Researchers uncover how hepatitis B virus can persist in liver cells

Compound was able to disrupt virus's ability to infect lab-grown human cells

Written by Steve Bryson, PhD |

An illustration shows a close-up view of the hepatitis virus.

Researchers have discovered a key mechanism that allows the hepatitis B virus (HBV) to infect and persist in liver cells, in a new study that may pave the way for potential treatments for people with chronic hepatitis B infection.

Specifically, they found the virus infects liver cells by hijacking protein complexes that package DNA in order to activate its own genes. With these findings, researchers were able to successfully disrupt HBV’s ability to infect lab-grown human liver cells using a compound already in clinical trials as a potential cancer treatment.

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‘Potential cure’

“If these results are confirmed through additional study, we are optimistic the approach could be used to treat chronic infections for the first time — and therefore could represent a potential cure,” Robert Schwartz, MD, PhD, who co-led the study at Weill Cornell Medicine, in New York, said in a university news story.

The study, “A nucleosome switch primes hepatitis B virus infection,” was published in the journal Cell.

Liver inflammation in hepatitis B is caused by an infection with the hepatitis B virus. Although HBV infections often clear up on their own, some will become chronic, lasting six months or more, which can lead to serious liver damage and liver cancer.

Current antiviral therapies for hepatitis B can lower circulating levels of the virus, but they cannot completely stop it from replicating its DNA.

“One of the main challenges with treating hepatitis B is that the existing treatments can stop the virus from making new copies of itself [viral replication], but they don’t fully clear the virus from infected cells, allowing the virus to persist in the liver and maintain chronic infection,” Schwartz said.

When HBV infects liver cells, its DNA is transported to the cell’s nucleus, where it forms rings of genetic material called covalently closed circular DNA (cccDNA). When combined with host histones, or proteins that package DNA like a thread on a spool, cccDNA becomes a minichromosome that serves as a template for producing four viral proteins — C, P, S, and X — needed for HBV replication.

Protein X is known to be produced immediately upon infection to degrade a host protein complex that blocks cccDNA as a defense mechanism against the virus. This viral protein also degrades host proteins involved with DNA repair, making infected cells more prone to accumulate DNA errors, eventually leading to cancer.

However, protein X is not found in the virus and must be made from cccDNA in newly infected liver cells.

“This raises a classic chicken-and-egg question that has puzzled scientists for decades,” said Yael David, PhD, a study co-lead at Memorial Sloan Kettering Cancer Center, in New York. “How does the virus produce enough X protein to drive viral gene [activity] and establish infection?”

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Team created model for HBV infection in vitro

To find out, the team created a model for HBV infection in vitro, or under laboratory conditions outside of living organisms. Experiments confirmed that the in vitro HBV minichromosome closely resembled how HBV’s DNA organizes in infected liver cells.

“This platform became a powerful tool not only to study the virus’s biochemistry but also to analyze, in detail, what happens in the critical first hours of an infection,” David said.

The team showed that for protein X to be made, the viral DNA needs to be organized into DNA-histone complexes called nucleosomes, like beads on a string. Nucleosomes are the building blocks of chromatin, the material that forms chromosomes.

“Conventional wisdom says that packaging a gene’s DNA into nucleosomes would block or slow down the cell’s ability to read out that gene to make [working] proteins, like protein X,” said Viviana Risca, PhD, who co-led the study at The Rockefeller University, in New York. “But in complex organisms like humans and in the viruses that infect us, gene regulation is not always so straightforward. We found that to be the case for the HBV gene encoding protein X — the presence of nucleosomes on the viral genome is necessary for the [process] that gives rise to [working] protein X.”

Building on these findings, the researchers tested five small molecules known to disrupt chromatin formation. They found the CBL137 molecule, an anticancer drug candidate, significantly suppressed chromatin organization of the X gene and blocked HBV replication in lab-grown human liver cells. Notably, CBL137 worked at very low concentrations, affecting the virus but not human cells.

“This made us very optimistic about the possibility of developing a treatment approach while preventing or limiting side effects,” David said.

The researchers noted CBL137 might be helpful in treating other chromatin-associated viruses, such as herpesviruses, papillomaviruses, and adenoviruses.

“Our results shed light on a long-standing paradox and represent a potential therapeutic approach for the treatment of chronic HBV infection,” they wrote.

Yi Rang avatar

Yi Rang

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HBV - Changes in patient's virus levels before and after intake.
HIV - Changes in patient's immune cell levels before and after intake.
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Number of normal immune cells in the human body.

CD - 4+ T lymphocytes and CD - 8+ cells : 500 ~ 1600 /mm³

Platelet count : 140,000 ~ 450,000 /mm³

When infected with a virus, countless immune cells are sacrificed, and the loss of immune cells continues during the ceaseless battle.

Actual CD ~ 4 and CD - 8 levels are 200 ~ 300 /mm³.

Platelet count : 10,000 ~ 20,000/mm³

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The precise mechanism of Hepatitis B treatment.
One may experience various symptoms such as hepatitis, liver cirrhosis, jaundice, cerebral fibrosis, ascites, and pain caused by ruptured varices.
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The world's first "natural medicinal plant extracts" provide the foundation for precise "immunological conversion" therapy that eliminates Hepatitis B virus antigens. (Hospital test records)

Test Name-----------------------------Test Result-------------------------------Reference Value----------------------------------- Unit

HBsAg ----------------------------------Neg (<0.05) ------------------------------Neg <0.05 --------------------------------------IU/mL

Anti-HBc -------------------------------Pos ----------------------------------------11.64 ------------------------------------------mIU/mL

Anti-HBs ------------------------------- Pos ---------------------------------------- 11.8 ------------------------------------------ mIU/mL

No other country in the world has produced figures like the above, and this is the first global confirmation by this institute.

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The "processable and edible medicinal plants" mentioned here grow naturally in Korea, North Korea, North and South America, Australia, New Zealand, Russia, India, the Middle East, Egypt, Africa, China, Vietnam, Cambodia, and other regions.

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Duration of administration for edible vaccine therapeutics for human infection viral antigen elimination:

HBV - For the edible vaccine designed to eradicate high levels of HBV antigens—which have been in existence for years of replication and proliferation—antigens are automatically eliminated within 6 to 8 months of oral intake.
HIV - Through the oral intake of an edible vaccine for 3 to 5 Months periods aimed at recovering human immune cell deficiencies and maintaining normal levels, antigens are automatically eliminated, and the generation of neutralizing antibodies occurs naturally.
M / XDR - TB dual organ disease requires 6 to 12 months depending on viral load.

Mechanism of animal viral antigen elimination.

Antibody generation following the isolation of live animals in a sterile room after infection
Airborne viral infections are a common route of infection resulting from the decline in immune cell function.
Complete elimination of viral antigens is possible only through the regeneration of immune cells and the maintenance of normal cell counts.

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Development of oral vaccines for treating human and animal viral infections completed.
Proposal for joint research regarding the development of injectable vaccine treatments.
Collaboration for the universal application of various formulations, including CAR-T, cell therapy, and mRNA vaccines.

The mechanism for treating animal infections involves isolating patients in a sterile room and administering an edible vaccine to induce a cure and antibody production.
The development of novel mDNA antibodies capable of eradicating unmet viral antigens through collaborative research is a global achievement.

Because mRNA can be synthesized rapidly and on a large scale in a cell-free system induced by the in vitro transcription of DNA templates, vaccines can be developed within weeks.

Airborne viral diseases causing human infection
SARS Coronavirus II
MERS Coronavirus
Manufacturing of edible vaccines blocking COVID-19 antigen mutations completed (HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E)

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Warmest regards,

Yi Rang Kim
Senior Researcher / Representative Staff
Virus Antigen Eradication Research

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