with a microscope, the virus faintly resembles a pineapple—the
universal symbol of welcome. But HIV, the virus that causes AIDS, is
anything but that. It has claimed the lives of more than 35 million
people so far.
In a study led by the University of Delaware and the University of
Pittsburgh School of Medicine, researchers discovered a “brake” that
interferes with HIV’s development into an infectious agent. This
mechanism prevents the capsid—the protein shell covering the virus—from
The finding, which was published in Nature Communications, was made
by an interdisciplinary research team from UD, the University of
Pittsburgh School of Medicine, University of Illinois, National Cancer
Institute, DFH Pharma and Vanderbilt University Medical Center. The
results are based on seven years of excruciatingly detailed studies of
the structure and dynamics of HIV early and late in its life cycle. The
movements of the virus molecules were measured experimentally and
simulated in quadrillionths of a second—that’s much faster than the
blink of an eye or the flutter of a hummingbird’s wings.
“People used to be fixated on the static structures of viruses, but
they are not rock solid,” said Tatyana Polenova, professor in UD’s Department of Chemistry and Biochemistry.
She is an expert in nuclear magnetic resonance (NMR) spectroscopy,
which helps scientists identify and pinpoint the location of every atom
in a structure and how each atom moves.
“Viruses like HIV and their constituent protein and nucleic acid
molecules are dynamic entities that are constantly expanding and
shrinking,” she added. “Their motions are like breathing.”
Polenova said molecules in the HIV virus operate in concert, yet
within each molecule motions occur over many different time scales, a
difficult scenario to simulate, to be sure. But not too complex for Juan
Perilla, who joined the UD faculty as an assistant professor this past
June. A quantitative biophysicist, Perilla created the first structural
models of HIV as a postdoctoral scientist at the University of Illinois.
Today, at UD, he routinely uses some of the world’s largest
supercomputers to generate simulations of the HIV virus and its many
Stopping a virus from maturing
As the HIV virus develops, a cascade of events occurs, affecting its
structure and ability to infect. Think of the TV cooking show “Chopped.”
But in this case, protein building blocks get methodically “cleaved” or
cut from a larger, master protein called Gag.
By integrating state-of-the-art techniques, including solid-state and
solution NMR, high-end computer simulations, and cryo-electron
microscopy (for which the Nobel Prize was awarded earlier this fall) the
researchers answered a longstanding question about how the final step
in the maturation of the virus occurs—a process in which a noninfectious
immature virion turns into an infectious virus particle.
The team discovered that a key peptide—spacer peptide 1 (SP1)—has to
be in a highly mobile structure to be cut by the virus protease, the
enzyme that acts like a cleaver. In simulations, the peptide resembles a
thin, yarn-like strand attached to corkscrews of curled ribbons in
“This peptide is always there in the final maturation step, but we
were surprised that it is so disordered and dynamic,” Polenova said.
Once the SP1 peptide is cut, the HIV virus forms its protective
capsid and becomes infectious. But how do you stop that process? In team
experiments at the University of Pittsburgh led by Angela Gronenborn,
the anti-HIV inhibitor Bevirimat was shown to interact with the SPI
peptide, thus preventing the development of the virus’s capsid “coat.”
Zeroing in on potential drug targets to stop HIV from becoming
infectious by disrupting the virus’s maturation is an ongoing goal for
“We have to have a sense of these short-lived molecular fluctuations
and processes—of protein cleavage and capsid generation,” Perilla said.
“To add a new generation of capsid inhibitors to prevent HIV, you have
to have very specific times and rates at which these drugs will work.”
The UD discovery team included, from left, staff scientist
Caitlyn Quinn, professors Juan Perilla and Tatyana Polenova, and
doctoral student Mingzhang “Maple” Wang. Under the auspices of the
Pittsburgh Center for HIV Protein Interactions, they collaborated with
researchers from the University of Pittsburgh School of Medicine,
University of Illinois, National Cancer Institute, DFH Pharma and
Vanderbilt University Medical Center.
Perilla and Polenova also said an
extensive team of people is critical, including experimentalists and
computational scientists, who have expertise in multiple biophysical
techniques, such as NMR and cryo-EM, and across the disciplines of
structural biology, biophysics, biochemistry and virology.
“This work would be impossible without our combined strength—I tell
my students they need to learn to collaborate with people in other
fields,” said Polenova. Also critical, she said, is the availability of
cutting edge infrastructure in high-field NMR at the University of
Delaware and at ultra-high field NMR centers across the U.S., including
the National High Magnetic Field Laboratory, and internationally, such
as the National Center for Scientific Research in Lyon, France, where
Polenova and her students travel to perform NMR experiments.
She and Perilla both credit Angela Gronenborn, their collaborator at
the University of Pittsburgh, for transforming their work through the
Pittsburgh Center for HIV Protein Interactions, a national research
center that Gronenborn established about a decade ago with funding from
the National Institutes of Health.
“Science is moving away from the single scientist being able to peer
at things at atomic resolution,” Polenova said. “It’s no longer the
situation of doing one thing as a single investigator. Now, we all come
The research was funded by the National Institutes of Health.
In addition to Polenova and Perilla, other UD authors of the paper
included doctoral student Mingzhang “Maple” Wang, staff scientists
Caitlin Quinn and Guangjin Hou, and postdoctoral researchers Huilan
Zhang and Christopher Suiter—all from the UD Department of Chemistry and
Biochemistry. Authors from the University of Pittsburgh School of
Medicine included Angela Gronenborn, Randall Shirra, Jr., In-Ja Byeon
and Peijun Zhang. Eric O. Freed from the National Cancer Institute,
Theodore J. Nitz from DFH Pharma, and Klaus Schulten from the University
of Illinois also were co-authors.
Article by Tracey Bryant; photo by Evan Krape and Jeffrey Chase