HIV and Dementia: Proceedings of the NIMH-Sponsored Conference “Pathogenesis of HIV Infection of the Brain: Impact on Function and Behavior”

284 Pages·1995·7.219 MB·English

by  R. T. Johnson (auth.), Michael B. A. Oldstone, Ljubiša Vitković (eds.)

Current Topics in
202 Microbiology
and Immunology
Editors
A. Capron, Lille . R.W. Compans, Atlanta/Georgia
M. Cooper, Birmingham/Alabama· H. Koprowski,
Philadelphia· I. McConnell. Edinburgh· F. Melchers, Basel
M. Oldstone, La Jolla/California· S. Olsnes, Oslo
M. Potter, Bethesda/Maryland· H. Saedler, Cologne
P.K. Vogt, La Jolla/California· H. Wagner, Munich
I. Wilson, La Jolla/California
Springer
Berlin
Heidelberg
New York
Barcelona
Budapest
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London
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Tokyo
H IV and Dementia
Proceedings of the NIMH
Sponsored Conference
IIPathogenesis of HIV Infection
of the Brain: Impact on Function
and Behavior
ll
Edited by M.B.A. Oldstone and L. Vitkovic
With 40 Figures
t
Springer
MICHAEL B.A. OLDSTONE
Department of Neuropharmacology
Division of Virology
The Scripps Research Institute
10666 North Torrey Pines Road
La Jolla, CA 92037, USA
LJUBISA VITKOVIC
Chief, Neuroimmunology/Neurovirology Program
Molecular and Cellular Neuroscience Research Branch
Division of Neuroscience and Behavioral Science
National Institutes of Health, National Institute of Mental Health
5600 Fishers Lane, Rm 11 C-06
Rockville, MD 20857, USA
Cover illustration: Cover depicts a prototypic immunodeficiency
virus and its "host range": humans, monkeys, and cats. Human
immunodeficiency virus (HIV) causes acquired immune
deficiency syndrome (AIDS), a disease ultimately resulting in
the death of a host, whereas simian (SIV) and feline (FIV) viruses
cause a mild, if any, disease. However, scientists have
discovered that some isolates of SIV and FIV can cause a
disease in monkeys and cats, respectively, that recapitulate
aspects of AIDS. These animal models of AIDS are yielding
important information on potential therapies of the human
disease. Courtesy of M.B. Gardner.
Cover design: Kunkel+Lopka, IIvesheim
ISSN 0070-217X
ISBN-13: 978-3-642-79659-3 e-ISBN-13: 978-3-642-79657-9
001: 10.1007/978-3-642-79657-9
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© Springer-Verlag.Berlin Heidelberg 1995
Softcover reprint of the hardcover 1st edition 1995
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Foreword
The National Institute of Mental Health (NIMH) AIDS Program is
the fourth largest acquired immune deficiency syndrome (AIDS)
program within the National Institutes of Health (NIH). Since
1983, our program's contributions have concentrated on two
major areas. The first has been to develop effective strategies
to prevent or reduce behaviors that place individuals at risk for
human immunodeficiency virus type 1 (HIV-1) infection. The
second has been to support and foster research to enhance our
understanding of the profound impact of H IV-1 infection on the
central nervous system (eNS). The brain appears to be a prime
target of the virus and may serve as a reservoir for the virus. Post
mortem examination of brain tissue has provided evidence of
eNS cell damage in 80%-90% of people who die with AIDS. For
about 10%-20% of people with AI DS, mild neuropsychological
symptoms are the first signs of the disease. Approximately
20% of individuals infected with HIV-1 develop AIDS dementia
complex. The symptoms include apathy, difficulty concentrat
ing, irritability, depression, and personality changes. In the later
stages of the disease, people may experience psychiatric disor
ders. Death usually occurs within 6 months of the appearance of
those more severe symptoms. Up to 90% of children infected
with H IV-1 experience attention and concentration difficulties and
often experience neurodevelopmental delay or regression over
time.
Investigators supported by NIMH have provided evidence
that HIV-1 reaches the eNS within days of penetrating the body,
and that there are high levels of H IV-1 expression and replication
in the cerebral spinal fluid throughout the time course of the
disease. Investigations comparing infected brain tissue from
adults and fetuses have found that the developing eNS clears
the virus more rapidly than the adult eNS; however, the mecha
nism by which this occurs remains unknown. The exact mecha
nism(s) by which H IV-1 crosses the blood-brain barrier and
ultimately produces eNS dysfunction remain unknown. It is
essential that the mode of entry and the direct as well as indirect
VI Foreword
mechanisms leading to the CNS damage are identified so that
the infection of the CNS can be prevented and/or the conse
quences of the infection be therapeutically ameliorated.
The objectives of the conference Pathogenesis of HIV
Infection of the Brain: Impact on Function and Behavior were to
examine current knowledge, to attract more neuroscientists to
AIDS research, and to generate new ideas and collaborations.
To further these objectives, the organizers asked the plenary
speakers to contribute papers to these proceedings. The papers
in this volume address the central questions in the neuro
science of AIDS and are likely to lead to research that will
discover ways to treat HIV/CNS disease.
Acknowledgements. These proceedings and the conference 'Pathogenesis
of HIV infection of the brain: impact on function and behavior', held from April 4-7,
1994 in Chantilly, VA, USA, could not have been successfully completed without
the diligent contributions from many individuals. Special thanks are due to the
editors of these proceedings who with the participation of Walter Goldschmidts,
Ph.D., organized the scientific program of the conference.
The organizers are extremely indebted to Ms. Sherry Roberts and Ms. Susan
Kennell, Office on AIDS, National Institute of Mental Health, National Institutes of
Health, USA, for their scrupulous attention to organizational details before and
after the meeting, respectively. Special thanks are due to Ms. Debra Woods,
Division of Neuroscience and Behavioral Science, National Institute of Mental
Health, National Institutes of Health, USA, for coordinating voluminous corres
pondence with the invited participants in the conference and contributors to this
volume.
Rockville E. STOVER
Director, Office on AIDS, NIMH, NIH
S.H. KOSLOW
Director, Division of Neuroscience
and Behavioral Science, NIMH, NIH
Preface
Almost 13 million people worldwide have been infected by
HIV-1, and nearly 6 million of these individuals have disorders of
the nervous system caused by the virus. The nervous system
illness ranges from the AIDS dementia complex, in which the
clinical disease is excessive for the observed end stage
neuropathologic changes and occurs often in the absence of a
perivascular infiltration, to the occurrence of peripheral
neuropathology, presenting a Guillian-Barre state-like picture
that is frequently associated with perivascular cuffing and
inflammation.
A current challenge is to understand how such disparate
neuropsychiatric disorders occur, with the hope of obtaining
rational therapies. In addition, it is clear that by preventing HIV
infection or amplification, the nervous system disorders can be
modulated. Hence, those interested in dementia need to be
interested in the host's immune response to combat the virus
and in the virus' countermove to cause immunosuppression.
Understanding the mechanism(s) by which the virus causes or
is associated with dementia may shed light on the mecha
nism(s) underlying dementia in general.
For the above reasons, a conference was sponsored by the
National Institute of Mental Health, NIH. The agenda was to
bring together three groups of scientists that often do not meet
jointly. One group, as represented by Drs. Richard Johnson,
Richard Price, Robert Heaton, Clayton Wiley, Diane Griffin,
Ashley Haase, Anthony Fauci, Bruce Chesebro, and Bruce
Walker, has worked with and studied HIV-1-infected patients
with associated mental and neurologic illnesses and
immunosuppression and/or investigated markers in nervous
tissues from such patients. The second group, as represented
by Drs. Murray Gardner, John Elder, Bill Narayan, Lennart Mucke,
and David Pauza, has developed or employed lentivirus animal
models, i.e., SIV in macaques, FIV in cats, and HIV gene
expression in brain using transgenic technology, or studied
HIV replication in vitro. The last group, as represented by
VIII Preface
Drs. Bernard Fields, Milton Brightman, William Hickey, Richard
Com pans, and Michael Oldstone, has been involved in under
standing general principles of viral pathogenesis, such as viral
entry and/or exit into the brain; blood-brain barrier organization or
disorganization; and penetration of immunocompetent cells
across the blood-brain barrier, including the state of their reco
gnition of eNS cells and the ability or inability of CNS cells to
present viral antigens to such immunocompetent cells.
Such cross-talk among these groups and other participants
attending this conference and participating in workshop discus
sions and poster presentations promoted lively discussions and
deb.ates frequently as reflected in the accompanying cartoon.
Bringing these disparate groups together is likely to lead to
rethinking and redefining several aspects of the problem. By
integrating the many approaches addressed at this meeting,
collaborations previously not considered are likely to be forged.
This will result in a better understanding of and novel clinical and
experimental approaches to AIDS CNS disease. Hopefully, the
end result will eventually lead to the control and prevention of
AIDS and its CNS manifestations.
Lastly, a personal comment. AIDS is a devastating dis
ease. Enormous research efforts have correctly been directed
towards understanding the lifestyle of the virus that causes
it-HIV-and towards its control by public health measures and
drug therapy, and its prevention by vaccine. Yet, much of what
..
CNS AIDS IS DUE TO
IMMUNOPATHOLOGY. CNS AIDS IS DUE
TO CYTOKINES
~
RESPOIaAND
MOLECULAR
Y
Preface IX
is being learned about HIV-1 and AIDS and other lentiviral
infections concerning persistence, immunosuppression, ac
companying disease manifestation and immune therapies to
prevent or treat opportunistic infections has already been re
vealed in data obtained from studies with other animal models
(murine leukemia viruses, lactic dehydrogenase virus, lympho
cytic choriomeningitis virus) and human disease (measles vi
rus). Thus, it seemed quite sensible to have included in the
program and volume a number of these insights.
La Jolla/Rockville M.BA OLDSTONE
L. VITKOVIC
List of Contents
A The Human Problem: HIV, Neuropsychiatric Disorders,
and Dementia
R.T. JOHNSON
The Pathogenesis of HIV Infections of the Brain 3
I. GRANT, R.K. HEATON, J.H. ATKINSON,
and the HNRC GROUP
Neurocognitive Disorders in HIV-1 Infection. . . . . . . . 11
R.W. PRICE
AIDS Dementia Complex and HIV-1 Brain Infection:
A Pathogenetic Framework for Treatment
and Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
CA WILEY
Quantitative Neuropathologic Assessment
of H IV-1 Encephalitis. . . . . . . . . . . . . . . . . . . . . . . . . . 55
M.W. BRIGHTMAN, S. ISHIHARA, and L. CHANG
Penetration of Solutes, Viruses, and Cells
Across the Blood-Brain Barrier . . . . . . . . . . . . . . . . . . 63
SA KALAMS and B.D. WALKER
Cytotoxic T Lymphocytes
and H IV-1-Related Neurologic Disorders. . . . . . . . . . . 79
C. POWER, J.C. McARTHUR, R.T. JOHNSON, D.E. GRIFFIN,
J.D. GLASS, R. DEWEY, and B. CHESEBRO
Distinct H IV-1 env Sequences Are Associated
with Neurotropism and Neurovirulence . . . . . . . . . . . 89
L. VITKOVIC and A. DA CUNHA
Role for Astrocytosis in H IV-1-Associated Dementia 105
C.D. PAUZA and D.N. STREBLOW
Therapeutic Approaches to HIV Infection
Based on Virus Structure
and the Host Pathogen Interaction. . . . . . . . . . . . . . . 117