- Current HIV treatment targets viral
enzymes but this has been plagued by drug resistance
- New capsid inhibitors that target
viral protein shell (capsid) could be potential therapeutic option, while
overcoming the issue of drug resistance as well
- HIV/AIDS has so far claimed nearly
35 million lives worldwide.
Novel "braking agent"
the development of the viral protein coat
which is normally responsible for HIV infectivity
been discovered by a group of scientists at the University of Delaware and the
University of Pittsburgh School of Medicine
The findings of their work appear
in Nature Communications
in November 2017 and included an
interdisciplinary research team from University of Delaware, the University of
Pittsburgh School of Medicine, University of Illinois, National Cancer
Institute, DFH Pharma and Vanderbilt University Medical Center.
Need of the Hour - Safe And Effective Antiretroviral Agents
For almost a decade from the mid-1990's to the mid 2000's, antiretroviral
therapy (ART) has targeted viral enzymes
. Although effective, resistance is emerging
to these forms
of treatment, especially with long term treatment. This has necessitated the
search for newer and more effective treatment options. A major candidate for newer treatment target is the viral coat or capsid
an option that has not been explored until recently.
Looking at the Viral Dynamics to Identify Potential Treatment Target
In the quest for newer capsid inhibitor
agents, the current team focused in
great depth on studying the constantly changing viral dynamics
early and late life cycle.
‘Newer anti-capsid agents such as Bevirimat could emerge as potential effective treatment options for AIDS overcoming the problem of drug resistance’
The motion of the virus molecules was
estimated experimentally and simulated to about quadrillionths of a second-i.e.
much faster than the flutter of a hummingbird's wings or blink of an eye.
"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.
Although extremely challenging, Juan Perilla,
who joined the UD faculty
as an assistant professor this past June as a quantitative biophysicist,
had created the earliest structural
models of HIV as a postdoctoral scientist at the University of Illinois.
Currently, at the University of Delaware, he regularly employs some of the world's largest supercomputers to create simulations of the various viral
moving parts and study viral dynamics in the laboratory.
"Viruses like HIV
and their constituent protein and nucleic acid molecules are dynamic entities
that are constantly expanding and shrinking," Polenova added. "Their
motions are like breathing."
For Answers to a Long Unanswered Question
Using state of the art techniques,
including solid-state and solution
nuclear magnetic resonance (NMR) spectroscopy, high-end computer simulations,
and cryo-electron microscopy
(for which the
Nobel Prize was awarded earlier this year) the research team analyzed the
intricate protein structure of the virus during the various stages of its
This enabled them to get the answer to a
long standing question namely how what
happened in the final maturation stage of the virus where the immature non-infectious
virion matured into a mature infectious viral particle
Structure of the Viral Capsid - What Changes Occur During Maturation
It is known that the HIV-1 Gag precursor protein is the master protein
from which the protein blocks are separated off. The Gag
precursor protein is structurally
divided into four major domains
: the N-terminal matrix (MA), the capsid
(CA), the nucleocapsid (NC), and the C-terminal p6. Two spacer peptides are
located between CA and NC (SP1) and between NC and p6 (SP2).
The findings of the team with regards to
the protein structure alterations that
take place during viral development
were as follows
- The spacer peptide 1 (SP1), a key
peptide has to be in a highly mobile structure to be cleaved by the virus
protease, the enzyme that acts like a pair of scissors.
- In simulations, the peptide appears
like a thin, thread like strand attached to corkscrews of curled ribbons
that move constantly
- As soon as the SP1 peptide is
cleaved, the HIV virus matures forming its protective shell and becomes
transformed into an infectious particle.
"This peptide is always there in the
final maturation step, but we were surprised that it is so disordered and
dynamic," Polenova said.
Stopping this Final Step of Viral Maturation - Finding Newer Capsid Inhibitors
Seeking to prevent this final step in the
virus life cycle that rendered it infectious, experiments at the University of
Pittsburgh led by Angela Gronenborn, found the anti-HIV inhibitor Bevirimat interacted with the SPI peptide
thereby disrupting the development of the viral capsid "coat."
"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."
Preclinical drugs like Bevirimat (BVM)
target the SP domain to inhibit the SP-NC cleavage and further research to elucidate the
complex processes are needed. The outcome of future research in this direction
may have major implications in the quest for new therapeutic strategies and
novel drug targets for AIDS.
Importance of Interdisciplinary Collaboration and Teamwork
Perilla and Polenova acknowledge the
importance of interdisciplinary teamwork involving individuals with expertise
in techniques such as NMR and cryo-EM, and across the disciplines of virology,
structural biology, biophysics, and biochemistry has been a key factor in the
"This work would be impossible
without our combined strength--I tell my students they need to learn to
collaborate with people in other fields. 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 together."
- HIV-1 Capsid as a Target for Antiviral Therapy - (https://www.omicsonline.org/open-access/hiv1-capsid-as-a-target-for-antiviral-therapy-2155-6113-1000536.php?aid=66954)
- Molecular Mechanisms of Retrovirus Infection - (http://www.ks.uiuc.edu/Research/HIV/)
- Solid-state nuclear magnetic resonance - (https://en.wikipedia.org/wiki/Solid-state_nuclear_magnetic_resonance#Applications)