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Synopsis How Cowpox Virus Turns Back Cell Defenses Caitlin Sedwick* Freelance Science Writer, San Diego, California, United States of America Viruses follow a well-choreographed battle plan to mount an infection. First, they invade cells, then stage a takeover of its genetic and protein replication ma- chinery. Once the virus assumes control, it forces the cell to create thousands of copies of the virus, which usually ends up killing the cell. Organisms have evolved elaborate defenses to prevent viruses from entering cells in the first place or, as a last resort, to kill their own infected cells in order to prevent the infection from Cowpox-encoded CPXV203 subverts antigen presentation by engaging MHCI in the spreading. But viruses have also evolved Golgi and subjecting it to KDEL receptor mediated retrieval. countermeasures to these defense mecha- doi:10.1371/journal.pbio.1001431.g001 nisms. In this issue of PLOS Biology, William McCoy, David Fremont, and colleagues explain how a countermeasure cells detect MHCI molecules displaying explain, cowpox virus’ ability to thrive in devised by cowpox virus works to help the viral peptides, they kill the infected cell the cells of different species. virus establish and maintain its presence to stop the release of more viruses. But But McCoy and colleagues also noticed in an infected cell. CPXV203 somehow prevents MHCI a curious thing: in every case, the Cowpox virus can infect and replicate molecules from ever reaching the cell interaction between CPXV203 and in the cells of many different mammalian