Scientists Reveal How Protein Complex Fights Hepatitis B

Researchers from the University of Geneva (UNIGE) have discovered a mechanism that enables the body to fight against hepatitis B, raising hopes of possible near-future availability of more effective treatments for the disease.

Hepatitis B Virus

The scientists had earlier found out that a vital protein complex became active in a body infected by the hepatitis B virus (HBV). In this new research published in Nature Structural & Molecular Biology, they reported for the first time how the complex does this.

The findings are quite significant in that they uncover exciting targets for researchers working to develop helpful hepatitis B treatments.

Difficulty in dealing with HBV

Caused by HBV, hepatitis B is the most prevalent form of hepatitis. The virus that is responsible for this disease is highly contagious – researchers say it is as high as 100 times more contagious, compared to the human immunodeficiency virus (HIV).

The hepatitis B virus is transmitted from one host to another via biological fluids. People contract it mostly through sex and blood from an infected person. Once in the body, the bug attacks cells in the liver to cause transient organ inflammation that could become a chronic infection.

Chronic hepatitis B can result in severe complications, for example, cirrhosis or liver cancer. According to estimates, almost one million deaths occur globally from this viral disease every year.

Currently, there are no effective treatments for chronic hepatitis B cases. It is only possible to prevent it through vaccination.

A team of researchers at UNIGE, led by Michel Strubin, discovered in 2016 an interaction that takes place between a protective complex and the virus. It found that the complex of six interdependent proteins called SMC5/6 in human cells blocks the viral DNA on detection. However, the virus in return produces what is called the X protein, which gets into the cell to degrade the complex and so render it impotent.

The antiviral role of SMC5/6

Prior to the UNIGE team’s discovery in 2016, nothing was known about the antiviral purpose of this protein complex. Scientists thought of it as something needed for the structural upkeep of chromosomes.

The researchers, working in partnership with the American biopharmaceutical company Gilead Sciences, took their discovery further in this new work. They used in vitro cell cultures combined with molecular biology techniques, more especially the gene-editing tool CRISPR-Cas9.

According to Strubin, an author of the study and an associate professor in UNIGE’s Department of Microbiology and Molecular Medicine, the tool enabled the researchers to cut DNA strands in cells to modify or delete the gene that encoded for each protein in the complex. The team thus managed to figure out the role of each of the proteins.

Strubin and his colleagues successfully identified three steps that are involved in the antiviral mechanism of SMC5/6.

“In the first step, a protein of the SMC5/6 complex detects the virus’ DNA and traps it,” explained Fabien Abdul, the study’s first author. “Then, a second protein of the complex – SLF2 – takes the trapped DNA of the virus into a sub-compartment of the nucleus of the attacked cell, called the PML body. A third protein – Nse2 – then comes into play and inhibits the virus’ chromosome.”

The discovery of this three-step mechanism could serve as a boost for efforts to make effective treatments for hepatitis B. It provides much-needed clarity on how SMC5/6 performs its antiviral function.

The SMA family of protein complexes is a broad one. Therefore, the researchers went ahead to check if other members of the family could also help against HBV. They found, however, that this ability was unique to the SMC5/6 complex.

Aurélie Diman, a postdoc researcher in Strubin’s lab, revealed that the next research aim is to work out “the mechanism of inhibition of the virus in the sub-compartment of the cell nucleus.” Scientists will also need to learn more about the X protein, which HBV uses to degrade SMC5/6 in cells.