08:01am Wednesday 20 September 2017

Eyewitness to Infection

James Munro in his lab
“The goal of my work is really to bring these [virus] structures to life,” says James Munro. Photo: Kelvin Ma
By Jacqueline Mitchell
Composed of little more than a few strands of genetic material and some proteins, viruses are barely alive. Yet the tiny microorganisms are among humanity’s deadliest foes. Now, a Tufts microbiologist is using new imaging techniques to find out how they make us sick.

James Munro, who joined the School of Medicine faculty last fall, was part of a team that pioneered the use of fluorescent molecules that act as tiny beacons and allow researchers to watch in real time as an HIV virus prepares to infect a cell. What the team saw, in discerning distances as small as a billionth of an inch, could lead to new treatments or vaccines for infectious viral diseases such as HIV and Ebola.

Scientists already knew that certain viruses, including HIV, Ebola and influenza, use the proteins on their surfaces to infect host cells. The surface proteins function like skeleton keys: If they match the corresponding proteins on the host cell—think of them as the locks—the virus gains entry.

It’s by recognizing these viral proteins that your immune system remembers diseases you’ve been exposed to before. That’s why you won’t get the chicken pox or the same strain of the flu twice. Most vaccines—which teach the body to recognize and attack viruses—are designed based on the structure of these surface molecules.

But the surface proteins on HIV, which the World Health Organization says has killed 40 million people since the disease was identified in the early 1980s, have frustrated scientists for some 30 years. For one thing, the virus evolves too quickly for our immune systems or science to catch up—so far.

“They say that HIV makes every possible mutation every day,” says Munro, an assistant professor of molecular biology and microbiology at the Sackler School of Graduate Biomedical Sciences.

Beyond the virus’ continuous evolution, its surface protein is a remarkable shape-shifter, with the ability to change its three-dimensional structure in an origami-like process called molecular conformational dynamics, says Munro, who specializes in understanding how that happens. “The goal of my work is really to bring these structures to life,” he says.

High-powered scans of HIV reveal a spherical virus that looks like a pincushion. The virus uses the heads of those pins—the surface proteins—to glom onto and fuse with cells in the immune system called T cells.

In experiments reported in the journals Science and Nature in October 2014, Munro and his colleagues zoomed in on those protrusions, each made up of a long protein molecule covered in sugars, which is known as a glycoprotein. The team was led by Munro’s postdoctoral advisor, Walther Mothes of Yale University School of Medicine, as well as his former graduate advisor, Scott Blanchard at the Weill Cornell Medical College.

The researchers knew that the HIV surface protein underwent its origami act to match its intended target at the moment of infection. That allowed the glycoprotein key to open the T cells’ locks—a surface protein known as CD4—and gain entrance to the body. But they didn’t know what triggered the transformation.
A Virus Always in Motion

Conventional wisdom, says Munro, held that the protein transformed itself in response to something else in the environment—the presence of another molecule or cell, for example, or a change in temperature, salinity or pressure.

Using high-resolution cameras and high-powered computing, the team found that the HIV protein was, in fact, always in motion, cycling through different shapes, much like a person moving through a series of yoga poses.

This surprising result, which paints a far more detailed portrait of this enigmatic molecule, could one day produce a way to disable HIV and other viruses.

Here at Tufts, Munro is also studying how viruses assemble copies of themselves after they invade the host cell. He’s homing in on the virus’ genetic material, which is housed in another big, flexible molecule called RNA, the cousin to DNA. He’s also expanding his scope beyond HIV, applying the imaging techniques he used as part of the Yale team to spy on the Ebola and influenza viruses as they enter their host cells.

“That’s not as scary as it might sound,” says Munro. “You can study Ebola and flu safely in a normal laboratory by forming non-infectious particles called pseudo-viruses,” he says. These pseudo-viruses are made of the protein envelope of the virus in question, but contain none of its genetic material.

Munro says the surface glycoproteins of the Ebola and flu viruses are structurally similar to those of HIV and carry out the same function. Watching these proteins in action in the lab could give researchers more insight into all three deadly infections.

“There’s lots of expectation that these surface proteins are similar, but until recently, we’ve had no ability to image it.”

Jacqueline Mitchell can be reached at jacqueline.mitchell@tufts.edu.

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