Viewed
with a microscope, the virus faintly resembles a pineapplethe
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 HIVs development into an infectious agent. This
mechanism prevents the capsidthe protein shell covering the virusfrom
forming.
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 secondthats much faster than the
blink of an eye or the flutter of a hummingbirds wings.
People used to be fixated on the static structures of viruses, but
they are not rock solid, said Tatyana Polenova, professor in UDs 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 worlds largest
supercomputers to generate simulations of the HIV virus and its many
moving parts.
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 occursa process in which a noninfectious
immature virion turns into an infectious virus particle.
The team discovered that a key peptidespacer 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
constant motion.
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 viruss capsid coat.
Zeroing in on potential drug targets to stop HIV from becoming
infectious by disrupting the viruss maturation is an ongoing goal for
the team.
We have to have a sense of these short-lived molecular fluctuations
and processesof 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.
