Investigating if cccDNA Is the First Viral DNA Species to Be Cleared During HBV Clearance
Abstract
Hepatitis B is one of important diseases in Infectious Diseases Portfolio of Fiscal Year 2022 (FY22) Peer Reviewed Medical Research Program (PRMRP) Topic Area. This proposal aims to validate a new concept that hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is the first viral DNA species lost from HBV-infected cells, and the evidence generated from this proposal is expected to prompt the HBV field to think a new HBV cure strategy that shall focus on blocking cccDNA replenishment, not the existing cccDNA molecules. Thus, this project meets one of FY22 PRMRP Strategic Goals, i.e., improving treatment of severe/chronic diseases. HBV chronically infects 292 million people worldwide. Nearly one million people die of HBV-related liver diseases each year. Current HBV cure strategies aim to directly eliminate existing HBV cccDNA in the nuclei of infected cells, which serve as HBV transcriptional template. cccDNA molecules have been conventionally considered long-lived in the infected cells. A lack of therapeutics that directly eliminate cccDNA is the main hurdle to conducting HBV curative treatment. The Principal Investigator (PI) started questioning the view of cccDNA longevity because average cccDNA pool per cell in HBV-infected human livers is very small, ranging between 1 to a few copies while rcDNA (relaxed circular DNA), another viral DNA species is 100-fold higher than cccDNA. The low copies of cccDNA imply that cccDNA likely is the first viral DNA species to get lost from infected cells. Subsequently, the PI obtained preliminary data suggesting that cccDNA is spontaneously lost in a fraction of infected cells. The PI hypothesizes that cccDNA is the first viral DNA species lost during persistent HBV infection, but the lost cccDNA is frequently replenished through new rounds of infection. In this proposal, the PI aims to establish direct evidence at a single cell level that cccDNA is the first viral DNA species lost from infected cells. In addition, this project will also generate the results that the size of infected cells cleared of cccDNA is significantly expanded in HBV-infected animals treated with anti-HBs antibody than untreated animals. If this hypothesis is validated through this project, the persistent presence of cccDNA in infected cells does not mean the longevity of cccDNA, rather a result of spontaneous cccDNA loss and subsequent replenishment. This discovery will likely direct a new HBV cure strategy that focuses on blocking cccDNA replenishment, a shifting from eliminating the existing cccDNA pool. Since blocking cccDNA replenishment can easily get done with anti-HBs antibody, curing chronic HBV infection would soon become a reality. Innovations of this proposal include: (1) A novel concept that cccDNA is the first viral DNA species lost from infected cells. (2) A new HBV cure strategy that includes anti-HBs antibody as an indispensable part of new HBV curative treatment, for interrupting cccDNA replenishment. (3) An improvement in HBV cccDNA and rcDNA detection that allows specifically and simultaneously to detect both cccDNA and rcDNA in the same infected individual cells.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310121
Entities
People
- Yong-yuan Zhang
Organizations
- United States Army