New imaging reveals hidden details of viruses


Molecular-scale microscopy promises a boon for gene therapy researchers. Andrew Masterson reports.


A section of an AAV2 virion (inset), showing its components in unprecedented detail. The full atomic structure can be seen, including oxygens (red), nitrogens (blue), carbons (yellow), and sulfurs (green).

A section of an AAV2 virion (inset), showing its components in unprecedented detail. The full atomic structure can be seen, including oxygens (red), nitrogens (blue), carbons (yellow), and sulfurs (green).

Lyumkis, et al

The use of viruses as delivery mechanisms capable of altering human genes and curing disease has taken a big step forward with the development of a new form of imaging that allows researchers to examine them in unprecedented detail.

In a study published in the journal Nature Communications a team led by Dmitry Lyumkis from the Salk Institute in California, US, reports on the refinement of cryo-electron microscopy in order to study one of the best candidates for virus-initiated gene therapies, adeno-associated virus serotype 2, or AAV2.

AAV virus strains infect humans and some other species of primate, but do so without ill effects except occasional mild immune responses. They are adept at integrating into the host genome, which makes them potentially very useful as gene therapy vectors.

This use was recognised early in the century, although initial progress was slow. A report in 2008 reported that AAV was a promising prospect – not least because it didn’t cause illness – but, at that point, “no proven efficacy has been observed”.

One of the difficulties encountered by researchers in the field was that it was extremely challenging to observe how the virus functioned on a molecular level – a critical requirement for being able to control its interactions within host cells.

Now, however, Lyumkis and colleagues have succeeded in producing a “cryo-EM” image of a single AAV2 virion that permits a reconstruction of amino acids in which almost every atom is visible, and distinguishable as oxygens, nitrogens, carbons and sulfurs.

“It's not an overstatement to say that this is one of the best cryo-EM structures that's ever been achieved in this field,’ says Lyumkis.

“We applied a number of different procedures that have previously only been described in theory. We demonstrated experimentally, for the first time, that they can be used to dramatically improve the quality of this kind of imaging.”

The work will be of interest to researchers not only in the field of gene therapy, but also for those in fields such as immunology and virology.

“Ultimately, this kind of research has important implications for understanding the interactions between these different viruses and the types of cells they infect," says co-author Sriram Aiyer.

“This is important for developing a greater understanding of the human immune system and how it recognises viruses.”

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  1. http://dx.doi.org/10.1038/s41467-018-06076-6
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570152/
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