CN113061612A - Gene for inhibiting chronic hepatitis B virus infection and application thereof - Google Patents

Gene for inhibiting chronic hepatitis B virus infection and application thereof Download PDF

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CN113061612A
CN113061612A CN202110341781.0A CN202110341781A CN113061612A CN 113061612 A CN113061612 A CN 113061612A CN 202110341781 A CN202110341781 A CN 202110341781A CN 113061612 A CN113061612 A CN 113061612A
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gene
mice
aav
hepatitis
virus infection
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沈忠良
谢幼华
刘晶
张继明
高子翔
吴婧雯
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Fudan University
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Abstract

The gene for inhibiting the chronic hepatitis B virus infection is an IL-21 gene, a large number of experiments prove that the gene fragment can effectively inhibit the chronic hepatitis B virus infection, and the IL-21 gene provides a new thought for preventing and treating the chronic hepatitis B virus infection.

Description

Gene for inhibiting chronic hepatitis B virus infection and application thereof
Technical Field
The invention relates to the technical field of biology, in particular to a gene for inhibiting chronic hepatitis B virus infection and application thereof.
Background
Chronic Hepatitis B Virus (HBV) infection is a global public health problem. Prevention of HBV infection is an important approach to reduce patients with new onset chronic hepatitis b. In the prior art, the main approach for preventing HBV infection is to inoculate hepatitis B vaccine.
Chinese patent with publication No. CN201210272762.8, a hepatitis B vaccine for inducing organism to generate specific immunity under the condition of chronic hepatitis B virus infection, and discloses a hepatitis B vaccine. Specifically, the invention discloses a hepatitis B vaccine containing an immunopotentiator, which can induce a body to generate specific immunity in a chronic hepatitis B virus infection state. The hepatitis B vaccine of the invention contains an agonist of Toll-like receptors as an immunopotentiator.
However, in clinical practice, not all hepatitis B vaccines can produce protective effect for vaccinees, so that a new hepatitis B prevention strategy needs to be developed urgently.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a novel and effective gene for inhibiting chronic hepatitis B virus infection and application thereof.
In a first aspect of the present invention, there is provided a gene inhibiting chronic hepatitis B virus infection, which is the IL-21 gene.
In a second aspect of the present invention, there is provided a recombinant vector comprising an empty vector and an IL-21 gene inserted into the empty vector.
Preferably, the empty vector comprises an AAV vector.
In a third aspect of the invention, a host cell is provided, said host cell comprising a recombinant vector provided by the invention.
In a fourth aspect of the invention, the invention provides the application of the gene, the recombinant vector and the host cell for inhibiting chronic hepatitis B virus infection in the preparation of drugs for inhibiting chronic hepatitis B virus infection.
In a fifth aspect of the present invention, there is provided a hepatitis virus drug inhibitor, wherein the active ingredient of said drug comprises the IL-21 gene, or a protein encoded thereby, or a biological material containing the IL-21 gene.
Preferably, the hepatitis virus drug inhibitor further comprises a pharmaceutically acceptable carrier.
Preferably, the dosage form of the medicament comprises any one of tablets, capsules, granules, oral agents, corrosion inhibitors and injections.
Compared with the prior art, the technical scheme provided by the invention has the following advantages: the invention provides a gene for inhibiting chronic hepatitis B virus infection and application thereof, and a large number of experiments prove that the gene fragment can effectively inhibit chronic hepatitis B virus infection.
Drawings
FIG. 1 is a graph showing the results of HBsAg in serum of 3 groups of mice in example 3 of the present invention;
FIG. 2 is a graph showing the results of HBsAg antibody in serum of 3 groups of mice in example 3 of the present invention;
FIG. 3 is a graph showing the results of HBeAg in serum of 3 groups of mice in example 3 of the present invention;
FIG. 4 is a graph showing the results of HBV DNA copy number in serum of 3 groups of mice in example 4 of the present invention;
FIG. 5 is a graph showing the results of glutamic-pyruvic transaminase in the serum of 3 groups of mice in example 5 of the present invention;
FIG. 6 is a graph showing the result of H & E staining of liver cells of 3 groups of mice in example 6 of the present invention;
FIG. 7 is a graph showing the result of staining liver cells anti-CD8 of 3 groups of mice in example 6 of the present invention;
FIG. 8 is a graph showing the results of IFN-. gamma.related mRNA levels in liver cells of 3 groups of mice in example 7 of the present invention;
FIG. 9 is a graph showing the results of PD 1-related mRNA levels in liver cells of 3 groups of mice in example 7 of the present invention;
Detailed Description
The following description of the embodiments of the present invention will be made with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby. Experimental procedures without specific conditions noted in the following examples were selected according to methods and conditions conventional in the art, or according to the commercial specifications.
Example 1 adenovirus packaging and pBPS plasmid construction
1. Construction of recombinant plasmids
Murine IL-21 gene (GenBank Accession Number: NM-021782.2) was cloned into serotype 8 AAV packaging plasmid pCMV-ISRE-EGFP (Shanghai and Yuan biol.), the constructed recombinant plasmid was transfected into HEK293T cells, and the control group was set as blank plasmid pCMV-ISRE-EGFP.
2. Harvesting viruses
The supernatant was collected and concentrated to obtain adeno-associated virus (AAV-IL-21) and control virus (AAV-Ctrl) overexpressing IL-21.
pBPS plasmid construction
The 1.3-fold genome of HBV quasi-strain BPS (GenBank Accession Number: AF100309.1) is cloned to skeleton plasmid pUC18, namely pBPS plasmid.
Example 2 mouse samples
1. 2X 10 of the experimental group10AAV-IL-21 virus with genome copy and AAV-Ctrl virus of a control group were injected into male BALB/c mice for 6-8 weeks, respectively, and the mice were not treated with a blank control group. Each group had 5 mice.
After 2.12 weeks, 10ug of pBPS prepared in example 1 was injected into each mouse in the above 3 groups via the hyperbaric tail vein. The chronic infection with HBV was simulated by injecting pBPS into mice by high pressure tail vein injection as described in the prior art literature (Nat Commun.2017Dec 14; 8(1):2119.doi:10.1038/s 41467-017-02304-7).
Example 3 antibody antigen detection
Orbital blood of the mice was collected 1, 2,3,4 weeks after pBPS injection in the mouse samples of example 2, respectively. As a test sample.
The serum levels of HBsAg, HBsAg antibody and HBeAg antigen were detected by an immunoenzyme-linked immunosorbent assay (ELISA), and the 3 groups of mouse sera obtained in example 2 (AAV-IL-21, AAV-Ctrl and blank control group) were diluted 10-fold in Phosphate Buffered Saline (PBS), and then the serum levels of HBsAg, HBsAb or HBeAg were detected by ELISA kit from Shanghai Kowa Biotechnology Co., Ltd. The relative absorbance (OD450) at 450nm of the detected light wave reflects the relative levels of antigen and antibody. Each group had 6 mice.
The specific method comprises the following steps: adding the diluted serum into an ELISA (enzyme-linked immunosorbent assay) enzyme-linked plate, adding an enzyme reaction solution into each well, standing at 37 ℃ for 30min, pouring the reaction solution, washing for 5 times by using a washing solution, adding the reaction solutions A and B, standing at 37 ℃ for 10min, adding a stop solution, and reading the light absorption value at 450nm by using a spectrometer.
The results are shown in FIGS. 1 to 3, respectively.
In FIG. 1, the left graph shows HBsAg in serum, and the broken line in the left graph represents the lower limit of detection. The right panel shows the positive rate curve for HBsAg. It can be seen from the figure that the content of HBsAg in the serum of the mice in the AAV-IL-21 group is obviously lower than that of the mice in the AAV-Ctrl and blank control groups. As HBsAg is a sign of chronic infection of the liver virus, the risk of infecting the liver virus by the mice in the AAV-IL-21 group is obviously lower than that by the mice in the AAV-Ctrl and blank control groups.
In FIG. 2, the left graph shows HBsAg antibody in serum, and the broken line in the left graph represents the lower limit of detection. The right panel shows the positive rate curve for the HBsAg antibody. As can be seen from the figure, the content of HBsAg antibody in AAV-Ctrl and blank control mice is almost 0, and the content of HBsAg antibody in AAV-IL-21 mice is gradually increased from 0 at the beginning. As can be seen, more HBsAg antibody has been produced in the mice of AAV-IL-21 group, the antibody for continuously preventing hepatitis B virus infection has been established in the mice of AAV-IL-21 group, and the mice of AAV-Ctrl and blank control group have no resistance to hepatitis virus infection.
In FIG. 3, the left graph shows HBeAg in serum, and the broken line in the left graph represents the lower limit of detection. The right panel shows the positive rate curve for HBeAg. It can be seen from the figure that the content of HBeAg in the serum of the AAV-IL-21 group mice is obviously lower than that of the AAV-Ctrl and blank control group mice. Since HBeAg is the hallmark of chronic infection by liver virus, and HBeAg is more active when the virus replicates. As can be seen, the risk of infecting the liver virus in the AAV-IL-21 mice is significantly lower than that of AAV-Ctrl and blank control mice.
Example 4HBV DNA copy number detection
Orbital blood of the mice was collected 1, 2,3,4 weeks after pBPS injection in the mouse samples of example 2, respectively. As a test sample.
Detecting HBV DNA copy number in serum by real-time fluorescent quantitative PCR, directly sending the serum to Shanghai Aidekang medical detection center for detection, and detecting HBV DNA copy number in the serum by real-time fluorescent quantitative PCR method, wherein the detection method refers to Nat Commun.2017Dec 14 in the prior art; 8(1) 2119.doi 10.1038/s41467-017-02304-7. the results are shown in FIG. 4.
In FIG. 4, the dotted line represents the lower limit of detection, and it can be seen that the HBV DNA copy number in the serum of AAV-IL-21 mice is significantly lower than that of AAV-Ctrl and blank control mice. HBV DNA is a detection index of chronic infection, and the risk of infecting liver virus by AAV-IL-21 mice is obviously lower than that of AAV-Ctrl and blank control mice.
EXAMPLE 5 alanine aminotransferase assay
Orbital blood of the mice was collected 1, 2,3,4 weeks after pBPS injection in the mouse samples of example 2, respectively. As a test sample.
Detecting glutamic-pyruvic transaminase (ALT) level in serum, directly sending the serum to Shanghai Aidikang medical detection center for detection, and referring to Nat Commun.2017Dec 14 in the prior art; 8(1) 2119.doi 10.1038/s41467-017-02304-7. the results are shown in FIG. 5.
In FIG. 5, the dotted line in the graph represents the lower limit of detection, ALT in serum of AAV-Ctrl and blank control mice is always at normal level, ALT in serum of AAV-IL-21 mice is increased significantly in hepatitis virus elimination, until ALT in serum of AAV-IL-21 mice is restored to normal level after hepatitis virus elimination. It can be seen that the acute clearance process shown in the figure, AAV-IL-21 mice can prevent the establishment of persistent hepatitis B virus infection, whereas AAV-Ctrl and blank control mice have no acute clearance response.
Example 6 hepatocyte staining
Liver samples from group 3 mice from example 2 were stained for H & E and anti-CD 8. After staining, observation was performed under a microscope. Each group contained 3 mouse liver samples and the results are shown in figures 6 and 7.
In FIG. 6, after H & E staining, there was significant inflammatory cell infiltration in liver tissue of AAV-IL-21 group mice, as indicated by the arrows. There was no inflammatory cell infiltration in liver tissue of AAV-Ctrl and placebo mice. It can be seen that AAV-IL-21 mice can initiate anti-HBV inflammatory response after injection of BPS plasmid.
In FIG. 7, anti-CD8 stained, and AAV-IL-21 group mice had a large number of CD8 cells in liver tissue. While AAV-Ctrl and blank control mice showed no significant accumulation of CD8 cells in liver tissue. It can be seen that AAV-IL-21 mice can initiate anti-HBV CD 8T cell immune response after injection of BPS plasmid.
Example 7 hepatocyte IFN-. gamma.and PD1 levels
Liver samples of 3 groups of mice from example 2 were taken and assayed for IFN-. gamma.related mRNA and PD 1-related mRNA levels sequentially by real-time quantitative PCR. Each group contained 3 mouse samples and the results are shown in figures 8 and 9.
In FIG. 8, the IFN-. gamma.related mRNA levels in hepatocytes of AAV-IL-21 group mice were approximately 700%, while those in mice of the blank control group and AAV-Ctrl group were approximately 140% and 60%, respectively. The level of IFN-gamma related mRNA in hepatocytes of mice in the AAV-IL-21 group was significantly higher than that in the blank control group and AAV-Ctrl group. Because IFN-gamma can inhibit the replication of HBV in hepatitis virus infected liver cells and activate cellular immune response, the anti-virus effect is achieved. As can be seen, the anti-HBV immune response in the mice of the AAV-IL-21 group is obviously stronger than that of the blank control group and the AAV-Ctrl group.
In FIG. 9, the PD 1-related mRNA levels in hepatocytes of the AV-IL-21 group of mice were approximately 25%, while the PD 1-related mRNA levels in hepatocytes of the blank control group and AAV-Ctrl group of mice were approximately 110% and 90%, respectively. The level of PD 1-associated mRNA in hepatocytes of AAV-IL-21 group mice was significantly lower than that of the blank control group and AAV-Ctrl group. PD1 is an important immunosuppressive molecule, and the intrahepatic immunosuppressive molecules of the mice in the blank control group and the AAV-Ctrl group are higher than those of the mice in the AV-IL-21 group, so that the mice in the blank control group and the AAV-Ctrl group are more easily infected by liver viruses than the mice in the AV-IL-21 group.
The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.

Claims (8)

1. A gene that inhibits chronic hepatitis b virus infection, wherein the gene is the IL-21 gene.
2. A recombinant vector comprising an empty vector and an IL-21 gene inserted into said empty vector.
3. The recombinant vector of claim 2, wherein the empty vector comprises an AAV vector.
4. A host cell comprising the recombinant vector of claim 3.
5. Use of any one of the gene of claim 1, the recombinant vector of claim 2 or 3, and the host cell of claim 4 in the preparation of a medicament for inhibiting chronic hepatitis B virus infection.
6. A hepatitis virus drug inhibitor, wherein the active ingredient of said drug comprises the IL-21 gene, or a protein encoded thereby, or a biomaterial containing the IL-21 gene.
7. The hepatitis virus drug inhibitor of claim 6, further comprising a pharmaceutically acceptable carrier.
8. The hepatitis virus drug inhibitor according to claim 6, wherein the dosage form of the drug comprises any one of tablets, capsules, granules, oral agents, corrosion inhibitors and injections.
CN202110341781.0A 2021-03-30 2021-03-30 Gene for inhibiting chronic hepatitis B virus infection and application thereof Pending CN113061612A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108324930A (en) * 2017-01-18 2018-07-27 复旦大学 Interleukin-22 1（IL-21）Purposes in preparing hepatitis B virus resisting medicine preparation
WO2020023702A1 (en) * 2018-07-25 2020-01-30 AskGene Pharma, Inc. Novel il-21 prodrugs and methods of use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108324930A (en) * 2017-01-18 2018-07-27 复旦大学 Interleukin-22 1（IL-21）Purposes in preparing hepatitis B virus resisting medicine preparation
WO2020023702A1 (en) * 2018-07-25 2020-01-30 AskGene Pharma, Inc. Novel il-21 prodrugs and methods of use thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ZHONGLIANG SHEN等: "Hepatitis B virus persistence in mice reveals IL-21 and IL-33 as regulators of viral clearance", 《NATURE COMMUNICATIONS》 *
ZHONGLIANG SHEN等: "IL-21-based therapies induce clearance of hepatitis B virus persistence in mouse models", 《THERANOSTICS》 *
陈谦明: "《口腔分子生物学》", 31 August 2000, 军事医学科学出版社 *
鲁晓娟等: "乙型肝炎病毒感染患者血清IL-12、IL-21、IFN-γ、OPN水平变化及意义", 《山东医药》 *

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Application publication date: 20210702