UC San Diego

Viruses with a positive-sense single-stranded RNA genome [(+)ssRNA] encode proteases that antagonize the host immune system. Examples include picornaviruses, flaviviruses, and coronaviruses. The proteases they encode cleave not only key host proteins but also process viral polyproteins. Due to their dual role of cleaving numerous polyprotein sites as well as diverse host proteins, viral proteases’ evolution is highly constrained. In spite of the strong evolutionary constraint, evidence suggests that viral proteases are engaged in a molecular ‘arms race” with host proteins. Examples of such proteases include picornavirus 3C, flavivirus NS2B/NS3, and coronavirus 3CL. When proteases successfully cleave host proteins, it puts evolutionary pressure on the protein to escape viral antagonism. As a response, viral proteases undergo evolution to antagonize the newly evolved protein keeping its constraints in mind. Both these cases help explain why these evolutionary conflicts result in diverse protease-host interactions. It contributes to existing scientific findings on the pathogenicity of viral infection in hosts. Such examples highlight the importance of examining viral protease-host interactions through an evolutionary lens.