Understand the Hepatitis B

Posted by Jerry Carter on April 1st, 2021

Hepatitis B virus (HBV) infection is the leading cause of global morbidity and mortality. The WHO estimates that approximately 20 million people worldwide are infected with HBV. Among those chronically infected, it is estimated that 65 million people die of liver disease due to their HBV infection.

Trace of HBV

In 1963, Baruch Blumberg and Harvey Alter first discovered the antigenic substance Aa (Australian antigen, later renamed HBsAg, hepatitis B surface antigen) in the blood of indigenous Australians.

In 1966, Baruch Blumberg et al. detected Aa in the blood of a 12-year-old boy with Down syndrome, who had hepatitis symptoms, indicating that Aa is related to hepatitis. When testing the serum, it was found that the positive rate of Aa in the serum of hepatitis patients was higher than that of non-hepatitis patients.

In 1967, Baruch Blumberg, Kazuo Okochi, Alfred Prince, Alberto Vierrucci, and their colleagues reported specifically that Aa is related to hepatitis B.

The structure of hepatitis B virus

The liver is the main detoxification site of the human body, which mainly detoxifies through both physical and chemical aspects to ensure human health. Physical detoxification refers to the phagocytosis of foreign bodies, bacteria, and other harmful substances in the blood through the reticuloendothelial phagocytic system. Chemical detoxification is the conversion of toxic substances into non-toxic substances through enzymes in the body, which are subsequently excreted from the body through the kidney.

HBV is the pathogen that causes hepatitis B, which belongs to the family of hepatotropic DNA viruses and resides in the liver. The three forms are large spherical particles (diameter 42nm), small spherical particles (diameter 22nm), and tubular particles (diameter 22nm). HBV consists of the envelope and core. The envelope is the surface antigen (HBsAg). In the core part, there are core antigen (HBcAg), e antigen (HBeAg), HBV-DNA, and DNA polymerase. Among them, the e antigen is a non-structural protein, which, after synthesis, is secreted out of the liver cells through the endoplasmic reticulum and participates in virus replication, while the core antigen and DNA often exist in the liver cells.

HBV infection process

HBVs interact with heparin sulfate proteoglycan (HSPG) and (GPC5) on the surface of liver cells, and then bind with the receptor sodium taurocholate cotransport peptide (NTCP) with high affinity to remove hepatitis B surface antigen (HBsAg), and enter liver cells by endocytosis. The remaining virus particles invade the cell and transport the loose double-stranded DNA into the nucleus. Viral DNA enters the nucleus of the host cell and forms a covalently closed circular supercoiled DNA molecule called cccDNA under the action of DNA polymerase, which resides in the nucleus of the liver cell for a long time and is extremely stable. The RNA pre-genome can be reverse transcribed into rcDNA. The mature capsid containing double-stranded rcDNA can be redirected to the nucleus to form more cccDNA, or it can be wrapped for the release of virus particles.

Hepatitis B treatment

There are three lines of defense. The first line is skin, mucous membranes and their secretions, cell membranes, etc. The second line is phagocytosis, antibacterial proteins, and inflammation. The third line of defense is mainly composed of immune organs (tonsils, lymph nodes, thymus, bone marrow, spleen, etc.) and immune cells (lymphocytes, phagocytes, etc.) with the help of blood circulation and lymphatic circulation. Immune cells mainly include B cells that can produce antibodies and specifically bind to the virus antigens, and T cells that can recognize and kill viruses. The two prerequisites for immune cells to function are virus recognition and that virus needs to be outside the cell. However, HBV is a hepatotropic virus that mainly exists in liver cells, so it cannot be cleared by immune cells. Besides, there are many cytokines secreted by immune cells that can regulate immune response, such as interferon, which can activate the human immune system.

The treatment destination is to remove HBV DNA to prevent liver cirrhosis, liver failure, and liver cancer.

There are currently seven drugs available for HB treatment, including five nucleotide compound analogs (NUC) (lamivudine, adefovir, entecavir, tenofovir, and telbivudine) and two interferon-based therapies (conventional interferon and pegylated interferon alpha). NUC inhibits virus replication by inhibiting HBV viral polymerase, while interferon therapy works by enhancing the host's immune response. The main treatment strategy is to use interferon and NUC for combined administration. While NUC drugs inhibit virus replication, interferon is used to enhance the body's immunity.

Scientists expect to improve the cure rate of chronic HBV persistent infection from the following methods.

* Entry Inhibitors: Inhibit the entry of HBV into cells by inhibiting the expression of NTCP receptors. Currently, the existing NTCP inhibitors include FDA-approved drugs (ezetimibe and irbesartan), bile acids (such as tallow deoxygenation), and tricyclic polyketides (such as vanitaracin A).

* Destroy HBV cccDNA by CRISPR/Cas9: Intervene cccDNA synthesis by means of gene editing.

* Inhibit the excretion of newly assembled virus: HBV first needs to be wrapped by HBsAg glycoprotein to be secreted, so it can inhibit the secretion of the newly assembled virus by interfering with endoplasmic reticulum or Golgi glycosylation.

* Therapeutic HBV vaccine: mainly for patients with damaged T cells and immune tolerance. Currently, there are many drugs under clinical studies, such as ABX203 and TG1050.