Scientists test new approach to fighting viruses

Russian scientists have tested a new approach to fighting viruses. They used the technology of genetic editing to activate the protective mechanisms of cells into which the pathogen has already penetrated, reports Izvestia daily.

By artificially activating the APOBEC/AID family of proteins, they managed to suppress the reproduction of hepatitis B and D viruses by 80-85%. Now, specialists plan to identify the most universal intracellular factors and create the first broad-spectrum drug based on them. According to experts, the new method can be an effective treatment, but the side effects should be studied in detail.

Specialists at the laboratory of genetic technologies for the creation of drugs at the Institute of Medical Parasitology, Tropical and Transmissible Diseases of Sechenov University have proposed a new method of combating infections. They discovered a number of proteins that suppress the activity of virus particles that have entered the cell. Scientists have managed to trigger this mechanism using the CRISPR/Cas9 gene editing system. Now they plan to identify the most universal proteins that are effective against most viruses, and based on them create a broad-spectrum drug for such diseases.

Today, the main means of fighting viruses are antibody-based vaccines and drugs. They should prevent particles from entering the cell.

But if this has already happened and the person has already fallen ill, then the only way to fight can be interferon. This type of protein activates hundreds of antiviral genes, enabling to stop or slow down replication. However, this substance is effective against only a few types of infection.

"We have developed an approach using the CRISPR/Cas9 gene editing system to identify and activate individual major antiviral factors that are independent of interferon but block infections. This technology can be used in order to create an effective drug against a wide range of diseases," said the head of the aforesaid laboratory, Dmitry Kostyushev.

This team of scientists selected 157 genes and analyzed their response to hepatitis B and D pathogens, which enabled to identify a number of antiviral factors in cells.

The APOBEC/AID protein family has been found to be effective against DNA and RNA viruses. Experiments on cell models of chronic infections have shown that activation of just a few of these proteins is sufficient to suppress the disease by 80-85%. Analysis of the utility of this approach against a number of other severe cases showed similar results.

"Our hypothesis that individual intracellular factors can effectively suppress virus replication was confirmed. Now the primary task is to analyze not individual genes, but complete groups of the widest possible range and select the most universal antiviral factors. In the future, they can be used to fight not only existing, but also emerging infections. Judging by the conjectures of the WHO and the [Russian] Ministry of Health, epidemics will be more and more frequent, so the arsenal of measures to combat them should be expanded," said Dmitry Kostyushev.

Antibodies and T-cells, which uniquely respond to viral proteins, are adaptive immunity that is formed after encountering a causative agent, Mikhail Bolkov, a researcher at the Institute of Immunology and Physiology of the Ural branch of the Russian Academy of Sciences, explained to Izvestia. In addition, there are also innate mechanisms, one of which is APOBEC/AID. They often prevent the infection from developing and overcome it without triggering adaptive immunity. This is 90% of the body's defenses, which work continuously.

Scientists have discovered that APOBEC/AID proteins can destroy the virus right inside the cell.

They reformulate the code, changing one "letter" to another without having a toxic effect. But overactivation of the proteins leads to mutations in genes in a person's own genome, including genes that lead to cancer. The therapy can have side effects, including oncological, said Mikhail Bolkov.

According to him, a set of precise tools called CRISPRa has been developed based on modified CRISPR-Cas9 systems to directly activate the necessary genes. This approach has been shown to be safe and effective, for example in correcting genetic defects and suppressing HIV infection.

"This is a very topical topic because we still don't have reliable drugs that treat hepatitis B and D. Available drugs only suppress the activity of these viruses. These studies are welcome, but so far they have achieved an 80% reduction in breeding—and only in testing. Much work still needs to be done to make such a drug effective,” says Vadim Pokrovsky, academician and epidemiologist of the Russian Academy of Sciences.

The scientists propose to target CRISPR/Cas9 sequences that trigger antiviral reactions into cells using a delivery system they previously developed based on biological nanoparticles.

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