An I2SysBio team determines the factors that allow the mutation of a human RNA virus and facilitate its contagion

The Institute of Integrative Systems Biology, located at the University of Valencia Science Park, is performing the first analysis of all the mutations in the set of proteins of the human 'coxsackievirus B3' virus, which causes severe inflammation of the heart. The results, published in 'Plos Biology', will help to identify regions of the virus genome with low tolerance to mutations, facilitating the development of drugs directed to these targets

RNA viruses have some of the highest mutation rates in nature. This allows them to circumvent the immune system to continue infecting, and hinders the development of drugs to prevent it. Now, a team from the Institute for Integrative Systems Biology (I2SysBio), a joint center of the University of Valencia (UV) and the Spanish National Research Council (CSIC), has analyzed for the first time how mutations affect the entire proteome of an RNA virus and has found significant variability in mutation tolerance between different viral proteins. This will facilitate the development of drugs that reduce the likelihood of the virus developing resistance.

Based on a first comprehensive analysis of coxsackievirus B3, a human RNA virus that causes severe inflammation of the heart in humans, and using a technique called 'deep mutational scanning', the team has determined the effect of more than 40,000 mutations and 1,300 deletions - loss of genetic material - on the viability of the virus. The results show significant variability in mutation tolerance among different viral proteins, and point to the importance of entry factors in the viral expansion process.

“We analyzed so-called pockets, which are holes in viral proteins with favorable properties for being targeted by small drug molecules, and found twelve of these spread across different viral proteins,” explains Ron Geller, I2SysBio researcher and project leader. “Next, we discovered that some of these pockets are very intolerant to mutations, so it is likely that any mutations leading to drug resistance would also be lethal to the virus, which would prevent the spread of such mutants. Others showed a very high tolerance to mutations, so they may not be good drug targets,” argues the CSIC researcher at this joint center located at the Parc Científic de la Universitat de València.

Drug development

This is the first analysis of mutations affecting a complete proteome of a human RNA virus to date. The results published in the journal Plos Biology help to better understand the biology and evolution of this type of viruses of medical relevance for humans (poliovirus, rhinovirus, enterovirus A71...).

“One of the main challenges in the development of antiviral molecules is the emergence of mutations that allow the virus to escape these drugs,” explains Geller. “The data provided in this study could be used to identify regions with low tolerance to mutations, facilitating the development of drugs that reduce the likelihood of the virus developing resistance,” the scientist concludes.