Abstract Viruses are a major threat to human health. Our laboratory uses various structural biology techniques to dissect molecular mechanisms of how viruses replicate and invade the host cell or its genome. One area of our major interest is retroviral integration, a critical step in the lifecycle of retroviruses that achieves permanent insertion of the reverse-transcribed viral genome into a host chromosome. We will build on our recent structural studies of the Human T-cell Leukemia virus and Rous sarcoma virus intasomes and further investigate the roles of host factors during integration of these retroviruses. Another area that we are pursuing is the replication of coronavirus RNA genomes and host cell invasion. In particular, we are interested in how a virally encoded exoribonuclease complex facilitates faithful replication of the large RNA genomes of coronaviruses, and how this unique proofreading activity could be modulated by small molecules. We are also investigating inhibition of the receptor binding of the coronavirus spike protein by novel antibodies and antibody-mimics. Overall, the studies proposed in this application will help better understand important RNA-based human pathogens and could aid in the development of antiviral strategies, or alternatively, gene delivery tools useful in research or gene therapy applications.