HBV Life cycle and Modes of Transmission

Life Cycle of Hepatitis B Virus

Liver cells (hepatocytes) have numerous important functions. One of these functions is to produce bile salts from cholesterol and release them into the small intestine via the bile duct. Bile salts are crucial for the digestion of fat. Bile salts, after they have performed their function, 97% of them are reabsorbed back into the liver and then can be re-circulated. They re-enter into the hepatocyte by a special channel that co-transports bile salt (taurocholate) with sodium. This channel is called sodium-taurocholate Co-transporting polypeptide (NTCP). It is actually a misnomer as it is also involved in the uptake of bile acids and bile salts other than taurocholate. The bile salts are then re-secreted back into bile and this cycle continues. This is called enterohepatic circulation.

Let us suppose the Hepatitis B virus enters into the blood of a normal person after he was injected with a contaminated syringe. Hepatitis B virus while wandering into the bloodstream comes across its beloved liver. Due to its predilection towards the liver, it belongs to the family of viruses called “Hepadnaviridae”. It reaches the hepatocyte. Here first it loosely binds with heparan sulfate on the sinusoidal surface of hepatocyte and then it undergoes a high-affinity binding with NTCP channels. As it binds with NTCP hepatocyte thinks that something very useful and nutritious is coming for it.

Unaware of the unseen enemy, poor unsuspecting hepatocyte engulfs this hepatitis B virus by pitching inwards into this part of the membrane on which the virus attaches itself. This process is called endocytosis.

An experimental drug called Myrcludex B binds with NTCP and inhibits the entry of Hepatitis B virus into the cell.

As the virus enters into the cell, it then fuses it’s envelope with the endocytic vesicle and releases the nucleocapsid core inside the cytoplasm of the hepatocyte. The endocytotic vesicle then re-fuses back with the cell membrane of hepatocyte.

As the nucleocapsid enters into the cell, it finds the nucleus, and at its nuclear pore, capsid disintegrates, and DNA of the virus enters into the nucleus along with its DNA polymerase.

The DNA of hepatitis B is partially double-stranded, circular and each strand is loosely wound around the other. Thus, it is also called relaxed circular DNA (rcDNA).

Inside the nucleus, rcDNA utilizes the host’s DNA repair mechanisms to complete its partial strand along with the removal of the attached viral polymerase. The fate of this viral polymerase beyond this point is unclear. Perhaps it is somehow degraded. Nonetheless, as the incomplete strand is completely formed DNA by host’s repair mechanisms, it is now said to be a covalently closed circular DNA (cccDNA)

From this cccDNA, mRNA transcripts are formed. The human RNA Polymerase II considers this viral cccDNA as it’s own DNA and faithfully transcribes its genes into their complementary mRNA strands.

A complete strand that is complementary to the whole sequence of cccDNA, (not a particular gene) is also formed. This longest mRNA transcript is called Pre-genomic mRNA because it is the precursor of the genome of virus.

This pre-genomic, as well as other mRNA transcripts, are exported out of the nucleus into the cytoplasm.

In the cytoplasm, from pregenomic mRNA transcript, viral polymerase enzyme is created by the host’s cytoplasmic protein synthesis machinery.

As soon as it is born, this Polymerase finds the pre-genomic mRNA (pgRNA) and quickly associates and attaches with it. This is because polymerase has an inbuilt 8-10 nucleotide sequence complementary to the pgRNA strand.

Meanwhile, from its mRNA transcript, capsid proteins are also synthesized. Several capsid proteins find the pgRNA-Polymerase complex and interact with it in a specialized and intricate fashion to form an icosahedral capsid core with a precursor genome inside it.

Inside the capsid core, viral polymerase enzyme creates the DNA from pgRNA as it has inherent reverse transcriptase activity. It then degrades the pgRNA by its RNAse activity and starts creating the other strand of DNA. Even before it completes the other DNA strand it hastens to come out of the cell. Let’s see how it acquires it’s envelope and then how it manages to come out of the cell.

Surface proteins, Pre-S1, Pre-S2, and S and translated by ribosomes attached to the surface of Rough Endoplasmic reticulum and then processed inside the lumen of RER and final proteins are then embedded onto the membrane of RER. e-protein is also translated by RER associated Ribosomes and is processed in RER but is not embedded onto the membrane of RER but dissolved into its matrix because of its soluble protein.

Nucleocapsid core finds the RER embedded surface proteins, buds inside at this place, and then pinches out. It is then packed like the body’s own precious substance by the Golgi apparatus and sent out of the cell.

Unlike, other viruses that require the nucleocapsid core to be associated with the surface protein embedded RER, Hepatitis B surface protein can be exported out as such. Even the e-proteins can be exported out in the absence of surface proteins and nucleocapsid core. That is the reason why we have so many empty envelopes (spherical and longitudinal subviral particles) along with e-protein that gets dissolved into plasma as soluble proteins.

This nascent infectious virion or Dane particle is now ready to infect the neighboring hepatocyte or even the hepatocyte of a new host if it happens to get lodged inside a new host.

It’s noteworthy that a special protein called HBx is also synthesized during this process. This protein has oncogenic properties and can lead to hepatocellular carcinoma in some patients. It also acts as a transcription factor and enhances the rate of viral gene transcription.

Modes of Transmission:

Hepatitis B virus is blood-borne. Transfusion of Hepatitis B infected Blood to a normal person can transmit the disease. The incidence of such accidents has been strongly reduced by the standard practice of screening before transfusion. It was the commonest route of Hepatitis B transmission in the past.

Unlike other enveloped viruses, Hepatitis B virus is relatively much more sturdy and tough that it can remain viable outside the body for up to 7 days.

That’s why sharp instruments (needles and surgical equipment) can transmit this virus when re-used without proper sterilization. Even the sharing of the toothbrush can transmit this as it incurs small injuries into the oral mucosa.

Hepatitis B virus is also found in the body fluids especially seminal and vaginal fluids. When these fluids are secreted into their respective glands, the Hepatitis B virus being small particle extravasates out from the plasma in this fluid.

During the sexual act, due to the exchange of this fluid, hepatitis B can also be transmitted.

During the sexual act especially anal sex, microabrasions on the mucosa are usually occurred. When the seminal fluid from an infected person containing the Hep B virus is released it may get inoculated into these microabrasions and seep through them into the blood.

Microabrasions is less common in vaginal sex, that’s why Hepatitis B is more often transmitted through anal sex than vaginal sex.

Intact skin provides a sufficient barrier to prevent the entry of the hepatitis B virus. However, it is not clearly known whether this virus can pass through the intact mucosa. It has been observed the deep kissing does not transmit this virus. Wet mucosa can however theoretically support the virus and can keep it viable for longer.

Hepatitis B virus can also be transmitted from mother to newborn during childbirth.