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Increased frequency of the tumor necrosis factor--308 a allele in adults with human immunodeficiency virus dementia.

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Increased Frequency of the Tumor Necrosis
Factor-␣-308 A Allele in Adults With
Human Immunodeficiency Virus Dementia
Michael W. Quasney, MD, PhD,1,2 Qing Zhang, BS,2 Susie Sargent, MD,3 Margaret Mynatt, BS,4
Jonathan Glass, MD,5 and Justin McArthur, MD6
Genetic polymorphisms in the regulatory regions of various cytokine genes influence the amount of cytokine produced
in response to inflammatory stimuli. To determine whether such polymorphisms might play a role in human immunodeficiency virus (HIV) dementia, a disease process in which tumor necrosis factor (TNF)-␣ is believed to play a role, we
analyzed HIV-infected adults with and without dementia and control populations for a polymorphic site located in the
promoter region of the gene coding for TNF-␣. The presence of the A allele at the TNF-␣-308 site was overrepresented
among adults with HIV dementia compared to those without dementia (0.28 vs 0.07; OR 5.5; 95% CI 1.8 –17.0) and a
healthy control population (0.28 vs 0.11). The increased frequency of the A allele in HIV-infected adults with dementia
suggests that this locus may play a role in the pathophysiology of dementia and suggests a genetic predisposition for the
development of HIV dementia.
Ann Neurol 2001;50:157–162
Acquired immunodeficiency syndrome (AIDS) dementia is one of the most devastating complications of infection with the human immunodeficiency virus
(HIV). It is considered the most frequent form of dementia in young adults in the United States.1 Patients
exhibit a variety of cognitive and motor dysfunctions,
including psychomotor slowing, memory impairment,
behavioral dysfunction, and ataxia.2– 6 Although the
etiology of the dementia is unclear, specific pathological and histological changes are present in the central
nervous system (CNS). These include diffuse damage
to white matter, multinucleated giant cells, astrocyte
proliferation, microglial nodules, and macrophage infiltration.7–9 Damaged dendrites, neuronal loss in the
neocortex and subcortical brain, and a loss of synapses
have also been documented in brain specimens of
AIDS patients.10 –16
The pathophysiology of HIV dementia remains unknown, although interactions between viral products
and mediators from macrophage and microglia are believed to be involved directly in the neuronal damage.17–22 Indeed, the severity of the dementia appears
to correlate best with the degree of macrophage infiltration and glial cell activation and not with viral
load.23,24 Potential mediators that are neurotoxic include various cytokines, and some investigators have
proposed that cytokines are the major cause of the neuropathology observed in HIV infection.20,25,26 Supporting this role for cytokines is the observation that
cytokine levels are elevated in brain and cerebral spinal
fluid (CSF) in HIV-infected patients with dementia
compared to HIV-infected patients without dementia.21,27,28 Tumor necrosis factor-␣ (TNF-␣) in particular may play a direct role in the neuropathology in
HIV dementia because of its direct toxic effects on
neurons and oligodendrocytes.29 –31 Indeed, TNF-␣27,32
and TNF-␣ mRNA25 are elevated in the brains of
HIV-infected patients with dementia.
The stimulus for the increased amounts of TNF-␣
mRNA observed in the brains of HIV-infected adults
with dementia remains unknown, although the viral
proteins Tat, gp160, and gp120 are suspected.25,33–38
Several genetic polymorphisms have been found within
the promoter region of the TNF-␣ gene that are associated with elevated TNF-␣ production,39 – 41 including a G to A transition at the ⫺308 site (Fig 1). The
presence of an adenine at the ⫺308 site is associated
with elevated TNF-␣ production in response to endo-
From the 1Division of Critical Care, Department of Pediatrics, University of Tennessee, Memphis; 2Crippled Children’s Foundation
Research Center, Le Bonheur Children’s Medical Center, Memphis;
3
Department of Medicine, University of Tennessee, Memphis; 4Le
Bonheur Children’s Medical Center, Memphis, TN; 5Department
of Neurology, Emory University School of Medicine, Atlanta, GA;
and 6Department of Neurology, Johns Hopkins Hospital, Baltimore, MD.
Received Nov 15, 2000, and in revised form Mar 6, 2001. Accepted
for publication Mar 6, 2001.
Published online May 16, 2001.
Address correspondence to Dr Quasney, Division of Critical Care,
Department of Pediatrics, Crippled Children’s Foundation Research
Center, Le Bonheur Children’s Medical Center, 50 N. Dunlap,
Memphis, TN 38103. E-mail: mquasney@utmem.edu
© 2001 Wiley-Liss, Inc.
157
Fig 1. Location of the polymorphic sites affecting the TNF-␣
response. The more frequent allele at the TNF␣-308 site is a
guanine, and the less frequent allele is an adenine. Light grey
boxes ⫽ exons; dark gray boxes ⫽ introns; hatched area ⫽
promotor; white boxes ⫽ 5⬘- and 3⬘-untranslated regions.
toxin compared to the more common G allele.39 Thus,
there appears to be a genetic propensity to secrete
higher amounts of TNF-␣. We tested the hypothesis
that adults with HIV dementia may have a higher frequency of the A allele associated with elevated levels of
TNF␣ at the TNF-␣-308 site.
Patients and Methods
Patients
Brain autopsy specimens from HIV-infected adults with and
without dementia were obtained from at the AIDS Brain
Bank at Johns Hopkins University (Baltimore, MD). Patients were evaluated for dementia within 90 days prior to
their death. Neurological and neuropathological abnormalities were defined using the American Academy of Neurology
criteria42 and included (1) HIV-1 seropositivity, (2) progressive cognitive and behavioral decline, (3) neurological and/or
neuropsychological findings consistent with a decline from
premorbid baseline levels, and (4) CNS opportunistic process
excluded by computed tomography or magnetic resonance
imaging and CSF analysis. The severity of neurologic disease
was scored using the Memorial Sloan-Kettering (MSK) criteria.43 HIV-seropositive, dementia-negative control samples
were obtained from two sources: brain specimens from the
AIDS Brain Bank and adults infected with HIV without dementia who were recruited through the Adult Special Care
Clinic at the University of Tennessee, Memphis. Informed
consent was obtained from patients, and human experimentation guidelines of the U.S. Department of Health and Human Services and the University of Tennessee were followed.
The control populations consisted of healthy adult volunteers
with no history of HIV infection, neurologic or autoimmune
diseases, or chronic treatment with antiinflammatory agents.
using the Genomic DNA Purification Kit (Promega, Madison, WI). The region containing the TNF-␣-308 locus
was amplified using the primers TNFA-308-1 (5⬘AGGCAATAGGTTTTGAGGGCCAT-3⬘) and TNFA-308-2
(5⬘-ACACTCCCCATCCTCCCTGCT-3⬘).40 The TNFA308-1 primer contains 4 bp of the NcoI recognition sequence, including a mismatched cytosine as shown by the C
in the TNFA-308-1 primer sequence. This mismatched cytosine allows for creation of an NcoI restriction site
(CCATGG) when the G allele is present at position ⫺308.
A 116 bp polymerase chain reaction (PCR) product was generated using the following reaction conditions: 35 cycles of
denaturation at 95°C for 30 seconds, annealing at 64°C for
15 seconds, and extension at 74°C for 15 seconds. The amplified DNA was digested with NcoI, and the fragments were
analyzed by electrophoresis in a 3% agarose gel and visualized by ethidium bromide staining. Interpretation was as follows: A single band at 116 bp identified individuals homozygous for an adenine at the TNF-␣-308 locus; two bands at
96 and 20 bp identified individuals homozygous for a guanine at the TNF-␣-308 locus; three bands at 116, 96, and
20 bp identified individuals heterozygous at the TNF-␣-308
locus.
Statistical Analysis
Statistical analysis of genotypic and allelic frequencies was
performed using Fisher’s exact test. Univariate logistic analysis was performed to obtain the odds ratio between the genotype and the dependent variable of HIV infection with
dementia. Statistical analysis was performed using the statistical software package GB-Stat (New England Software, Inc.,
Greenwich, CT).
Results
Patient Characteristics
Sixteen HIV-infected adults with dementia, 45 HIVinfected adults without dementia, and 231 healthy
adult controls were evaluated (Table 1). There were no
racial differences among the 3 groups of samples analyzed.
Genotypic and Allelic Frequencies at the
TNF-␣-308 Site
The genotypic frequencies of the TNF-␣-308 polymorphic site located in the promoter region of the gene
coding for TNF-␣ were compared between HIVTable 1. Characteristics of HIV-Infected Adults With and
Without Dementia and Healthy Controls
Genotypic Analysis
For analysis of brain samples, brain tissue was thawed, and
approximately 25 mg of tissue was minced. DNA was extracted using the QIAamp Tissue Kit (Qiagen, Inc., Chatsworth, CA). For analysis of blood samples obtained from
HIV-infected nondemented patients and healthy controls,
whole blood (1.0 ml) was collected, and DNA was extracted
158
Annals of Neurology
Vol 50
No 2
August 2001
Total
Race (% Caucasian)
Controls
HIV ⫹
Dementia⫺
HIV ⫹
Dementia⫹
231
0.45
45
0.47
16
0.56
HIV-infected adults with dementia compared to healthy controls,
p ⫽ 0.4453; HIV-infected adults with dementia compared to HIV
infected adults without dementia, p ⫽ 0.57. Statistical analysis using
Fisher’s exact test.
infected adults with and without dementia and a
healthy control population (Table 2). There were significantly more heterozygotes in the group of HIVinfected adults with dementia than in either the group
of patients with HIV-infection without dementia (0.56
vs 0.13; p ⫽ 0.002; OR 10.3; 95% CI 2.6 –39.9) or
the healthy control group (0.56 vs 0.19; p ⫽ 0.004;
OR 4.9; 95% CI 1.7–13.8). There were no individuals
with the A/A genotype at the TNF-␣-308 site in either
of the HIV-infected groups. The frequencies of the A
and G alleles at the TNF-␣-308 site in HIV-infected
adults with dementia were also significantly higher
compared to either the nondemented group or the
healthy controls (Table 2; A allele: 0.28 vs 0.07; p ⬍
0.003; G allele: 0.28 vs 0.11; p ⬍ 0.012). There were
no differences in the genotypic or allelic frequencies
between those samples obtained from brain vs blood in
the group of patients with HIV-infection without dementia. The allelic frequencies for the healthy control
population were similar to those in previous reports.39,41,44
Discussion
Several factors affect the degree of the inflammatory
reaction produced by a host. These include the type of
inflammatory stimulus, dose of the stimulus, and genetic characteristics of the host. In this study, HIVinfected adults with dementia were more likely to have
the A allele at the TNF-␣-308 site compared to either
HIV-infected adults without dementia or a healthy
control population. This allele is associated with higher
TNF-␣ secretion in response to an inflammatory stimulus than that in individuals with the G allele. Thus,
development of dementia in HIV-infected adults may
be related to the amount of TNF-␣ secreted in the
brain, which in turn may be influenced by individual’s
genetic predisposition to secrete higher amounts of
TNF-␣.
The stimulus for the increased CNS levels of TNF-␣
mRNA and TNF-␣ observed in the brains of HIVinfected adults with dementia remains unknown, although the viral proteins Tat, gp160, and gp120 are
suspected.25,33–38 Exposure of human astrocytes to Tat
has been shown to result in prolonged production of
cytokines, including TNF-␣. However, little is known
about genetic variability in the TNF-␣ response to
these stimuli. Current work in our laboratory is investigating whether genetic factors influence the degree of
the TNF-␣ response in the setting of infection with
HIV.
Evidence supports a role for TNF-␣ in neuronal
damage. TNF-␣ has been shown to damage human
brain cells and disrupt normal neuronal cell physiology
in a number of studies. For example, TNF-␣ is neurotoxic to human cortical neurons,21 potentiates glutamate receptor-mediated neurotoxicity,45 disrupts
Na⫹/K⫹ transport in astrocytes,46 disrupts glutamate
uptake by astrocytes,47 and damages oligodendrocytes
and myelin in vitro.29
The presence of the A allele at the ⫺308 site has
been shown to result in elevated TNF-␣ production
with concanavallin A41 and endotoxin.39 Polymorphic
sites at positions ⫺1,031, ⫺863, ⫺857, and ⫺238 relative to the TNF-␣ transcriptional start site also have
been demonstrated to have elevated TNF-␣ levels after
in vitro stimulation.41 We chose to study the ⫺308
site because of the strong association of the A allele
with poor outcome following other infections. For example, an association between serum TNF-␣ levels and
mortality in meningococcal meningitis has been observed,48 and children with the A allele at the TNF-␣308 site have a worse outcome following meningococcal infection.49 Similar associations have been observed
in individuals with malaria; those with higher TNF-␣
levels had a worse outcome,50 and the TNF-␣-308 A
allele site was overrepresented among patients with cerebral malaria and among those who died from malaria.51 These previous studies prompted the present
study because of the previous demonstration of elevated mRNA levels of TNF-␣ in the brains of HIVinfected adults with dementia.25 We believe that the
results of this study warrant further analysis of HIVinfected patients to delineate better the association between the “high-secretor” A allele and dementia.
Table 2. Genotypic and Allelic Frequencies at the TNF-␣-308 Site in HIV-Infected Adults With and Without Dementia
Compared to Healthy Control Populations
Genotypic Frequency
Allelic Frequency
Population
n
A/A
A/G
G/G
A
G
Healthy controls
HIV-infected without dementia
HIV-infected with dementia
231
45
16
0.02
0.00
0.00
0.19
0.13
0.56a
0.79
0.87
0.44
0.11
0.07
0.28b
0.89
0.93
0.72
HIV-infected adults with dementia compared to HIV-infected adults without dementia, p ⫽ 0.0023; OR 7.7; 95% CI 2.1–28.7; HIV-infected
adults with dementia compared to healthy controls, p ⫽ 0.0035; OR 4.8; 95% CI 1.7–13.5.
b
HIV-infected adults with dementia compared to HIV-infected adults without dementia, p ⫽ 0.0034; OR 5.5; 95% CI 1.8 –17.0; HIVinfected adults with dementia compared to healthy controls, p ⫽ 0.0115; OR 3.0; 95% CI 1.3– 6.9. Statistical analysis using Fisher’s exact test.
a
Quasney et al: TNF-␣ Polymorphisms in HIV Dementia
159
A previous report did not find an association between the high secretor allele at the TNF-␣-308 site
and HIV encephalitis and/or HIV leukoencephalopathy.52 However, our study differs in that we compared
brain samples HIV-infected patients with clinically
demonstrated dementia to DNA extracted from HIVinfected patients without dementia. In contrast, the
previous study evaluated brain samples that were histologically classified as demonstrating either HIV encephalitis or HIV leukoencephalopathy or both. No mention is made of whether these patients exhibited clinical
signs of dementia. Thus, although the previous report
concludes that there is no association of the high secretor allele with HIV encephalitis and/or HIV leukoencephalopathy, we conclude that an association exists between the presence of a “high secretor” allele and
HIV dementia.
We found an association between the frequency of
the A allele at the TNF-␣-308 locus and the presence
of dementia in HIV-infected adults. This suggests the
possibility that the TNF-␣ induced neuronal injury
observed in HIV dementia is the result of a local inflammatory reaction in individuals genetically predisposed to have a more vigorous inflammatory response.
It also raises the possibility of using polymorphic analysis to identify HIV-infected individuals at risk for the
development of dementia and for therapies to reduce
TNF-␣ secretion to prevent neuronal injury. Before
such an approach could be recommended, much larger
numbers of patients with and without dementia must
be studied to assess more accurately the association between the TNF-␣-308 allele and the development of
dementia in HIV infection.
The mechanisms by which the polymorphic sites at
position TNF-␣-308 affect TNF-␣ levels are unknown. The polymorphism at the TNF-␣-308 site lies
within the promoter region for the TNF-␣ gene and
may alter the binding of transcription factors. Studies
with the TNF-␣ promoter linked to a chloramphenicol
acetyltransferase reporter gene have demonstrated that
the A allele at TNF-␣-308 site is associated with higher
constitutive and inducible levels of transcription than
the more common G allele.53 Kroeger, et al,54 demonstrated, furthermore, a variability in the ability of this
region to bind nuclear proteins depending on a single
nucleotide difference in the oligonucleotide. Current
studies are continuing in our laboratory to identify the
molecular mechanisms by which this region affects serum levels of TNF-␣.
There are some limitations to our study. First, it
may be that the precise genetic variation associated
with dementia in HIV-infected adults is not at the
TNF-␣-308 site but rather at one closely linked to it.
The gene for TNF-␣ is located in the MHC complex,
raising the possibility that the MHC type or another
closely linked gene is more directly responsible for the
160
Annals of Neurology
Vol 50
No 2
August 2001
dementia. Second, a possibility exists that tissuespecific genetic variations at the TNF-␣-308 site are
present in the brain and blood samples and that our
observed differences are the result of these tissuespecific differences. However, several of the samples in
the group of HIV-infected adults without dementia
were obtained from brain specimens, and there were
no differences in the genotypic or allelic frequencies
between those samples obtained from brain vs blood in
this group. Finally, the cohort of HIV-infected patients
with dementia is small. We suggest that a larger prospective study evaluating the association of TNF-␣
polymorphisms with dementia in HIV-infected adults
is warranted.
In summary, HIV-infected adults with dementia
have a higher frequency than HIV-infected adults
without dementia or a healthy control group of the A
allele at the TNF-␣-308 site in the promoter of the
gene coding for TNF-␣. These findings suggest that
the development of dementia in adults with HIV may
be in part influenced by genetic factors. These findings
also suggest the possibility of identifying HIV-infected
adults who may be at risk for the development of dementia and for whom anti-TNF-␣ strategies may be
developed to lessen this risk. Further studies are needed
to test the hypothesis supported by this study that genetic polymorphisms that influence the host immune
response may play an important role in HIV dementia.
This project was supported in part by the Crippled Children’s
Foundation (M.W.Q.) and NIH grant NS26643 ( J.M.).
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