Nanodiamonds as sensitive sensors to study tetherin structure and dynamics

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Human tetherin blocks virus release and also acts as a pattern recognition receptor to induce NF-kB-dependent antiviral gene expression in HIV-1 infected cells. The ability to restrict virion release is conserved among tetherin orthologues from different species and evolved hundreds of millions of years ago. However, innate viral sensing seems to be an evolutionarily recent activity of tetherin and only human and (to a lesser extent) greater apes tetherin orthologues were reported to act as innate immune sensors, whereas tetherins from monkeys and other species lack this function. Viral sensing involves the phosphorylation of conserved tyrosine residues in the cytoplasmic tails of tetherin dimers but the exact mechanism and the structural requirements for viral sensing by tetherin remain to be determined. Quantum sensors based on nitrogen-vacancy defects (N-V) in nanodiamonds offer great potential to achieve single molecule detection of proteins in their native environment with atomic resolution of ligand binding sites under ambient conditions. Our collaborative project focuses on the application of N-V magnetometry for resolving the virion capturing site of the membrane receptor tetherin with atomic precision and for monitoring tetherin dynamics inside the membrane upon virion binding. Thus, analyses with ND sensors could yield fundamental information regarding the dynamics of HIV-1 binding and signal transduction of this important innate antiviral factor. Overall, it is expected that the implementation of quantum sensing in biology provides radically new insights into the structure and dynamics of challenging biomolecules such as the membrane tetherin in its native environement thus providing the first method that would allow collecting structural information with atomic resolution in a non-invasive fashion under physiological conditions.