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April 6, 2018
QUEASY QUASISPECIES
Encapsulated Viruses Are More Infectious Than Single Ones

Once thought to infect cells as a single discrete unit, viruses such as poliovirus, rotavirus and norovirus have now been found to be more infectious when they are wrapped up together in capsules called vesicles than as a single virus, said Dr. Nihal Altan-Bonnet at a Director’s Seminar Series in Bldg. 1’s Wilson Hall on Feb. 23.

Viruses were thought to enter cells, replicate and exit as single particles that would then go on to infect other cells.

Dr. Nihal Altan-Bonnet lectures at a recent Director’s Seminar Series in Wilson Hall.
Dr. Nihal Altan-Bonnet lectures at a recent Director’s Seminar Series in Wilson Hall.

“This is how pretty much everybody—including myself—was thinking of viral transmission,” explained Altan-Bonnet, senior investigator and head of the Laboratory of Host-Pathogen Dynamics in NHLBI’s Cell Biology and Physiology Center.

Thanks to advances in imaging and spectroscopic technologies, this view is beginning to change as scientists can now observe how viruses transmit themselves between cells.

Another advance in our understanding of viral transmission has come from new genetic sequencing methods that have revealed that most viruses don’t always copy themselves when they infect a cell—something that’s “particularly true for RNA viruses,” Altan-Bonnet noted.

This type of virus has its genetic code on strands of RNA. These viruses inject their genetic material into the host cell to replicate themselves.

Whereas previously everyone thought that the progeny viral genomes would be exact copies of the parental viral genome, new sequencing methods have revealed that there is a high level of genetic variation among the replicated RNA genomes.

As a consequence of this finding, these viral progeny genomes are now called “quasispecies.”

“Having mutations can have profound effects on the next life cycle for each one of these viral progeny,” she said, as some mutations can affect a virus’s ability to function by preventing replication.

Altan-Bonnet was curious to know what happened to these viruses as some of them, even with mutations, were still able to transmit infection, go on to another cell and evade detection by the immune system. So she began imaging cells infected with an RNA virus—poliovirus. A few hours after infection, Altan-Bonnet noticed vesicles containing clusters of polioviruses forming on the cell’s surface and budding off.

Before she began her experiments, Altan-Bonnet thought the free poliovirus particles would replicate more efficiently than the same number of poliovirus particles encased in a vesicle. She reasoned that since the particles were independent of one another, they would have opportunity to sample more physical space and infect many more cells.

That was not the case, however. The free poliovirus- infected cell cultures did not yield more virus than the cell cultures infected with vesicles.

NIH deputy director for intramural research Dr. Michael Gottesman chats with Altan-Bonnet.
NIH deputy director for intramural research Dr. Michael Gottesman chats with Altan-Bonnet.

PHOTOS: ANDREW PROPP

She thinks this is because when one or two viruses infect a cell, replication is not that efficient: it takes time for an RNA virus to replicate, and if a virus has a mutation that affects its ability to replicate, the process stops. All the while, the host cell’s defenses are trying to stop the virus from replicating.

“A single viral genome, entering a cell, is going to be up against a lot until it gets enough viral proteins made and viral genome replicated to take over the entire cell,” she said.

However, when multiple viruses in a vesicle infect a cell, they’re “going in with, essentially, an army.” Furthermore, she thinks that different quasispecies carried by the vesicle might work with each other to compensate for each other’s weaknesses (i.e. mutations) to become more infectious.

Remarkably, she has found that these vesicles also can transmit infection among organisms. She added that rotavirus, a contagious virus that causes gastroenteritis, and norovirus, an infection that causes sudden vomiting and diarrhea, are traveling as gangs inside vesicles. These vesicles are remarkably stable and stay intact as they pass through the mammalian digestive system.

Altan-Bonnet thinks that the benefits of vesicular transmission, such as generating a high multiplicity of infection, enabling cooperative interactions among quasispecies and suppression of immune responses, are likely exploited by many other viruses including SARS and HIV through other strategies that cluster viruses together so they enter cells in armies.

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