Genetic Code Expansion and Bio-Orthogonal Labeling Reveal Intact HIV-1 Capsids inside the Nucleus

Microscopy is one of the few techniques that can directly observe the HIV-1 capsid as it traverses the cell. However, an extrinsic or intrinsic label is needed to facilitate detection and this can perturb capsid behavior. Now, S. Schifferdecker, V. Zila, T. G. Muller, V. Sakin, et al. (mBio:e0195922, 2022, https://journals.asm.org/doi/10.1128/mbio.01959-22) have developed an ingenious direct labeling technology that uses genetic code expansion and click chemistry to produce infectious viruses whose capsids are labeled with only a single modified amino acid. Using this new system, together with electron tomography, the authors demonstrate that the capsid remains intact during its transport into the nucleus of T cells, supporting a late model of uncoating immediately before integration. Combining direct-labeled capsids with fluorescent nonstructural viral proteins or host cofactors promises to be hugely enabling for future studies. Moreover, the potential to install a bio-orthogonal label site specifically in the capsid is likely to have exciting applications beyond imaging.