Transmission electron microscopy and the molecular structure of icosahedral viruses

The field of structural virology developed in parallel with methodological advances in X-ray crystallography and cryo-electron microscopy. At the end of the 1970s, crystallography yielded the first high resolution structure of an icosahedral virus, the T = 3 tomato bushy stunt virus at 2.9 Å. It took longer to reach near-atomic resolution in three-dimensional virus maps derived from electron microscopy data, but this was finally achieved, with the solution of complex icosahedral capsids such as the T = 25 human adenovirus at ∼3.5 Å. Both techniques now work hand-in-hand to determine those aspects of virus assembly and biology that remain unclear. This review examines the trajectory followed by EM imaging techniques in showing the molecular structure of icosahedral viruses, from the first two-dimensional negative staining images of capsids to the latest sophisticated techniques that provide high resolution three-dimensional data, or snapshots of the conformational changes necessary to complete the infectious cycle.