Harvard Team Reveals How Rotavirus Punches Through Cell Membranes

Viruses fall into two categories: those wrapped in a membrane, like herpesvirus, influenza, HIV, and SARS-CoV-2, and those without one, like poliovirus, HPV, rotavirus, and adenovirus.

Scientists have long understood more about how enveloped viruses cross the cell membrane to cause infection than about how non-enveloped viruses manage the same feat. Harvard Medical School structural biologist Stephen Harrison has spent decades narrowing that gap, and his lab has now resolved one of the remaining unknowns for non-enveloped viruses that deliver their genomes inside a protein shell.

Their latest study, led by first author Marilina de Sautu, was published in Science. Using a rotavirus strain, the team built on earlier work showing how rotaviruses attach to the cell membrane and get pulled into a membrane-bound compartment inside the cell. What remained unclear was how the virus then breaches that membrane to release its DNA or RNA.

De Sautu and colleagues found that viral protein 5 (VP5) makes the membrane permeable to calcium, and the resulting loss of calcium ions causes viral protein 7 (VP7) to detach from the virus particle and form a pore. Harrison noted the outcome ran counter to his expectations: “All along I had thought it would be VP5 that punched the hole, but it’s VP7,” he said, adding that earlier hints had pointed toward VP7. “This turns out to be hole punching of a particularly satisfying type.”

The discovery relied on cryo-electron tomography, a technique that flash-freezes biological samples and captures multi-angle snapshots for 3D reconstruction, letting the team assemble a step-by-step “molecular movie” of infection.

Beyond basic virology, Harrison said the findings speak to “the general question of what are the mechanisms for delivering large cargo into cells,” with potential relevance to biotech efforts to deliver gene therapies. Researchers next plan to examine whether similar mechanisms apply to other non-enveloped viruses, including adeno-associated viruses used in gene therapy.