Novel Toll-Like Receptor 7 Agonist Suppresses Replication of Hepatitis B Virus in Chimps

An experimental low molecular weight drug that activates the protein Toll-Like Receptor 7 on cells of the immune system was found to suppress viral replication and delay progression of liver disease in chimpanzees chronically infected with hepatitis B virus (HBV).

Toll-Like Receptor 7 normally recognizes invading viruses and signals the immune system to suppress viral replication via the innate immune response and to kill infected cells via the adaptive immune response. The experimental drug GS-620, developed by the biopharmaceutical company Gilead Sciences (Foster City, CA, USA) is a potent and selective orally active small molecule agonist of Toll-like receptor 7.

Investigators from Gilead Sciences and colleagues at Texas Biomedical Research Institute's Southwest National Primate Research Center (San Antonio, USA) administered GS-9620 was to HBV-infected chimpanzees every other day for four weeks and, after a one-week rest, for an additional four weeks at a higher dosage. They measured viral load in plasma and liver samples, the pharmacokinetics of GS-9620, and the following pharmacodynamics parameters: interferon-stimulated gene expression, cytokine and chemokine levels, lymphocyte and natural killer cell activation, and viral antigen expression. Clinical pathology parameters were monitored to determine the safety and tolerability of GS-9620.

Results published in the February 14, 2013, online edition of the journal Gastroenterology revealed that short-term oral administration of GS-9620 provided long-term suppression of serum and liver HBV DNA. Serum levels of HBV surface antigen, HBV e antigen, and numbers of HBV antigen-positive liver cells were reduced as liver cell apoptosis increased. GS-9620 administration induced production of interferon-alpha and other cytokines and chemokines, and activated interferon-stimulated genes, natural killer cells, and lymphocyte subsets.

"This GS-9620 therapy represents the first conceptually new treatment for HBV in more than a decade, and combining it with the existing antiviral therapy could be transformative in dealing with this disease," said first author Dr. Robert E. Lanford, a virologist and immunologist at the Texas Biomedical Research Institute. "This is an important proof-of-concept study demonstrating that the therapy stimulates the immune system to suppress the virus and eliminate infected liver cells. One of the key observations was that the therapy continued to suppress virus levels for months after therapy was stopped."

Related Links:
Gilead Sciences
Texas Biomedical Research Institute