HBV cccDNA is organized into mini-chromosomes within the nucleus of infected cells by histone and non-histone proteins. Despite the availability of efficient therapies against HBV, long-term persistence of cccDNA necessitates life-long treatments to suppress the virus. The following three experimental studies demonstrate effective HBV-cccDNA targeting/depletion using novel therapeutic approaches which offer the potential of a cure.
Liver regeneration induces strong reduction of viral replication and cccDNA levels, but not complete cccDNA eradication; without antiviral treatment, de novo HBV infection can be re-established.
Key findings of research in HBV-infected human hepatocytes using the uPA/SCID chimeric mouse system show that liver regeneration induces strong reduction of viral replication and cccDNA levels, with rapid formation of cccDNA-free hepatocytes. However, because complete cccDNA eradication is not achieved, in the absence of antiviral treatment, de novo HBV infection could be re-established in quiescent (non-dividing) human hepatocytes. This suggests that induction of hepatocyte turn-over together with antiviral drugs inducing viral suppression, such as nucleoside analogues and IFN, or blocking cell entry, may accelerate the clearance of the viral minichromosome.
Targeting epigenetic control of nuclear cccDNA minichromosome to suppress HBV transcription and replication may form basis for other therapeutic approaches to curing chronic HBV infection.
In the infected liver cell the rate of replication of HBV is regulated by the acetylation or methylation of histone proteins which surround the cccDNA minichromosome – so called epigenetic regulation. In a separate innovative study, the suppression of HBV transcription and replication by small molecules that target the epigenetic control of nuclear cccDNA minichromosome was investigated. The different classes of small molecules studied included: Class I, II and III histone deacetylase inhibitors (HDACi); p300 and PCAF histone acetyltransferases (HAT) inhibitors; hSirt1 activators; JMJD3 histone demethylase inhibitors.
The combined inhibition of p300 and PCAF HATs resulted in an evident reduction of HBV replication which mirrored the decrease of pgRNA transcription. The hSirt1/2 activator MC2791 and the JMJD3 inhibitor MC3119, albeit with different efficiency, inhibited both HBV replication and cccDNA transcription. Results represent a proof of concept that activation of hSirt1 and Ezh2 (through the inhibition of its functional antagonist JMJD3) by small molecules can induce an active epigenetic suppression of HBV cccDNA minichromosome similar to that observed with IFNá, and lead to persistent cccDNA silencing.
Lymphtoxin beta receptor (LTbR) agonisation represents basis for novel alternative therapeutic approach to curing chronic HBV infection.
The final study demonstrated that stimulating the lymphtoxin beta receptor (LTbR) provides an effective, long lasting and non-cytopathic mechanism for achieving effective HBV-cccDNA depletion in infected hepatocytes. Cell culture models including HBV-infected HepaRG cells and primary human hepatocytes were used to test the effect of antibodies stimulating human LTbR (BS1 or CBE11). Results show that a strong and dose-dependent anti-HBV effect was achieved by activation of the LTbR. All HBV replication markers were decreased with this treatment, including cccDNA in cells where HBV infection was already established.
Hepatitis B is the most prevalent cause of chronic viral hepatitis and a major global health problem. Prof. Fabien Zoulim, EASL Educational Councillor commented on the exciting new data: "In chronic hepatitis B infection, the viral genome forms a stable minichromosome - the covalently closed circular DNA (cccDNA) - which can persist throughout the lifespan of the hepatocyte."
"Current treatments focus on suppression of HBV and discovery of compounds directly targeting cccDNA has been one of the major challenges to curing HBV infection; but these preliminary data show novel therapeutic approaches can be applied to successfully target cccDNA with the long-term aspiration of finding a cure" added Prof. Fabien Zoulim.
Disclaimer: the data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2013.
About EASLEASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.
References:1 Allweiss L et al, PROLIFERATION OF HEPATITIS B VIRUS INFECTED HUMAN HEPATOCYTES INDUCES SUPPRESSION OF VIRAL REPLICATION AND RAPID CCCDNA DECREASE IN HUMANIZED MICE. Presented at the International Liver Congress™ 2013
Dimple Natali | EurekAlert!
NIST scientists discover how to switch liver cancer cell growth from 2-D to 3-D structures
17.11.2017 | National Institute of Standards and Technology (NIST)
High speed video recording precisely measures blood cell velocity
15.11.2017 | ITMO University
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
17.11.2017 | Physics and Astronomy
17.11.2017 | Health and Medicine
17.11.2017 | Studies and Analyses