Genome Architecture and Evolution of RNA Viruses
RNA is a functionally versatile molecule. It can specifically interact with proteins, small molecules, and base pair to other nucleic acids with exquisite precision. RNA viruses exploit this functional versatility at almost every stage of their replication cycle, using non-coding RNA elements to influence splicing, protein translation, evasion of host cell defenses, viral evolution and accessibility towards drug binding. Consequently, non-coding RNA represents an extremely attractive target for antiviral intervention, with the potential to revolutionize the treatment of infectious disease.
We use an integrative structural, functional and evolutionary approach to discover and mechanistically characterize non-coding RNA structures involved in viral replication and evolution. As in the protein world, it is often the higher order structure of the RNA, rather than primary sequence, that determines its function. Currently, how RNA structure drives diverse biological functions is not yet fully understood. Moreover, RNA readily undergoes structural changes, allowing it to switch between different functions, between different on/off states, or to adopt specific folds in different environments or in the presence of ligands. RNA dynamics have traditionally frustrated RNA structural characterization by biochemical and biophysical approaches. Our research focuses on unravelling the relationship between RNA structure and function, and we are actively working on new methods to investigate RNA structural dynamics. In the long term, we plan to use this knowledge to rationally develop small molecule drugs that interfere with RNA structure as a novel antiviral strategy.
We are also interested in how RNA structure constrains viral evolution. Retroviruses, such as HIV, package two copies of their RNA genome into each virion leading to recombination (template switching) and the formation of genome chimeras during replication. Another widespread strategy, seen in rotaviruses and influenza viruses, is genome segmentation leading to reassortment. Reassortment and recombination are non-random processes that are known to depend on RNA sequence and structure, but the underlying mechanisms are poorly understood. We study these mechanisms with the goal of improving disease prevention and control strategies. At the population level, we hope to understand the emergence of novel viral strains, such as how potentially pandemic influenza arises from genetic reassortment in pigs or birds. At an individual level, we want to understand how RNA structure leads to immune evasion and the generation of multiple drug resistant viruses. Through our fundamental research we seek to rationally manipulate recombination and reassortment for the development of safer gene therapy vectors, as well as powerful new vaccine platforms.