A family of proteins could thwart emerging and re-emerging viruses

A family of proteins better known for their role in decreasing HIV infectivity could have the benefits of outwitting other emerging and re-emerging viruses, the scientists found.

The key to their newly discovered power: enhancing the signals sent to immune cells to unleash one of the innate antiviral response’s strongest fighters, proteins called type I interferons.

Experiments in cell cultures have shown that the cell signaling activities of these proteins, of the SERINC family, help protect cells from infection by the HIV, Ebola and Zika viruses. Researchers are currently testing whether this function is also effective against SARS-CoV-2, the virus that causes COVID-19.

It is one thing for a protein to act directly against a specific virus, as SERINC5 has been shown to incorporate into the HIV particle during viral production. But it’s another thing to reveal that a protein has an enhancing effect on an essential antiviral cell signaling pathway during host cell infection, said study lead author Shan-Lu Liu. , professor of virology in the Department of Veterinary Biosciences at Ohio State University. .

Viruses can bypass direct antiviral effects. But if this protein can also modulate key pathways without acting directly on the virus, then a virus may have limited ability to counter it. If this family of molecules can do it in animals and humans, then you may wonder if it could be used in broad antiviral therapy. “

Shan-Lu Liu, Researcher and Associate Director, Ohio State’s Center for Retrovirus Research

The research is published today (September 14, 2021) in the journal Scientific signage.

Liu has spent years studying what he calls the “evolutionary arms race” between HIV and the human immune system, and led a study in 2019 that described how an HIV protein called Nef can gain the upper hand in it. combat – in particular by interfering with SERINC proteins. in virus-producing cells.

In this study, Liu and his colleagues took a closer look at the functions of SERINC5 in target cells during the next stage of viral infection. They found that in addition to stimulating the signals that produce type I interferons, SERINC5 has the same effect on signals that generate another component of the early antiviral response – the inflammatory cytokines NF-kB.

SERINC5 does not modulate this signaling system on its own – it associates with other proteins called MAVS and TRAF6. But some of his exact behaviors remain a mystery, Liu said.

In cell cultures in which a viral infection had been initiated, the researchers observed that SERINC5 moves from the cell surface just outside the membrane around the mitochondria, the feeding center of a cell – an unusual movement . Once there, SERINC5 teamed up with MAVS and TRAF6 to form a large, multi-faceted complex – a likely explanation for why its role is so influential in what happens next in the signaling pathway.

“The aggregation of these proteins means they need each other – and it’s an exciting discovery,” said Liu, also co-director of the Emerging Viruses and Pathogens program at the Institute of Infectious Diseases of the United States of America. Ohio State. “A large complex like this can recruit additional molecules, thus improving the efficiency of the signal transduction pathway.”

These recruited molecules are part of a cascade of messages that lead to the production of type I interferon and NF-kB inflammatory cytokines from cells infected with the virus, both of which play a crucial role in limiting the disease. early-stage viral infection. In experiments using several types of human and animal cell cultures, this mechanism has been shown to inhibit infection of cells with HIV, Ebola and Zika viruses.

On the other hand, when the cells were modified not to produce the SERINC5 protein, these viruses took control of the cells and replicated more, which suggests how important the role of SERINC is in the process that potentiates the response. primary antiviral of host cells.

This work was carried out on two members of the SERINC family, SERINC3 and SERINC5, but Liu hypothesized that other versions might have similar effects. But there is still a lot to be learned, such as what causes SERINC5 to move from the cell surface to the mitochondria, and what its normal cellular functions are in the absence of viruses.

As to whether the functions of the protein can suppress the COVID-19 virus, Liu is optimistic.

“My speculation is that the SERINC protein would have an effect because we know that type I interferons are so important for controlling an early stage virus, and this molecule may enhance the response of type I interferon,” said he declared. “Find a protein that can modulate a key pathway that has broad antiviral effect – well, you can imagine that protein has broad antiviral function.”