA microarray technology to examine changes in gene expression in the liver during HCV-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. His lab recently compared the immune response to HCV and hepatitis A virus (HAV), a virus that never induces chronic infection. Remarkably, HAV infections induce little to no interferon response in the liver. 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 persists in the liver, and the need for research on persistent viral infections to aid in vaccine development.
Another goal of Dr. Lanford's HCV program is to help bring new antiviral therapies to the clinic. During the past several years, his lab examined 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 that they examined sequesters a liver-specific 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, and the success of the drug relies on the use of the Santaris technology called locked nucleic acid (LNA). This proof of concept study for LNAs suggest that this DNA based therapy can be used to target genes involved in other diseases including cancer and inflammatory diseases. In a collaboration with Santaris, Dr. Sanford's lab is using the LNA technology and the GBV-B surrogate model of HCV to elucidate the key factors in the innate immune response that are required to orchestrate the adaptive immune response and eliminate the virus. This research will also develop a small primate model for gene knockdown using the marmoset and LNA technology. This model could be used to elucidate the molecular basis for many different diseases.
Lanford RE, Feng Z, Chavez D, Guerra G, Brasky KM, Zhou Y, Yamane D, Perelson AS, Walker CM, Lemon SM (2011) Acute Hepatitis A Virus Infection is Associated with a Limited Type I Interferon Response and Persistence of Intrahepatic Viral RNA. Proc. Natl. Acad. Sci. USA 108:11223-11228.