Open up a new direction for the treatment of hepatitis B virus

Hepatitis B virus (HBV) is one of the
most serious and common infectious diseases.
It is transmitted through biological fluids and attacks liver cells
.
The chronic form of the disease can lead to serious complications, including cirrhosis and liver cancer
.
There is no effective treatment for this chronic disease, which can only be prevented
by vaccination.
After identifying a key protein complex that is active when our bodies are infected by a virus, a team at the University of Geneva (UNIGE) has deciphered the precise function of this protective mechanism, opening the way
to new therapeutic targets.
The findings were published in
the journal Nature Structural & Molecular Biology.

Hepatitis B is the most common hepatitis
.
This is a viral disease
caused by the hepatitis B virus.
It is mainly transmitted
through blood or sex.
It is 100 times
more contagious than HIV.
By infecting liver cells, the virus causes transient inflammation of this organ, which can also evolve into chronic infection
.
This can lead to serious pathologies such as cirrhosis or liver cancer
.
It is estimated that nearly 1 million people worldwide die from the disease
every year.
There is no clear treatment for
chronic hepatitis B.
The only way to prevent it is to get vaccinated
before the disease appears.

In 2016, a UNIGE team led by Michel Strubin, an associate professor at the Geneva Center for Inflammation Research in the Department of Microbiology and Molecular Medicine at the University of Michigan School of Medicine, revealed a mechanism critical to understanding the disease: When our immune system defends itself, a complex of six proteins called SMC5/6 present in our cells — the interdependent group — detects viral DNA
。 The virus then fights back, producing a special protein, protein
X.
This protein enters the cell and degrades SMC5/6, making it no longer able to function as
a sentinel.

A three-step mechanism

Prior to this discovery, the antiviral function of SMC5/6 was unknown
.
It is simply considered a key complex that maintains the structure of
our chromosomes.
Today, Michel Strubin's team broke new ground
.
In a recent study conducted in collaboration with the US pharmaceutical company Gilead Sciences, researchers at the UN ige identified three steps and specific proteins
required for SMC5/6 to exert its antiviral effects.

"In the first step, a protein of the SMC5/6 complex detects the DNA of the virus and captures it," explains
Fabien Abdul, Senior Research and Teaching Assistant in the Department of Microbiology and Molecular Medicine at the United Nations School of Health School of Medicine and first author of the study.
The complex's second protein, SLF2, then carries captured viral DNA into a subcompartment of the nucleus of the attacked cell, called the PML body
.
A third protein, NSE2, comes into play, suppressing the virus's chromosomes
.
”

Since SMCs are a large family of protein complexes, the researchers also wondered if other "members" of this family could bind
to hepatitis B virus DNA.
Fabien Abdul said: "We found this capability to be unique to
the SMC5/6.
"

Search for new therapeutic targets

To achieve these results, the team performed in vitro cell culture
.
"We used molecular biology techniques and more specific gene scissors called CRISPR-Cas9
.
This tool allows us to cut DNA strands within cells, thereby deleting or modifying the genetic code
of each protein that makes up the SMC5/6 complex.
Thanks to this technique, we were able to make one of the proteins disappear and thus understand their respective functions in the complex," based on these observations, three steps
in which the antiviral mechanism can be established.

This finding provides a basis for a
better understanding of how this complex works in antiviral effects.
As such, it could pave the way
for identifying new therapeutic targets to combat the hepatitis B virus.
Postdoctoral researcher Aurélie Diman said: "The next phase of research will include better deciphering the mechanisms
of virus inhibition in the nucleon compartment of cells.
" To better understand the mechanism by which hepatitis B counteracts against the antiviral activity of cellular SMC5/6, there is also a need to study protein X, whose role was identified
by researchers at the UN IGE in 2016.

Fabien Abdul, Auré lie Diman, Bastien Baechler, Dhivya Ramakrishnan, Dmytro Kornyeyev, Rudolf K.
Beran, Simon P.
Fletcher, Michel Strubin.
Smc5/6 silences episomal transcription by a three-step function.
Nature Structural & Molecular Biology, 2022; 29 (9): 922