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Immune Response to HIV in the Brain a “Double-Edged Sword”

Posted by pozlife on May 1, 2006

New Study Describes Molecular Basis of NeuroAIDS

LA JOLLA, CA, April 26, 2006—A team
of researchers at The Scripps Research Institute has shed new light on
the molecular basis of problems with brain function in models
chronically infected with an immune deficiency virus similar to human
immunodeficiency virus (HIV), the cause of acquired immune deficiency
syndrome (AIDS). The findings may ultimately lead to new therapeutic
interventions to prevent or reverse nervous system disorders in
HIV-infected individuals.

Using multi-disciplinary
analysis that included cognitive, neurophysiologic, virologic, and
molecular techniques, the team found both a low-level viral infection
in the brain and immune cells that had infiltrated the brain in order
to protect against the virus.

“As in the rest of
the body, in the brain immune cells achieve a level of control of the
virus, but are unable to clear the infection,” says Howard Fox,
associate professor at Scripps Research and director of Scripps
NeuroAIDS Preclinical Studies center, who led the study. “Over the
long-term, this immune response may act as a double-edged sword,
protecting against rampant viral replication in the brain but leading
to brain dysfunction.”

The paper was published in the April 26 issue of the Journal of Neuroscience, the official journal of the Society of Neuroscience.

The
study addresses a significant health problem. About one quarter to one
third of all AIDS patients suffer from some form of central nervous
system disorder in the course of their infection, ranging from minor
cognitive and motor disorders to severe dementia, collectively known as
neuroAIDS. Even subtle neurocognitive disorders limit quality of life
with symptoms such as fatigue, and are correlated with difficulties
ranging from a higher rate of traffic tickets to increased mortality.

In
recent years, access to potent antiretroviral drugs in the United
States and other developed countries has significantly improved the
health, survival, and functioning of HIV-infected individuals. But
since people are living longer with the virus, the overall prevalence
of neuroAIDS appears to be increasing.

“Now that
we’re better at treating the immune/viral aspect of HIV, in many ways
[AIDS] has turned into a chronic disease,” says Fox. “The fact that
many of the antiretroviral drugs do not show good penetration of the
blood-brain barrier further puts the brain at risk, since the brain is
infected soon after HIV exposure and infection.”

While
previous studies had linked end-stage dementia due to HIV to the
presence of infected and activated immune cells, the nature of
neurological changes in earlier stages of the disease, the so-called
“chronic phase,” were unknown—until now.

Using
simian immunodeficiency virus-infected models in the chronic phase, the
research team found both virus and infiltrating lymphocytes (CD8+ T
cells) in the brain. Molecular analysis revealed that the expression of
several immune response genes was increased, including CCL5, which has
multiple effects on neurons as well as immune cells. CCL5 was
significantly upregulated throughout the course of infection, and was
present in the infiltrating lymphocytes.

In addition to Fox, authors of the April 26, 2006 Journal of Neuroscience
(Volume 26, Number 17) paper, titled “Host Response and Dysfunction in
the CNS During Chronic SIV Infection,” are: Eleanor Roberts, Salvador
Huitron-Resendiz, Michael Taffe, Cecilia Marcondes, Claudia Flynn,
Caroline Lanigan, Jennifer Hammond, Steven Head, and Steven Henriksen.

The
recent research was supported by research grants from the National
Institute of Mental Health (NIMH) of the National Institutes of Health,
as well as an NIMH center grant, which provides support for
research-associated infrastructure and training.

Moving Research Forward

The
publication coincides with an $11.2 million award for a five-year
renewal of the center called Scripps NeuroAIDS Preclinical Studies
(a.k.a. SNAPS), which works with Scripps Research, local San Diego,
national, and international investigators to understand, treat, and
prevent neurological complications of HIV infection.

“The
renewal of the center’s grant will bring exciting new changes in the
approaches and techniques used to further the mission of the NIMH and
Scripps investigators,” says Fox. “This work is an example of how the
center is moving research forward.”

The multi-disciplinary center is built around a number of core facilities.

 • The Physiology Core, directed by Scripps Research Associate Professor Donna Gruol, provides in vivo, ex vivo, and in vitro studies essential to understanding how infection affects the central nervous system.


The Phenomics Core, led by Gary Siuzdak, senior director of Scripps
Research’s Mass Spectroscopy facility, with the assistance of Steve
Head, director of Scripps Research’s DNA Microarray Facility, combines
genomics, proteomics, and metabolomics.


The Chemical Library Screening Core, led by Scripps Research Professor
John Elder, is being instituted to provide the relevant biochemical and
cell-based screening for preclinical therapeutics. The core uses
chemical libraries provided by several members of the Scripps Research
Department of Chemistry.

• A Systems Biology
Core, led by Trey Ideker of the Bioengineering Department at the
University of California, San Diego, is also being launched. This core
enables the development of integrative models of HIV infection,
particularly in macrophages and brain tissue, by combining expression
data, transcription factor location data, protein-protein interaction
data, and metabolomic data, helping scientists to study multiple
aspects of the system as a single entity.

To
support the existing neuroAIDS research at Scripps Research and to
encourage other scientists to become interested in the area, the SNAPS
center holds monthly meetings focusing on recent research on neuroAIDS
and its basic scientific underpinnings.

For more information on the center, see the SNAPS’ web site at http://www.scripps.edu/services/snaps/

About The Scripps Research Institute

The
Scripps Research Institute, headquartered in La Jolla, California, in
18 buildings on 40 acres overlooking the Pacific Ocean, is one of the
world’s largest independent, non-profit biomedical research
organizations. It stands at the forefront of basic biomedical science
that seeks to comprehend the most fundamental processes of life.
Scripps Research is internationally recognized for its research into
immunology, molecular and cellular biology, chemistry, neurosciences,
autoimmune, cardiovascular, and infectious diseases, and synthetic
vaccine development. Established in its current configuration in 1961,
it employs approximately 3,000 scientists, postdoctoral fellows,
scientific and other technicians, doctoral degree graduate students,
and administrative and technical support personnel.

Scripps
Florida, a 364,000 square-foot, state-of-the-art biomedical research
facility, will be built in Palm Beach County. The facility will focus
on basic biomedical science, drug discovery, and technology
development. Palm Beach County and the State of Florida have provided
start-up economic packages for development, building, staffing, and
equipping the campus. Scripps Florida now operates with approximately
160 scientists, technicians, and administrative staff at 40,000
square-foot lab facilities on the Florida Atlantic University campus in
Jupiter.

 


For more information contact:
Keith McKeown
10550 North Torrey Pines Road
La Jolla, California 92037

Tel: 858.784.8134
Fax: 858.784.8118
kmckeown@scripps.edu

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