Identification and characterization of the human factors targeted by the Nucleic Acid Polymers (NAP) responsible for its antiviral activity against HBV and HDV.

点击翻译按钮获取中文摘要

Chronic infection by the hepatitis B virus (HBV) is a major etiologic factor in the development of severe liver diseases including fibrosis, cirrhosis and hepatocellular carcinoma. Over 290 million people worldwide and 54 000 Canadians are chronically infected with HBV and, at the moment, no cure has been discovered. In addition, when HBV infection is accompanied by coinfection with the hepatitis delta virus (HDV), a satellite virus of HBV, acceleration of the liver diseases progression is common. While currently approved therapies for HBV are used in coinfected patients in an attempt to limit liver disease progression they are only minimally effective in achieving this goal. Importantly, functional cure of HBV (where HBV viremia remains undetectable in the blood and liver function remains normal after removal of therapy), and similar control of HDV infection in coinfected patients has been observed lately with a new class of antiviral molecules named nucleic acid polymers (NAPs) when used in combination with existing approved therapies for HBV infection. However, the development and commercialization of NAPs is hampered by a lack of understanding of their mechanism-of-action. Therefore, this proposal is aimed at defining how this new class of molecules exert their antiviral effects during HBV infection as well as during coinfection with its satellite virus, HDV. In aim 1, we will characterize how NAPs selectively inhibit the assembly/secretion of HBV subviral particles without affecting the morphogenesis and secretion of infectious Dane particles. In aim 2, an in-depth analysis of the mechanism-of-action of NAPs on the HDV replication-cycle will be performed.