In depth review of nature: towards cure -- treatment strategy of hepatitis B virus infection
Last Update: 2020-06-19
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Chronic hepatitis B virus (HBV) infection is a common cause of liver disease worldwide, especially in Southeast AsiaAccording to the World Health Organization (who), there are about 257 million HBV infected patients in the worldAt present, vaccine, nucleoside or nucleotide (NUC) drugs can not only reduce the new infection rates, but also delay the progress of liver disease for HBV patients who insist on long-term viral suppression therapyHowever, the scientific and medical communities are not satisfied with the status quoThey have begun to work together to develop innovative antiviral drugs and immunotherapies aimed at curing this infectionRecently, a review on Nature Reviews Drug Discovery comprehensively reviewed the current research and development strategies for the treatment of HBV infectionThe content team of Wuxi apptec will share the highlights of this review with readers today< br / > the challenge of functional cure for HBV infection < br / > covalent closed loop DNA (cccDNA) < br / > HBV can generate cccDNA and integration sequence in the nucleus of infected cellsThese sequences are transcriptional templates of viral proteinsCccDNA is the template of pgRNAPgRNA provides a template for reverse transcription and viral genome replication< br / > cccDNA is a virus micro chromosome, which is the cause of the long-term existence of the virus in the infected cellsIts half-life is very long, and the current standard therapy can not effectively remove cccDNAThe epigenetic regulation of < br / > ▲ cccDNA (picture source: reference ) < br / > the special immune characteristics of HBV < br / > some important immunological characteristics of HBV enable them to exist for a long time and are not easy to clearHBV replication in hepatocytes is not detected by innate immune systemHBV can produce and secrete a large number of virus antigens, and gradually change and deplete the function of HBV specific T cells and B cellsEven with the current standard therapy, the deficiency of immune response makes it difficult for patients to recover the HBV specific immunity to normal level, so they can not effectively control infection < br / > the life cycle of HBV and the innovative treatment < br / > the genome of HBV is a 3.2kb relaxed circular DNA (rcdna) genome It is packaged with the polymerase in the viral capsid, which is covered with the envelope protein (hbsags) The life cycle of HBV can be divided into the following steps: < br / > HBV enters the cell through binding with NTCP receptor on the surface of hepatocyte, and then, the virus removes the envelope protein, the coat enters the nucleus, and releases circular DNA The host's DNA repair mechanism converts these foreign DNA into cccDNA They are packaged with host histones and other proteins into micro chromosomes This microchromosome is a long-term viral genome reserve in the liver nucleus, and its number can be increased continuously by infection of new hepatocytes and recovery of intercellular nucleocapsid CccDNA is the template of pgRNA It needs hepatitis X protein (HBx) to maintain normal expression CccDNA transcription produces six kinds of RNA, including pgRNA binding to HBV polymerase The pgRNA binding polymerases initiate nucleocapsid assembly by binding to a 6-mer of nucleoprotein and P-protein Prgrna guides the synthesis of relaxed circular DNA in immature nucleocapsid to form mature nucleocapsid If the mature nucleocapsid is combined with HBsAg, it will cause the virus to obtain the envelope protein and be released to the outside of the cell < br / > < br / > to prevent HBV from entering cells < br / > the continuous replication and release of the virus will lead to the infection of new hepatocytes, thus maintaining chronic infection and the stability of cccDNA library In most patients, NUC therapy can not completely inhibit virus production Therefore, the combination of virus entry inhibitor and replication inhibitor is a powerful method to reduce cccDNA library < br / > ways to prevent viruses from entering cells include the development of peptides derived from HBsAg It can prevent HBV from entering cells by binding to NTCP receptor For example, myrcludex B (also known as bulevirtide), a peptide used as a single drug therapy, can reduce the RNA level of HDV by 2.84 log after 48 weeks It works better when combined with interferon < br / > in addition to peptides, small molecular drugs (such as ezetimibe and cyclosporine derivatives) and monoclonal antibodies targeting HBsAg have also been used in the study to block HBV from entering cells It is an attractive strategy to directly target cccDNA < br / > and inhibit the generation of cccDNA However, we need to have a more comprehensive understanding of the process of cccDNA synthesis in order to target this process Because many key steps in the cccDNA generation process need protease in the host cell nucleus, and the formation of microchromosome also needs histone and other proteins of the host Therapies that inhibit cccDNA production may target host proteins, which may have more side effects than those that target viral proteins < br / > zinc finger nucleases can be used to directly target cccDNA, which has been successfully edited in cell culture model < br / > the treatment based on crispr-cas9 can add mutation or deletion to cccDNA, leading to cccDNA inactivation Preclinical studies have shown that more than 90% of HBV DNA can be cut by cas9 However, about 7% of cccDNA genome can be repaired to a state that does not affect the function of cccDNA after crispr-cas9-mediated cleavage Therefore, this strategy needs to introduce multiple guiding RNAs (gRNAs) targeting different sites in cccDNA to ensure the inactivation of cccDNA < br / > the development of gene editing therapy needs to solve the challenges of hepatocyte delivery and miss target effect However, at present, it is the only way to permanently inactivate cccDNA in tissues < br / > target viral gene expression < br / > high viral antigen load is considered to play an important role in maintaining chronic infection Therefore, researchers also pay attention to reducing the expression level of viral antigen by silencing the transcription of cccDNA or degrading viral RNA < br / > nucleotide based anti HBV therapy uses RNA interference or antisense oligonucleotide (ASO) to reduce HBV mRNA levels It is widely accepted in the industry that targeting HBV mRNA is an important part of therapeutic therapy It can limit the expression of HBsAg and help the recovery of HBV specific immunity Another feature of this technology platform is that it can design therapies targeting multiple HBV mRNA at the same time by screening the target sequence the schematic diagram of RNAi therapy targeting virus mRNA (picture source: reference ) Arrowhead 's performance of RNAi therapy ARC-520 in clinical trials shows the potential of such therapy Nowadays, the second generation of HBV RNAi therapy has shown promising results in clinical trials For example, jnj3989 (aro-hbv) can reduce the level of HBsAg protein by an average of 1.7-2.0 log < br / > ASO therapy uses RNase H to degrade the target RNA sequence Similar to RNAi therapy, it requires multiple ASOs to deal with the sequence variation between different patients Two ASO therapies developed by Ionis pharmaceuticals have also obtained gratifying results in phase 2 clinical trials Recently, GSK decided to acquire the rights and interests of the follow-up development and promotion of these two therapies < br / > in terms of curative potential, we do not know how low the level of HBsAg needs to be reduced and how long it needs to be maintained before it can lead to the recovery of HBV specific immunity The ongoing phase 2 clinical trials may provide insights into answering these questions Maybe after reducing the level of HBsAg, we need another immune stimulation to fully play the potential of antiviral immune response < br / > targeted capsid assembly procedure < br / > the combination of capsid assembly inhibitor and NUC may further reduce the level of virus, so as to improve the recovery of HBV specific immune response in patients with chronic hepatitis B At present, there are two kinds of small molecule drugs that inhibit capsid assembly: cpams can cause assembly errors of non capsid nucleoprotein polymers (such as gls4 and ro7049389); capsid assembly regulators can make the capsid assemble normally, but do not contain viral nucleotides (such as at-130, nvr-3778, jnj6379, etc.) These two inhibitors can not only reduce the release of virus particles, but also block the transport of nucleocapsid to nucleus, thus reducing the formation of cccDNA < br / > Image Source: reference  < br / > in short-term clinical trials (less than 12 months), coat assembly inhibitors can reduce HBV DNA and RNA levels For example, at the end of the application period, nvr-3778 can reduce the DNA level of HBV by 1.72 log, and jnj6379 shows 2.16-2.89 log < br / > the release of targeted HBsAg < br / > nucleic acid polymers (NAPs) can produce antiviral effect due to the characteristics of amphoteric polymers Their special effect on HBV infection is to inhibit the release of HBsAg from infected hepatocytes Recent clinical trials have shown that rep2139 (a nucleic acid polymer) developed by replicar, combined with tenofovir fumarate (TDF) and pegylated interferon α 2A (PEG IFN), can achieve "functional control" for 80% of HBV infected patients < br / > immunomodulatory therapy < br / > CO activation of antiviral immunity may lead to functional cure of HBV Patients with controlled HBV showed coordinated HBV specific hormones and cellular immune responses They have strong T cell responses to different viral antigens, and B cells are able to secrete anti HBV antibodies Therefore, activating the immune mechanism to let the human body eliminate HBV infection spontaneously may become a treatment for chronic HBV infection < br / > the treatment strategy of targeting innate immunity < br / > the treatment of targeting innate immunity mainly uses the antiviral effect of cytokines (TNF, IFN α, IFN γ and IL-1 β), which can induce adaptive immunity at the same time IFN α is based on this principle IFN α therapy can achieve functional cure in 5-10% of chronic hepatitis B patients The mechanism of this therapy is that IFN α not only has direct antiviral effect, but also can improve the response of natural killer (NK) cells Moreover, patients who had reached HBsAg negative after IFN α therapy recovered HBV specific T cell response < br / > antiviral cytokines may also clear cccDNA, which is the most direct and effective way to cure chronic hepatitis B patients In vitro studies have shown that IFN α or lymphotoxin β may induce APOBEC dependent deamination of viral DNA This may reduce the level of cccDNA in infected hepatocytes < br / > activation of innate immunity in patients with chronic hepatitis B can also be achieved by toll like receptor (TLR) or RIG-I agonist RIG-I agonists can directly activate innate immunity in hepatocytes, while TLR7 or tlr8 agonists can activate immune cells around hepatocytes The RIG-I agonist named inarigivir also has direct antiviral effect In clinical trials, it can reduce HBV DNA and RNA levels in a dose-dependent manner, and 26% of patients have a decrease in HBsAg levels < br / > TLR7 agonist gs-9620 can activate IFN α production in plasma like dendritic cells Tlr8 agonists can strongly activate monocytes and dendritic cells in the liver to generate and secrete IL-12 and IL-18 IL-12 and IL-18 can stimulate the production of IFN α, and IL-12 can partially restore the activity of depleted HBV specific T cells < br / > the strategy of targeting adaptive immunity < br / > HBV specific immune response is defective in patients with chronic hepatitis B theoretically
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