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Current
HIV Research
ISSN: 1570-162X
Current HIV Research
Volume 4, Number 3, July 2006
Contents
Focus on NeuroAIDS
Preface Pp. 243
Jon W. Marsh and Ted M. Ross
Editorial: NeuroAIDS:
A Neuroscience Problem with Global Impact Pp. 245-247
Michael F. Nunn
Impact of HIV on Regional & Cellular Organisation
of the Brain Pp. 249-257
Jeanne E. Bell, Iain C. Anthony and Peter Simmonds
[Abstract]
The Blood-Brain Barrier in NeuroAIDS Pp. 259-266
Wiliam A. Banks, Nuran Ercal and Tulin Otamis Price
[Abstract]
Mechanisms of HIV-1 Neurotropism Pp. 267-278
Rebecca Dunfee, Elaine R. Thomas, Paul R. Gorry, Jianbin
Wang, Petronela Ancuta and Dana Gabuzda
[Abstract]
Human Immunodeficiency Virus-Mononuclear
Phagocyte Interactions: Emerging Avenues of Biomarker Discovery,
Modes of Viral Persistence and Disease Pathogenesis
Pp. 279-291
Pawel Ciborowski and Howard E. Gendelman
[Abstract]
From Mice to Macaques – Animal Models of
HIV Nervous System Disease Pp. 293-305
M. Christine Zink, Victoria A. Laast, Kristi L. Helke,
Angela K. Brice, Sheila A. Barber, Janice E. Clements and
Joseph L. Mankowski
[Abstract]
Mechanisms of Neuronal Injury and Death in HIV-1 Associated
Dementia Pp. 307-318
Marcus Kaul and Stuart A. Lipton
[Abstract]
Neural Progenitors and HIV-1- Associated Central Nervous
System Disease in Adults and Children Pp. 319-327
Lynnae Schwartz and Eugene O. Major
[Abstract]
Review Articles
Novel Broad-Spectrum Thiourea Non-Nucleoside Inhibitors
for the Prevention of Mucosal HIV Transmission Pp.
329-345
Osmond J. D’Cruz and Fatih M. Uckun
[Abstract]
Coumarins as Inhibitors of HIV Reverse Transcriptase
Pp. 347-363
Irena Kostova
[Abstract]
Global Genetic Variation of HIV-1 Infection Pp.
365-373
Cleo G. Anastassopoulou and Leondios G. Kostrikis
[Abstract]
Original Research Papers
Highly Active Antiretroviral Therapy is Associated
with Improved Survival among Patients with AIDS-Related Primary
Central Nervous System Non-Hodgkin’s Lymphoma
Pp. 375-378
Catherine Diamond, Thomas H. Taylor, Theresa Im, Mohammed
Miradi, Mark Wallace and Hoda Anton-Culver
[Abstract]
Preclinical Evaluation of a Zinc Finger Inhibitor
Targeting Lentivirus Nucleocapsid Protein in SIV-Infected
Monkeys Pp. 379-386
Marco L. Schito, Adam C. Soloff, Danielle Slovitz, Anita
Trichel, John K. Inman, Ettore Appella, Jim A. Turpin and
Simon M. Barratt-Boyes
[Abstract]
Abstracts
[Back to top]
Preface
Focus on NeuroAIDS
Millions of individuals worldwide have been infected with
the human immunodeficiency virus (HIV) and developed the disease
known as acquired immunodeficiency syndrome (AIDS). Untreated,
the infection can lead to dissolution of both the immunological
and central neurological systems. A fraction of the world
population of HIV-infected individuals is receiving medications
that diminish the peripheral viral burden, but it remains
unclear whether drug inaccessibility to the brain and the
inability to eliminate existing virus will, in the long-term,
lead to increased neurological complications. Preliminary
findings indicate that neurological pathologies will remain
a consequence of HIV infection. HIV is a lentivirus, a subgroup
of retroviruses that uniformly cause CNS disease.
Part of this issue of Current HIV Research is focused
on our present scientific understanding of neuroAIDS. Nunn
provides an overview of neuroAIDS with respect to the scientific
and clinical questions being addressed and the present day
status of neuroAIDS in the global HIV epidemic [1]. Bell et
al. provide an introduction to the component structures
and cells of the brain and an overview of their involvement
in HIV-induced pathologies [2] and Banks et al. summarize
the major role that the blood brain barrier (BBB) plays in
establishing and maintaining virus within the CNS and the
consequential dysfunction [3]. Dunfee et al. discuss
neurotropism of HIV and the dynamic interactions between the
evolving virus and the macrophage/microglial brain cells [4].
Ciborowski and Gendelman discuss the central role of mononuclear
phagocytes in the development of HIV-associated dementia (HAD)
and describe approaches to define the molecular events and
biomarkers for HAD [5]. Neurological diseases and productive
lentiviral replication in the CNS occur in both rodent and
primate macrophages. Zink et al. describe the characterized
members of the lentiviral genus that infect varied animals,
their similarities and differences and how they may serve
as models for understanding HIV infection [6]. Kaul and Lipton
describe the complex cellular interplay that potentially contributes
to neuronal death in association with HIV-1 disease and discuss
recent and prospective approaches for therapy and prevention
of HAD [7]. Lastly, Schwartz and Major [8] compare the clinical
syndromes of AIDS-dementia complex (ADC) in adults and HIV-associated
progressive encephalopathy (PE) in pediatric patients, and
they discuss the potential role of neural progenitors in HIV-mediated
brain disease.
As co-editors of this issue of Current HIV Research,
we are very grateful for the time and effort that all of the
authors and co-authors have committed to each review article.
Furthermore, we hope that the reader will be stimulated by
this collection of insightful review articles.
REFERENCES
[1] Nunn MF. (2006). NeuroAIDS: A Neuroscience Problem with
Global Impact. Current HIV Research. 4:245-247.
[2] Bell JE, Anthony IC, Simmonds P. (2006). Impact of HIV
on Regional & Cellular Organisation of the Brain. Current
HIV Research. 4: 249-257.
[3] Banks WA, Ercal N, Price TO. (2006). The Blood-Brain Barrier
in NeuroAIDS. Current HIV Research. 4: 259-266.
[4] Dunfee R, Thomas E, Gorry PR, Wang J, Ancuta P, Gabuzda
D. (2006). Mechanisms of HIV-1 Neurotropism. Current HIV Research.
4: 267-278.
[5] Ciborowski P, Gendelman HE. (2006). Human Immunodeficiency
Virus-Mononuclear Phagocyte Interactions: Emerging Avenues
of Biomarker Discovery, Modes of Viral Persistence and Disease
Pathogenesis. Current HIV Research. 4: 279-291.
[6] Zink MC, Laast VA, Helke KL, Brice AK, Barber SA, Clements
JE, Mankowski JL. (2006). From Mice to Macaques – Animal
Models of HIV Nervous System Disease. Current HIV Research.
4: 293-305.
[7] Kaul M, Lipton SA. (2006). Mechanisms of Neuronal Injury
and Death in HIV-1 Associated Dementia. Current HIV Research.
4: 307-318.
[8] Schwartz L, Major EO. (2006). Neural Progenitors and HIV-1-
Associated Central Nervous System Disease in Adults and Children.
Current HIV Research. 4: 319-327.
Jon W. Marsh
Laboratory of Cellular and Molecular Regulation
National Institute of Mental Health
Bethesda
Maryland
USA
E-mail: marshj@mail.nih.gov
USA
Ted M. Ross
University of Pittsburgh
Department of Medicine
Division of Infectious Diseases
Pittsburgh
Pennsylvania
USA
E-mail: RossT@dom.pitt.edu
[Back to top]
Editorial
NeuroAIDS: A Neuroscience Problem with Global Impact
Early in the HIV/AIDS epidemic, it was recognized that there
were many syndrome-defining illnesses involving the nervous
system, including peripheral neuropathies and dementia, opportunistic
infections of the central nervous system (CNS) such as cryptococcal
and tubercular meningitis, and progressive multifocal leukencephalopathy
(PML). Fast on the heels of the discovery of HIV-1 as the
causative agent for AIDS, several studies pointed to the viral
envelope glycoprotein gp120 as a principal suspect for neuropathology
[1,7]. The neurotoxic potential of other viral proteins has
also been demonstrated, most notably Tat, however the mechanisms
for delivery of these viral proteins into the central nervous
system remain unclear [10]. The obvious vehicle for virus
delivery to the brain would be an HIV infected T-cell, the
predominant source for HIV in the periphery, yet it has been
difficult to demonstrate the presence of these cells in CNS
tissue. Instead, infected perivascular macrophages and microglia
are often found in brain tissue from patients with viral encephalitis
or HIV-associated dementia (HAD) [15,17]. Although there is
clearly neuronal loss in HAD, neurons and oligodendrocytes
are not infected directly by HIV. Astrocytes can be infected
but without the production of virus. This profile of cellular
tropism in CNS infection is consistent with several other
animal lentiviruses that infect monocytic cells exclusively
over T-cells [2].
The background outlined above will be discussed in much more
detail in the articles to follow. While macrophages/monocytes
and activated glial cells have recently taken center stage
in the study of the neuropathogenesis of HIV, several key
questions in HIV neurovirology remain. First, what is the
mechanism by which HIV causes neuronal cell death? It remains
unclear whether HAD is the product of a chronic neuroinflammatory
environment set up in the course of HIV infection, or is due
instead to the direct toxicity of viral gene products. Both
mechanisms may ultimately be important. It is possible that
traffic of HIV-infected monocytes into the CNS early in the
course of the disease establishes a chronic inflammatory environment
and activation of the innate immune system. This inflammation
would lead to the eventual recruitment of other components
of the cellular immune response to the brain, including T-cells
and the potent neurotoxic viral strains that infect them.
Breakdown of the neuroprotective blood-brain barrier some
time in the course of disease may also be important for neuropathogenesis.
Studies of animal models for neuroAIDS such as SIV infection
in the macaque [3,18] or a recently developed HIV/MLV chimera
which can infect the CNS of mice [11] will surely provide
important answers toward understanding the mechanisms of HIV
neuropathogenesis.
A second question, the focus of significant efforts in neuroAIDS,
is whether the CNS can serve as an immunologically and therapeutically
privileged reservoir for harboring HIV. Many current anti-retroviral
drugs may have limited diffusion or transport across the blood-brain
barrier into the CNS [9]. Do drug-resistant viruses develop
in this environment, and if so, can HIV from the CNS affect
the course of patient treatment and outcomes? A recent study
from Hawaii has demonstrated that patients with HAD receiving
highly active antiretroviral therapy (HAART) had significantly
higher levels integrated HIV provirus in peripheral blood
mononuclear cells when compared to matched HAD-negative controls
[14]. This finding suggests the possibility that the CNS could
serve as a source of HIV-infected monocytes when there is
active replication of HIV in the brain. If the CNS is a reservoir
for active viral replication it is hoped that this virus can
be eliminated through the development of improved HAART components
with better CNS penetration or other therapeutic strategies
eliminating HIV-infected cells. It is also unclear whether
there is latent, non-replicating virus within the CNS. The
non-productive infection of astrocytes or perhaps brain progenitor
cell populations might provide such a host for latent HIV
[6].
Will HAART therapy will eventually eliminate the neurological
complications of AIDS? With the advent of protease inhibitors
and combination therapy for HIV the landscape of HIV/AIDS
neurological disorders has certainly changed. In the developed
world, where HAART therapy is widely available, the incidence
of opportunistic infections in the CNS of AIDS patients has
declined with the rebound of their immune function. Over the
past decade the incidence of HAD has also decreased. Despite
these successes, some studies suggest the overall prevalence
of HAD may be increasing as patients survive longer living
with HIV/AIDS [4]. Peripheral neuropathies also remain a problem
for patients [5]. Several of the nucleoside reverse transcriptase
inhibitors can be directly neurotoxic, and painful neuropathies
have been attributed their use. Discontinuation of the use
of these drugs and development of improved of antiretroviral
therapies and HAART treatment strategies will improve the
neurological outcomes for AIDS patients. However, the trend
toward improved clinical outcomes through HAART may ultimately
stop short of curing neuroAIDS. In particular, it has been
difficult to come to a definitive statement regarding the
success of HAART in treating HIV-induced cognitive disorders,
including minor cognitive motor disorder (MCMD) and HAD. A
large number of factors can potentially affect cognition,
such as the changing demographics of the HIV/AIDS patient
populations, the advancing age of patients, changing HAART
regimens and potential HAART toxicities [16]. In order to
foster clarity and focus in this area, the National Institutes
of Neurological Disorders and Stroke (NINDS) and National
Institute of Mental Health (NIMH) convened a workshop entitled
“Update on Diagnostic Definitions of HIV-Associated
Dementia and Minor Cognitive Motor Disorder in the Era of
HAART”. This meeting brought together leading HIV/AIDS
neurologists and psychiatrists to discuss key issues affecting
the diagnosis of cognitive changes in HIV/AIDS patients receiving
combination antiretroviral therapy. The NIH is currently supporting
several large longitudinal studies to evaluate the therapeutic
effect of HAART on cognition and neurological function in
AIDS with the expectation that definitive answers to some
of these critical clinical questions will be forthcoming.
Although outcomes for AIDS patients in the developed world
have improved with the advent of HAART, over 70% of AIDS patients
live in resource-limited settings where HAART therapy is widely
unavailable. At a recent conference, “HIV Infection
and the Central Nervous System: Developed and Resource Limited
Settings” (Paola Cinque and Andrea Antinori organizers),
AIDS clinicians and researchers from around the globe presented
data on neuroAIDS from their local clinics. The list of neurological
complications of HIV/AIDS in resource-limited settings is
the same as those previously identified elsewhere. However,
the discussions at the meeting highlighted how strikingly
different the presentation of neurological complications of
HIV/AIDS can be depending on the clinical setting. The distribution
of AIDS-defining neurological illnesses and their clinical
outcomes vary widely by setting. In resource-limited or underdeveloped
settings many patients currently die from cryptococcal or
tubucular meningitis, and these meningitides, mostly fatal,
accounted for nearly a quarter of hospital admissions in one
setting [8]. Such opportunistic infections are rarely fatal
in developed countries where antibiotics and anti-fungal agents
are widely available.
In addition to the lack of access to available therapies,
clinicians in resource-limited settings are hampered by a
lack of many diagnostic tools that are taken for granted elsewhere.
For example, MRI imaging technologies are not widespread in
Africa and when available are not connected to consistent
power supplies or maintained by qualified service personnel.
Insufficient trained clinical staff, particularly in neurology
and psychiatry, also hampers the diagnosis and care of HIV/AIDS
patients. HAD in particular is difficult to study since significant
stigma is associated with dementia worldwide. HAD is considered
relatively rare in some areas, such as India [12]; however,
studies in Uganda have indicated prevalence rates for dementia
of roughly 30% for AIDS patients, a rate similar to the pre-HAART
era in the United States [13]. These differences might be
due to differences in HIV viral clade: clade C is widespread
in India, while clade D is seen in Uganda and clade B in the
United States. There are also differences in nutritional,
genetic and other factors that might affect the psychiatric
health of these populations. In addition, comparison of neuropsychological
evaluations across cultural and language boundaries complicate
the analysis. The development of robust, inexpensive biomarkers
for the diagnosis of HAD and MCMD would eliminate these uncertainties.
The questions facing HIV neurovirologists are clear: what
is the mechanism of neurodegeneration in neuroAIDS and is
the CNS a reservoir of consequence in HIV/AIDS? The research
tools and resources needed to answer these questions are largely
available and important discoveries in these areas continue
to be forthcoming. For clinicians and patients the most pressing
issue is the development of effective antiretroviral drugs
for treatment of HIV in the CNS. Here, the delivery of drugs
across the blood-brain barrier and the neurotoxicity of current
therapies are key hurdles. With patients surviving longer
with HIV/AIDS, research efforts are also focused on the identification
of neuroprotective strategies for the treatment of the complications
of HIV/AIDS, and the development of approaches for purging
CNS viral reservoirs. These research goals are also within
our scientific grasp. In resource-poor settings newer therapies
may remain beyond the reach of the majority of those with
HIV/AIDS for many years to come, however the complications
of neuroAIDS appear to be underappreciated and deserve immediate
attention. Broader education about the neurological complications
of HIV/AIDS worldwide and wider appreciation of, and access
to, the inexpensive therapies already available for treating
CNS opportunistic infections will save thousands, if not millions
of lives.
REFERENCES
[1] Brenneman DE, Westbrook GL, Fitzgerald SP, Ennist DL,
Elkins KL, Ruff MR, Pert CB. (1988). Neuronal cell killing
by the envelope protein of HIV and its prevention by vasoactive
intestinal peptide. Nature. 335:639-642.
[2] Clements JE, Zink MC. (1996). Molecular Biology and Pathogenesis
of Animal Lentivirus Infections. Clinical Microbiology Reviews.
9:100-117.
[3] Gaskill PJ, Watry DD, Burdo TH, Fox HS. (2005). Development
and characterization of positively selected brain-adapted
SIV. Virology Journal. 2:44.
[4] Grant I, Sacktor N, McArthur J. (2005). HIV Neurocognitive
Disorders. In: Gendelman HE, Grant I, Everall IP, Lipton SA,
Swindells S Eds/ The Neurology of AIDS. New York, Oxford University
Press. pp 357-373.
[5] Keswani SC, Luciano C, Pardo C, Cherry CL, Hoke A, McArthur
JC. (2005). The Spectrum of Peripheral Neuropathies in AIDS.
In: Gendelman HE, Grant I, Everall IP, Lipton SA, Swindells
S Eds/ The Neurology of AIDS. New York, Oxford University
Press. pp 423-443.
[6] Lawrence DM, Durham LC, Schwartz L, Seth P, Maric D, Major
EO. (2004). Human immunodeficiency virus type 1 infection
of human brain-derived progenitor cells. Journal of Virology.
78:7319-7328.
[7] Lee MR, Ho DD, Gurney ME. (1987). Functional interaction
and partial homology between human immunodeficiency virus
and neuroleukin. Science. 237:1047-1051.
[8] Mayanja-Kizza H. (2004). Changing Pattern of HIV Opportunistic
Infections in Kampala, Uganda. Presentation at the XV International
AIDS Conference, Bangkok, Thailand.
[9] McCutchan JA, Letendre S. (2005). Pharmacology of Antiretroviral
Drugs in the Central Nervous System: Pharmakokinetics, Antiviral
Resistance, and Pharmakodynamics. In: Gendelman HE, Grant
I, Everall IP, Lipton SA, Swindells S Eds/ The Neurology of
AIDS. New York, Oxford University Press. pp 729-734.
[10] Nath A. (2002). Human immunodeficiency virus (HIV) proteins
in neuropathogenesis of HIV dementia. Journal of Infectious
Diseases.186(Suppl 2):S193 198.
[11] Potash MJ, Chao W, Bentsman G, Paris N, Saini M, Nitkiewicz
J, Belem P, Sharer L, Brooks AI, Volsky DJ. (2005). A mouse
model for study of systemic HIV-1 infection, antiviral immune
responses, and neuroinvasiveness. Proceedings of the National
Academy of Sciences, U. S. A. 102:3760-3765.
[12] Ranga U, Shankarappa R, Siddappa NB, Ramakrishna L, Nagendran
R, Mahalingam M, Mahadevan A, Jayasuryan N, Satishchandra
P, Shankar SK, Prasad VR. (2004). Tat protein of human immunodeficiency
virus type 1 subtype C strains is a defective chemokine. Journal
of Virology. 78:2586-2590.
[13] Sacktor NC, Wong M, Nakasujja N, Skolasky RL, Selnes
OA, Musisi S, Robertson K, McArthur JC, Ronald A, Katabira
E. (2005). The International HIV Dementia Scale: a new rapid
screening test for HIV dementia. AIDS. 19:1367-1374.
[14] Shiramizu B, Gartner S, Williams A, Shikuma C, Ratto-Kim
S, Watters M, Aguon J, Valcour V. (2005) Circulating proviral
HIV DNA and HIV-associated dementia. AIDS. 19:45-52.
[15] Takahashi K, Wesselingh SL, Griffin DE, McArthur JC,
Johnson RT, Glass JD (1996) Localization of HIV-1 in human
brain using polymerase chain reaction/in situ hybridization
and immunocytochemistry. Annals of Neurology. 39:705 711.
[16] Valcour VG, Shikuma CM, Shiramizu BT, Williams AE, Watters
MR, Poff PW, Grove JS, Selnes OA, Sacktor NC (2005) Diabetes,
insulin resistance, and dementia among HIV-1-infected patients.
Journal of Acquired Immune Deficiency Syndrome. 38:31-36.
[17] Wiley CA, Achim CL, Christopherson C, Kidane Y, Kwok
S, Masliah E, Mellors J, Radhakrishnan L, Wang G, Soontornniyomkij
V. (1999) HIV mediates a productive infection of the brain.
AIDS. 13:2055-2059.
[18] Zink MC, Clements JE (2002) A novel simian immunodeficiency
virus model that provides insight into mechanisms of human
immunodeficiency virus central nervous system disease. Journal
of Neurovirology. 8 Suppl 2:42-48.
Michael F. Nunn
National Institute of Neurological Disorders and Stroke
National Institutes of Health
6001 Executive Boulevard
Room 2115
Bethesda
Maryland 20892-9521
USA
E-mail: nunnm@ninds.nih.gov
[Back to top]
Impact of HIV on Regional & Cellular Organisation
of the Brain
Jeanne E. Bell, Iain C. Anthony and Peter Simmonds
There are many excellent reviews of HIV infection of
the nervous system. However these all assume that the reader
has a working knowledge of the structure and cellular architecture
of the brain. It may be that specialised brain vocabulary
represents an unwelcome hurdle for those scientists with expert
knowledge of the effects of HIV in other cell systems and
who wish to extend that interest to the brain. This review
provides an introduction to the component structures and cells
of the brain and an overview of their involvement in HIV/AIDS.
HIV infection leads to death through its capacity to progressively
devastate the immune system. Current anti-HIV therapy has
achieved considerable success in halting and partially reversing
this process. In the absence of treatment, the breakdown of
immunity is marked by declining CD4 counts and increasing
vulnerability to opportunistic infections. In parallel with
these effects on the lymphoid system, the nervous system is
frequently the site of an initially stealthy infection which
leads ultimately to symptomatic disease in a significant proportion
of HIV infected individuals. The most feared manifestation
of central nervous system (CNS) involvement is dementia. Unfortunately,
serial CD4 counts and measurement of blood viral load do not
serve to identify or monitor early infection of brain tissue.
Since effective anti-HIV therapy has not achieved eradication
of virus from lymphoid tissues, and anti-HIV drugs do not
enter the nervous system easily, it is hardly surprising that
HIV infection of the nervous system continues to cause clinical
problems. Even in treatment-compliant patients, a measurable
degree of cognitive impairment may develop, signalling previous
or present HIV-related brain injury. The cause of HIV associated
dementia and cognitive disability remains poorly understood.
Perhaps most significantly, the long-term consequences of
clinically occult brain infection are unknown and will require
further investigation.
[Back to top]
The Blood-Brain Barrier in NeuroAIDS
Wiliam A. Banks, Nuran Ercal and Tulin Otamis Price
Nearly every aspect of blood-brain barrier (BBB) function
is involved in or affected by HIV-1. The disruption of the
BBB tends to be minimal and is not likely the mechanism by
which infected immune cells and virus enter the brain. Instead,
immune cells, virus and viral proteins likely activate brain
endothelial cells and enable their own passage across the
BBB by way of highly regulated processes such as diapedesis
and adsorptive endocytosis. Viral proteins and cytokines can
enter the CNS from the blood and provide a mechanism by which
HIV-1 can affect CNS function independent of viral transport.
Brain endothelial cells can also secrete neuroimmunoactive
substances when stimulated by HIV-1, gp120, and Tat. Efflux
systems such as p-glycoprotein transport anti-virals in the
brain-to-blood direction, thus hampering effective accumulation
of drug by the CNS. Overall, the BBB plays a major role in
establishing and maintaining virus within the CNS and neuroAIDS.
[Back to top]
Mechanisms of HIV-1 Neurotropism
Rebecca Dunfee, Elaine R. Thomas, Paul R. Gorry, Jianbin
Wang, Petronela Ancuta and Dana Gabuzda
Human immunodeficiency virus type 1 (HIV) infects macrophages
and microglia in the CNS and frequently causes neurocognitive
impairment. Although antiviral therapy generally reduces the
viral load in the CNS and improves HIV-associated neurological
dysfunction, most current antiviral drugs have poor CNS penetrance
and cannot completely suppress viral replication. Furthermore,
drug-resistance mutations can evolve independently in the
CNS. Thus, a long-lived viral reservoir persists in macrophages
and microglia in the brain despite antiviral therapy. This
review discusses mechanisms underlying the neurotropism of
HIV, focusing on the role of the HIV envelope glycoproteins
and their interactions with CD4 and the chemokine receptors
CCR5 and CXCR4. We review data from studies of neurotropic
HIV derived from the brains of patients with HIV-associated
neurocognitive impairment as well as studies of nonhuman primate
models. Understanding mechanisms that underlie HIV neurotropism
and neurovirulence is critical for development of therapeutics
to inhibit CNS infection and preventing neurological injury
in HIV-infected individuals.
[Back to top]
Human Immunodeficiency Virus-Mononuclear Phagocyte
Interactions: Emerging Avenues of Biomarker Discovery, Modes
of Viral Persistence and Disease Pathogenesis
Pawel Ciborowski and Howard E. Gendelman
Mononuclear phagocytes (MP; bone marrow monocyte-derived
macrophages, histiocytes, alveolar macrophages, Kupffer cells,
perivascular macrophages, and microglia) function as sentry
and surveillance cells by acting as debris scavengers, killers
of microbial pathogens, and regulators of immune responses.
Interestingly, these same cells are reservoirs and vehicles
of dissemination for the human immunodeficiency virus (HIV).
How virus alters the MP immunoregulatory activities so it
can complete its own life cycle and affect disease is only
recently being unravelled. Physiologic, anatomic and functional
changes also underlie virus-MP interactions and include multinucleated
giant cell formation, changes in ion channel expression and
cell volume, and robust secretory responses with the production
of numerous secretory factors affecting tissue injury. The
balance between such MP activities and ability to both mobilize
an adaptive immune response to thwart viral growth underlies
the progression of viral infection and clinical disease. This
review serves to discuss the functions of MP in HIV disease
by bringing together what is known with what remains unknown.
The advent of functional genomics and proteomics has opened
the ways to address the intricacies of viral-host interactions
and has provided new avenues for therapeutic interventions
and disease monitoring that takes advantage of specific intracellular
relationships between the virus and its host cell.
[Back to top]
From Mice to Macaques – Animal Models of
HIV Nervous System Disease
M. Christine Zink, Victoria A. Laast, Kristi L. Helke,
Angela K. Brice, Sheila A. Barber, Janice E. Clements and
Joseph L. Mankowski
Lenviviral diseases of animals have been recognized for
over a century, long before HIV was recognized as the cause
of AIDS. All lentiviruses cause neurological disease and productive
virus replication in the CNS occurs exclusively in cells of
macrophage lineage. The ability to molecularly engineer the
inoculum virus, to sample the brain at many different time
points from acute through terminal infection and to correlate
in vivo with in vitro findings are significant
advantages of animal models of HIV CNS disease. The lentiviruses
can be divided into two pathogenetic groups – those
that cause immunosuppression, including the lentiviruses of
humans (HIV), non-human primates (SIV), cats (FIV), and cattle
(BIV), and those that cause immunoproliferation, including
the lentiviruses of horses (EIAV), sheep (OvLV) and goats
(CAEV). Despite extensive study, no rodent lentivirus has
been identified, prompting development of alternate strategies
to study lentiviral pathogenesis using rodents. The immunosuppressive
lentiviruses most closely recapitulate the disease manifestations
of HIV infection, and both SIV and FIV have contributed significantly
to our understanding of how HIV causes both central and peripheral
nervous system disease.
[Back to top]
Mechanisms of Neuronal Injury and Death in HIV-1 Associated
Dementia
Marcus Kaul and Stuart A. Lipton
Infection with the human immunodeficiency virus-1 (HIV-1)
and acquired immunodeficiency syndrome (AIDS) remain a persistent
and even growing health problem worldwide. Besides its detrimental
systemic effects on the immune system, HIV-1 seems to enter
the brain very soon after peripheral infection and can induce
severe and debilitating neurological problems that include
behavioral abnormalities, motor dysfunction and frank dementia.
Infected peripheral immune cells, in particular macrophages,
appear to infiltrate the CNS and provoke a neuropathological
response involving all cell types in the brain. Both viral
and host factors, such as the viral strain and the response
of the host's immune system, strongly influence the course
of HIV-1 disease. Moreover, HIV-1-dependent disease processes
in the periphery have a substantial effect on the pathology
developing in the central nervous system (CNS), although the
brain eventually harbors a distinctive viral population of
its own. In the CNS, HIV-1 also initiates activation of chemokine
receptors, inflammatory mediators, extracellular matrix-degrading
enzymes and glutamate receptor-mediated excitotoxicity, all
of which can activate numerous downstream signaling pathways
and disturb neuronal and glial function. Although there have
been substantial improvements in the control of viral infection
in the periphery, an effective therapy for HIV-1 associated
dementia (HAD) is still not in sight. This article will review
recently identified injurious mechanisms potentially contributing
to neuronal death in association with HIV-1 disease and discuss
recent and prospective approaches for therapy and prevention
of HAD.
[Back to top]
Neural Progenitors and HIV-1- Associated Central Nervous
System Disease in Adults and Children
Lynnae Schwartz and Eugene O. Major
The human immunodeficiency virus type 1 (HIV-1) is a neurotrophic
lentivirus that enters and infects the central nervous system
(CNS) of adults and children, giving rise to the clinical
syndromes of AIDS-dementia complex (ADC) in adults and HIV-1-associated
progressive encephalopathy (PE) in pediatric patients. The
clinical presentation and progression of neuroAIDS in the
developing brain of children is distinct from that seen in
adult patients. Neuroimaging, and upon autopsy, neuropathological
findings corresponding to clinical disease in pediatric patients
include impaired brain growth, reactive gliosis, myelin pallor,
calcifications of the basal ganglia, cortical and cerebral
atrophy with neuronal loss and ventricular enlargement, and
abnormalities of cerebral vasculature. Although there is some
overlap with neuropathologic findings in adult patients, ADC
in adults is more typically a late development, often complicated
by opportunistic infections of the CNS.
The neuropathogenesis of ADC and PE is incompletely understood.
One population of CNS cells critical for brain development
and response to injury and inflammation are neural progenitors
cells, and it has therefore been suggested that these cells
may be involved in the neuropathogenesis of ADC, and especially
PE. This review examines the neurobiology of neural progenitor
cells and the possibility that HIV-1 infection of neural progenitors,
exposure of neural progenitors to virus, viral products, or
progenitor exposure to HIV-1 associated neuroinflammatory
substances and neurotoxins might contribute to the neuropathogenesis
of AIDS in adults and children. That some of the clinical
differences between ADC and PE might, in part, be explained
by differences in neural progenitor involvement will also
be considered.
[Back to top]
Novel Broad-Spectrum Thiourea Non-Nucleoside Inhibitors
for the Prevention of Mucosal HIV Transmission
Osmond J. D’Cruz and Fatih M. Uckun
Non-nucleoside inhibitors of HIV-1 reverse transcriptase
(NNRTI) are an integral part of combination therapy comprising
three classes of antiretroviral drugs for the management of
HIV/AIDS. NNRTIs are chemically diverse compounds that bind
to a common allosteric site of HIV-1 RT and noncompetitively
inhibit DNA polymerization. Resistance to NNRTIs arises rapidly
upon drug treatment and results from mutation of the amino
acids lining the HIV-1 RT binding pocket. Nevertheless, rationally
designed NNRTIs deduced from changes in binding pocket size,
shape, and residue character that result from clinically observed
NNRTI resistance mutations exhibit broad-spectrum anti-HIV-1
activity. Notably, membrane permeable tight binding NNRTIs
have utility as topical microbicides since they are capable
of blocking cell-free and cell-associated mucosal HIV-1 infection
without metabolic activation. This review summarizes the discovery
of highly potent tight binding phenethyl-thiazolyl-thiourea
(PETT) derivatives targeting the NNI binding pocket of HIV-1
RT. These NNRTIs were rationally designed by molecular docking
using a composite binding pocket constructed by superimposing
the crystal structure coordinate data of several NNI/RT ligand-binding
site complexes. Molecular modeling and score functions such
as molecular surface area, the buried surface, and binding
affinity values were used to analyze how drug-resistant mutations
would change the RT binding pocket shape, volume, and chemical
make-up of these NNRTIs, and how these changes could affect
drug binding. Several ligand derivatization sites were identified
for docked compounds that fit the binding pocket. The best
fit was determined by calculating an inhibition constant (Ludi
Ki )
of the docked compound for the composite binding pocket. Compounds
with a Ludi Ki
of <1 μM
were identified as the most promising tight binding NNRTIs.
This review highlights novel lipophilic thiourea NNRTIs that
display high binding affinity and selective indices with robust
anti-HIV-1 activity against the wild type as well as drug-resistant
isolates carrying multiple RT gene mutations. The increasing
prevalence of drug-escape mutants among recent HIV seroconverters
makes the discovery of these broad-spectrum thiourea NNRTIs
useful as a component of topical microbicide for the prevention
of mucosal HIV transmission.
[Back to top]
Coumarins as Inhibitors of HIV Reverse Transcriptase
Irena Kostova
Acquired immunodeficiency syndrome (AIDS), a degenerative
disease of the immune and central nervous systems, is an enormous
world-wide health threat. No cure has been found, and research
is aimed at developing chemotherapy against the causative
agent, human immunodeficiency virus (HIV). Chemotherapy for
AIDS has progressed steadily in the past decade. However,
new, effective, and less toxic chemotherapeutic agents are
still needed. Plants, particularly anti-infective or immunomodulating
herbal medicines, can serve as sources of new active leads
to be further developed as anti-AIDS drug candidates. A lot
of structurally different natural coumarins were found to
display potent anti-HIV activity and continued progress is
anticipated in the discovery of new leads and in the development
of these agents as potential anti-AIDS drug candidates. Recent
studies based on the account of various coumarins from plant
sources and their analogs- synthetic coumarins, indicate that
some of them serve as potent nonnucleoside RT-inhibitors,
another as inhibitors of HIV-integrase or HIV-protease. The
current review demonstrates the variety of coumarins of natural
plant origin and synthetic coumarins having unique mechanism
of action to one of the most important stage of HIV replication
(RT-inhibition). The merits of selecting potential anti-HIV
agents to be used in rational combination drugs design and
structure-activity relationships are discussed. The scientific
community is looking actively for new drugs and combinations
for treatment of HIV infection effective for first-line treatment,
as well as against drug-resistant mutants.
[Back to top]
Global Genetic Variation of HIV-1 Infection
Cleo G. Anastassopoulou and Leondios G. Kostrikis
Variability, both at the population (interhost) as well as
at the individual (intrahost) level is a key property of HIV
that stems mainly from the inherent infidelity of the reverse
transcriptase enzyme that the virus uses to transcribe its
RNA genome into DNA so that it may be integrated into the
human genetic material and propagated along with it. The lack
of proofreading mechanisms, high turnover of virions, and
propensity for recombination also contribute to the extensive
variability of HIV. These parameters provide the virus quasispecies
with an impressive capacity to adapt to immunologic, pharmacologic
or other selection pressures and have important implications
for the diagnosis of new infections, the monitoring of antiretroviral
treatment response, and effective vaccine(s) design. Herein,
we discuss in detail the global genetic variation of HIV-1
infection.
[Back to top]
Highly Active Antiretroviral Therapy is Associated
with Improved Survival among Patients with AIDS-Related Primary
Central Nervous System Non-Hodgkin’s Lymphoma
Catherine Diamond, Thomas H. Taylor, Theresa Im, Mohammed
Miradi, Mark Wallace and Hoda Anton-Culver
Highly active retroviral therapy (HAART) has been in widespread
use in the United States since 1996. We sought to determine
how the use of HAART influenced survival among patients with
acquired immunodeficiency syndrome (AIDS) and primary central
nervous system (CNS) non-Hodgkin’s lymphoma (NHL). We
used the population-based San Diego and Orange County cancer
registry to identify 94 patients with both AIDS and CNS NHL
diagnosed 1994-1999, of whom 31 were diagnosed 1996-1999.
We performed Kaplan-Meier analyses to compare survival between
patients who received HAART at NHL diagnosis or thereafter
versus untreated patients and Cox proportional hazard models
for adjusted survival. Among the patients diagnosed with NHL
in 1996-1999, seven (23%) were taking HAART at the time of
NHL diagnosis. Median survival was eight months for those
who received HAART at the time of lymphoma diagnosis or after,
versus one month for untreated patients. HAART, radiation
therapy, and better performance status were associated with
improved survival. We conclude that HAART prolongs survival
in AIDS-related CNS NHL.
[Back to top]
Preclinical Evaluation of a Zinc Finger Inhibitor
Targeting Lentivirus Nucleocapsid Protein in SIV-Infected
Monkeys
Marco L. Schito, Adam C. Soloff, Danielle Slovitz, Anita
Trichel, John K. Inman, Ettore Appella, Jim A. Turpin and
Simon M. Barratt-Boyes
There is a continued need to develop inexpensive and effective
drugs specific for novel targets of human immunodeficiency
virus type 1 (HIV-1). The HIV-1 nucleocapsid p7 (NCp7) protein
plays a critical role in early and late stages of the virus
life cycle and possesses two highly conserved retroviral zinc
fingers that are essential for its function. We have previously
shown that zinc finger inhibitors (ZFI) based on the S-acyl
2-mercaptobenzamide thioester (SAMT) chemotype specifically
target HIV NCp7 and are effective at reducing levels of infectious
virus in an HIV-1-transgenic mouse model. Here, we did an
initial proof-of-concept study to test the potential of a
lead SAMT compound to reduce virus infectivity in the simian
immunodeficiency virus (SIV) nonhuman primate model. SAMT-19
had potent antiviral and virucidal effects against the primary
pathogenic isolate SIV/DeltaB670 and was non-cytotoxic in
vitro. Cynomolgus macaques were infected intrarectally
with SIV/DeltaB670 and treated with a low dose of SAMT-19
by continuous infusion from day 8 to day 28 post infection.
Monkeys in the treatment group had significantly lower levels
of infectious virus in peripheral blood mononuclear cells
during the course of therapy as compared to monkeys in the
control group, although therapy had no demonstrable effect
on virus load. SAMT-19 therapy did not alter liver, kidney
or immunologic function and was well tolerated by all treated
monkeys. These data demonstrate that SAMT-19 is safe and virucidal
in the nonhuman primate model. Further studies directed at
optimizing SAMT bioavailability and pharmacokinetics likely
will result in enhanced therapeutic efficacy of this promising
HIV therapeutic.
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