SAN FRANCISCO, Aug. 17, 2021 /PRNewswire/ -- Over the last
40 years, HIV has shifted from a deadly and mysterious virus to one
that can be controlled with daily drugs. But attempts to completely
eliminate the virus from the bodies of people living with HIV,
curing them for good, have failed.
Now, with a $26.5-million grant
from the National Institutes of Health (NIH), a multi-disciplinary
group of researchers from institutions around the world is trying a
completely new strategy for curing HIV. The group, known as the HIV
Obstruction by Programmed Epigenetics (HOPE) Collaboratory, will be
led by researchers at Gladstone Institutes, Scripps Research
Florida, and Weill Cornell Medicine. Their approach, which aims to
both silence and permanently remove HIV from the body, takes
advantage of knowledge about how other viruses have become
naturally inactivated over time.
"This is a fundamentally different approach to targeting HIV
than what everyone else has been trying," says Melanie Ott, MD, PhD, director of the Gladstone
Institute of Virology, and the program director and a principal
investigator of the HOPE Collaboratory. "I think it's extremely
important for us to explore a broad range of scientific approaches
to find the best cure for people living with HIV, as quickly as we
can."
The HOPE Collaboratory is one of 10 groups awarded a 5-year
grant under the Martin Delaney Collaboratories program, the
flagship program on HIV cure research at the NIH.
Targeting Latent HIV in Novel Ways
HIV is notorious for its ability to hide in a latent state in
immune cells; while latent viruses don't cause overt symptoms or
full-blown AIDS, they can lead to long-term health complications
for those living with HIV and can't be targeted with standard
antiretroviral therapy. Moreover, a lapse in this daily therapy can
lead to a rapid rebound of the infection.
Most attempts at curing HIV have centered around purposefully
reactivating the latent virus in order to flush it out in the
presence of antiretroviral therapy—an approach called "shock and
kill." But researchers have struggled to reactivate every copy of
the virus in the body, or at least, to do so without severe
undesirable side effects. And even a small remaining reservoir of
latent virus means that someone living with HIV must remain on
daily treatments.
The researchers involved in the HOPE Collaboratory are calling
their new, alternative tactic "block-lock-excise," and it targets
latent HIV in new ways, without reactivating it.
The inspiration for the "block and lock" part of their strategy
comes from ancient viruses that have integrated themselves into the
human genome over millions of years of evolution. HIV also
integrates into the genome of a person living with HIV. However,
unlike HIV, the ancient viruses remain in a silenced state or are
defective.
Researchers have found that these ancient inactive viruses are
missing several genetic elements that HIV contains. Two particular
elements—a sequence of DNA at the start of HIV's genetic code and a
protein called Tat—are needed for latent HIV to reactivate and
begin replicating.
"We have shown that blocking Tat with certain drug-like small
molecules can lock HIV in its dormant stage, and this block stays
in place for some time, even if antiretroviral therapy is
interrupted," says Susana Valente,
PhD, one of the principal investigators of the HOPE Collaboratory
and associate professor of immunology and microbiology at Scripps
Research in Florida. "With the
'block and lock' approach, we basically want to push HIV into
becoming like a harmless, ancient virus."
Using drugs to block the elements needed for the virus to
reactivate could shift HIV from a transient latent state to a
robustly silenced one. The drugs would not only impede the Tat
protein, but also alter the three-dimensional structure of the HIV
genetic material, making it harder for other proteins to access the
HIV genes and turn them on. This dual strategy, the HOPE team
thinks, could lock HIV into a silent state for good, without
continuous treatment.
"The idea is not only to lock HIV so it cannot replicate, but
essentially to throw away the key, keeping it locked away forever,
unable to do any more harm to the host or to others," Valente
says.
"If cells infected with latent HIV could be solidly silenced, we
could take patients off their entire antiretroviral therapy
regimens and the virus would not reappear," says Ott.
Genome Editing Opens New Doors
The "excise" component of the HOPE Collaboratory's approach
takes advantage of recent advances in genome editing. The
development of the CRISPR/Cas9 genome-editing technology has given
researchers inroads into altering the DNA of human cells. This
means that the latent HIV inserted in the DNA of immune cells could
be edited.
The collaboratory plans to test the utility of a number of
gene-editing approaches in changing the DNA of latent HIV to such
an extent that the virus would be destroyed. This step, they say,
could follow the "block and lock" treatment that silences the
virus, or could be an alternative path depending on the
effectiveness and cost of each approach.
"We have not yet been able to achieve a cure for HIV because the
virus finds a way to hide out in reservoirs of cells in the body,"
says Lishomwa Ndhlovu, MD, PhD, a principal investigator of the
HOPE Collaboratory and a professor of immunology in medicine in the
Division of Infectious Diseases at Weill Cornell Medicine. "The
HOPE grant will allow us to test whether a 'block-lock-and-excise'
approach can achieve long-term silencing of HIV in all relevant
tissue sanctuaries so it cannot be released from cells. Coupled
with permanent removal of any remnants of the silenced virus, we
hope this will prevent the rebound of HIV when antiviral drugs are
stopped, and lead to a cure."
A Collaborative Approach
The collaboratory includes members from 12 institutions around
the world, and will also work with three pharmaceutical companies
with insight into the development of potential therapeutics from
the drugs studied in the labs. In addition, clinical groups will
help provide data and samples from people living with HIV in
Africa and Brazil.
With community partner San Francisco AIDS Foundation, the HOPE
team will also involve people living with HIV in their research
agenda. Discussion panels will bridge researchers and the community
to help ensure that any HIV therapeutics are welcomed—and
understood—by people living with HIV.
"It's absolutely key that this is a multi-institutional and
multidisciplinary approach," says Gladstone's Danielle Lyons, PhD, program manager for the
HOPE Collaboratory. "Bringing together this diverse group of people
with expertise across various disciplines is what will really drive
the discovery of a cure for HIV."
Individually, the principal investigators of the HOPE
Collaboratory have already been working on HIV latency,
retroviruses, and Tat inhibitors for many years, so they're ready
to hit the ground running as a team, they say.
Over the first 2 years of the 5-year grant, they plan to
complete feasibility studies and further investigate a handful of
potential drugs. The collaboratory nature of the grant means that,
once those initial studies are complete, the group can re-evaluate
and, if needed, shift their approach.
"We cannot be satisfied with the status quo, which is lifelong
therapy for people living with HIV," says Ott. "We need to continue
pushing for a cure—and that's exactly what we intend to do through
the HOPE Collaboratory."
About the HOPE Collaboratory
The executive committee for the HOPE Collaboratory is led by
Program Director Melanie Ott from
Gladstone Institutes, and includes Principal Investigators
Susana Valente from Scripps Research
and Lishomwa Ndhlovu from Weill Cornell Medicine, as well as
Co-Investigator Douglas Nixon from
Weill Cornell Medicine. Operations will be overseen by Danielle Lyons from Gladstone, the
collaboratory's program manager.
The Hope Collaboratory also includes three co-directors for
different research programs (Warner
Greene and Nadia Roan from
Gladstone, and Priti Kumar from
Yale School of Medicine), a community
engagement coordinator (Patricia
Defechereux from Gladstone), 10 members (Cedric Feschotte
from Cornell University; Joachim Hauber from Heinrich Pette Institute,
Leibniz Institute for Experimental Virology in Germany; Julie
Ake and Denise Hsu from the
US Military HIV Research Program; Esper
Kallas from the University of Sao
Paulo in Brazil;
Niren Murthy from UC Berkeley;
Eric Verdin from Buck Institute for
Research on Aging; Betty Mwesigwa
and Hannah Kibuuka from the Makerere
University Walter Reed Project in Uganda; and Pauline
Sameshima from Lakehead
University), and four consultants (Jennifer Doudna from UC Berkeley, Gladstone, and
the Innovative Genomics Institute; Peter
Glazer from Yale School of
Medicine; Avi Nath from the
National Institute of Neurological Disorders and Stroke; and
Mauricio Martins from Scripps
Research).
In addition, the HOPE Collaboratory will work in partnership
with the Last Gift Study led by Sara
Gianella and Davey Smith at
UC San Diego and the African Cohort Study (AFRICOS) led by
Julie Ake at the US Military HIV
Research Program, as well as with the San Francisco AIDS Foundation
and industry partners Amgen, Constellation Pharmaceuticals, and
Sangamo Therapeutics.
The HOPE Collaboratory is supported by the National Institute of
Allergy and Infectious Diseases of the National Institutes of
Health under award number UM1AI164559.
About Gladstone Institutes
To ensure our work does the greatest good, Gladstone Institutes
focuses on conditions with profound medical, economic, and social
impact—unsolved diseases. Gladstone is an independent, nonprofit
life science research organization that uses visionary science and
technology to overcome disease. It has an academic affiliation with
the University of California, San
Francisco.
About Scripps Research
Scripps Research is an independent, nonprofit biomedical
institute ranked the most influential in the world for its impact
on innovation by Nature Index. With campuses in La Jolla, California, and Jupiter, Florida, we are advancing human
health through profound discoveries that address pressing medical
concerns around the globe. Our drug discovery and development
division, Calibr, works hand-in-hand with scientists across
disciplines to bring new medicines to patients as quickly and
efficiently as possible, while teams at Scripps Research
Translational Institute harness genomics, digital medicine and
cutting-edge informatics to understand individual health and render
more effective healthcare. Scripps Research also trains the next
generation of leading scientists at our Skaggs Graduate School,
consistently named among the top 10 US programs for chemistry and
biological sciences. Learn more at www.scripps.edu.
About Weill Cornell Medicine
Weill Cornell Medicine is
committed to excellence in patient care, scientific discovery and
the education of future physicians in New
York City and around the world. The doctors and scientists
of Weill Cornell Medicine—faculty from Weill Cornell Medical
College, Weill Cornell Graduate School of Medical Sciences, and
Weill Cornell Physician Organization—are engaged in world-class
clinical care and cutting-edge research that connect patients to
the latest treatment innovations and prevention strategies. Located
in the heart of the Upper East Side's scientific corridor, Weill
Cornell Medicine's powerful network of collaborators extends to its
parent university Cornell University;
to Qatar, where Weill Cornell
Medicine-Qatar offers a Cornell
University medical degree; and to programs in Tanzania, Haiti, Brazil, Austria and Turkey. Weill Cornell
Medicine faculty provide exemplary patient care at New
York-Presbyterian/Weill Cornell Medical Center, New
York-Presbyterian Westchester Behavioral Health Center, New
York-Presbyterian Lower Manhattan Hospital, New York-Presbyterian
Queens and New York-Presbyterian Brooklyn Methodist Hospital. Weill
Cornell Medicine is also affiliated
with Houston Methodist. For more information, visit
weill.cornell.edu.
Media Contacts
Gladstone Institutes: Julie
Langelier | julie.langelier@gladstone.org | 415.734.5000
Scripps Research: press@scripps.edu |
561.228.2551
Weill Cornell Medicine:
Krystle Lopez |
krl2003@med.cornell.edu | 646.962.9516
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SOURCE Gladstone Institutes; Scripps Research; Weill Cornell
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