This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Viruses come in two major flavors—not chocolate and vanilla, quips Harvard Medical School structural biologist Stephen Harrison, but those enveloped in membranes, such as herpesvirus, influenza virus, HIV and SARS-CoV-2, and those that are not, such as poliovirus, HPV, rotavirus and adenovirus. Scientists know more about how enveloped viruses get their genetic material across the cell membrane and into our cells, thereby causing infection, than about how nonenveloped viruses do.
Harrison, the Giovanni Armenise-Harvard Professor of Basic Medical Sciences at HMS and HMS professor of pediatrics at Boston Children's Hospital, has spent decades closing this gap. Thanks to advanced imaging methods, his lab and collaborators have now filled in one of the final pieces of the puzzle for nonenveloped viruses that deliver their genomes packaged within a protein shell. The findings, reported Sept. 10 in Science, deepen understanding of virology and could help the biotechnology industry devise better methods to deliver gene therapies and other relatively large therapeutic agents into cells.
"This work is relevant not just for understanding infection by nonenveloped viruses but for addressing the general question of what are the mechanisms for delivering large cargo into cells," said Harrison, senior author of the study and a Howard Hughes Medical Institute investigator. "I've always thought if we can figure out how evolution did it for one virus, it puts us a step ahead." The work was led by first author Marilina de Sautu, a research fellow in the Harrison Lab, in close collaboration with Simon Jenni, an HMS research scientist in biological chemistry and molecular pharmacology. Previous studies from the Harrison Lab and others showed how rotaviruses attach to the cell membrane and then become engulfed and brought into a membrane-bound compartment inside the cell.
The virus then must somehow punch a hole in that membrane to get its DNA or RNA into the cell, take over the cell's molecular machinery and replicate itself. In the new study, which used a strain of rotavirus, de Sautu and colleagues identified the protein that punches the hole in the membrane and revealed how it does so. They showed that virus protein 5, or VP5, makes the membrane permeable to calcium, causing a loss of calcium ions.
This in turn makes virus protein 7, or VP7, dissociate from the virus particle and form a pore in the membrane. To Harrison's delight, neither the protein nor the mechanism proved to be what he expected. "All along I had thought it would be VP5 that punched the hole, but it's VP7," he said.
He noted that work from a former colleague at HMS and Boston Children's, Philip Dormitzer, who is now a biopharmaceutical executive, and their student, Shane Trask, had hinted that it would be VP7. "This turns out to be hole punching of a particularly satisfying type." The work fulfills Harrison's career-long goal of seeing exactly how nonenveloped viruses infect cells, step by step, as a "molecular movie." The team achieved this using a relatively new technology called cryo-electron tomography, or cryo-ET. Discover the latest in science, tech, and space with over 100,000 subscribers who rely on Phys.org for daily insights. d research that matter—daily or weekly.
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