Molecular Mechanism of the Dual Effects of Capsid Assembly Effectors on HBV Capsid Assembly and Disassembly
Abstract
Hepatitis B virus (HBV) chronically infects more than 240 million people worldwide. Approximately one-third of these chronically infected individuals will die from serious liver diseases, such as cirrhosis, hepatocellular carcinoma (HCC), and liver failure, if left untreated. Currently, seven drugs have been approved for the treatment of chronic hepatitis B, which include two formulations of alpha-interferon (standard and pegylated) that enhance the host antiviral immune response and five nucleos(t)ide analogues that inhibit HBV DNA polymerase with varying potencies and barriers to resistance. Sustained suppression of viral replication with long-term nucleos(t)ide analogue therapy or through a finite-duration of pegylated alpha interferon (IFN-a) therapy has been associated with improvement of liver diseases, prevention of liver decompensation, and reduction of hepatocellular carcinoma morbidity and mortality in a portion of treated patients. However, HBV surface antigen (HBsAg) seroconversion, the hallmark of a successful immunologic response to HBV with complete and durable control of infection, or a “functional cure,” is rarely achieved with the current therapies. The primary reasons for the failure of current therapeutics to achieve a functional cure are their inability to restore a functional host antiviral immune response against HBV and eliminate or functionally inactivate HBV cccDNA, the nuclear form of HBV genome replication intermediate. In order to achieve a functional cure of chronic hepatitis B, novel therapeutics that can (i) completely inhibit HBV replication to stop the spread of HBV infection to susceptible host cells and the amplification of cccDNA pool in infected cells, (ii) eradicate or functionally inactivate cccDNA to stop viral gene expression, and/or (iii) activate a functional immune response against HBV to durably control HBV replication should be developed. This project is to understand the molecular mechanism of the dual effects of HBV core protein allosteric modulators (CpAMs) that disrupt nucleocapsid assembly and induce the disassembly of matured HBV nucleocapsids as well as to investigate whether the CpAM-induced cytoplasmic disassembly of HBV nucleocapsid induces innate immune response in infected hepatocytes. Our study will provide the molecular basis for development of better CpAMs that not only suppress HBV replication and prevent cccDNA formation, but also help restore the host antiviral immunity to eradicate or functionally inactivate cccDNA, which works in concert to ultimately cure chronic hepatitis B.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710600
Entities
People
- Ju-Tao Guo
Organizations
- Baruch S. Blumberg Institute
- United States Army