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Elevated alphaЦtumor necrosis factor levels in spinal fluid from HIV-1Цinfected patients with central nervous system involvement.

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Elevated Alpha-Tumor Necrosis
Factor Levels in Spinal Fluid from
HIV-1-infected Patients with
Central Nervous System Involvement
L. M. E. Grimaldi, MD,* G. V. Martino, MD," D. M. Franciotta, MD,? R. Brustia, MD,S A. Castagna, MD,S
R. PristerP, MD," and A. Lazzarin, MDS
To assess the role of alpha-tumor necrosis factor in the pathogenesis of central nervous system involvement during
human immunodeficiency virus type 1 infection, we recorded clinical data and measured alpha-tumor necrosis factor
levels in serum and cerebrospinal fluid samples from 4 5 patients infected with human immunodeficiency virus type 1,
classified as group II/III (lo),group IV A ( 5 ) , group IV B (lo), and group IV C-l(20) of the Centers for Disease Control
acquired immunodeficiency syndrome classification system and 42 controls. Alpha-tumor necrosis factor was above
the limit of detection in only 3 of 15 sera and 3 of 15 cerebrospinal fluid samples from patients in group II/III and
group 1V A, whereas it was detected in 17 of 30 sera ( p < 0.05) and 22 of 30 cerebrospinal fluid @ < 0.0002) samples
from clinically more advanced patients (group IV B and group IV C-1). Alpha-tumor necrosis factor mean values were
21.5 pg/ml in sera and 50.0 pg/ml in cerebrospinal fluid from group IV B patients and 30.4 pg/ml in sera and 24 pg/ml
in cerebrospinal fluid from group IV C-1 patients. In 15 of 19 (79%)patients with human immunodeficiency virus type
1encephalopathy (group IV B, 9 of 10 patients) and with opportunistic infections of the central nervous system (group
Iv C-l,6 of 9 patients), alpha-tumor necrosis factor levels were more elevated in cerebrospinal fluid (mean value, 42
pglml) than in serum (mean value, 20.7 pg/ml), whereas the opposite ( p < 0.002) was found in 6 of 7 (86%) patients
with systemic opportunistic infections not involving the central nervous system (serum mean value, 38.9 pg/ml vs.
cerebrospinal fluid mean value, 15.0 pg/ml). No correlation was found between elevated alpha-tumor necrosis factor
levels and clinical evidence of dementia or central nervous system demyelination. We conclude that intrathecal
production of alpha-tumor necrosis factor occurs during central nervous system localization of human immunodeficiency virus type 1 infection. Alpha-tumor necrosis factor elevation seems to be related to active infection/inflammation.
Measurement of cerebrospinal fluid alpha-tumor necrosis factor levels may thus represent a useful marker for ongoing central nervous system localization of human immunodeficiency virus type 1 infection.
Grimaldi LME, Martino GV, Franciotta DM, Brustia R, Castagna A, Pristerh R, Lazzarin A. Elevated
alpha-tumor necrosis factor levels in spinal fluid from HIV-1-infected patients with
central nervous system involvement. Ann Neurol 1991;29:21-25
Alpha-tumor necrosis factor (alpha-TNF) is a cytokine produced by activated lymphocytes and macrophages that shows a broad spectrum of regulatory
effects on immunological, hematopoietic, and inflammatory processes (for review, see { 1)).Recently, a role
for alpha-TNF was proposed to explain the demyelination found in patients with multiple sclerosis
human T-cell lymphotropic virus type I-associated
myelopathy 13). Astrocytes, in fact, can be activated by
demyelinating viruses 141 and are able to produce in
vitro an alpha-TNF-like substance that kills primary
rat oligodendrocyte cultures [ 5 ] . Recombinant human
alpha-TNF (rHuTNF) also has direct demyelinating
effects on rat { 5 ] and mouse {G] cultured oligodendrocytes. Alpha-TNF may therefore participate in the demyelination occurring in brains from patients with
human immunodeficiency virus type 1 (HIV-1) encephalopathy, a subacute encephalitis commonly complicating HIV- 1 infection, clinically characterized by
subcortical dementia, with pathological evidence of
myelin loss, astrocyte proliferation, and presence of
multinucleated cells 17).
The relation between dementia and demyelination
during HIV-1 infection is unclear. Some patients with
From 'Clinica Neurologica IV, IRCCS San Raffaele, and 5Clinica
delle Malattie Infettive.. OsDedaie
L. Sacco. Universitl di Milano.
Milano, tIstituto Neurologic0 "Fondazione Mondino" and iClinica
delle Malattie Infettive, UniversitA di Pavia, Pavia, and "Divisione
Malattie Infettive, Ospedale Regionale, Bolzano, Italy.
Received Dec 27, 1989, and in revised form May 17 and Jun 29,
1990. Accepted
-Tul4, 1990.
Address correspondence to Dr Grimaldi, Clinics Neurologica Iv,
Universitl di Milano, Ospedale sari Raffaele, Via OIgettina, G ~ 20132 Milano, Italy.
Copyright 0 1991 by the American Neurological Association 21
HIV-1 encephalopathy do not show central nervous
system (CNS) demyelination [?I, whreas some patients infected with HIV-l have normal cognitive functions with white matter pallor at autopsy IS]. A cytokine involvement has also been suggested to explain
the pathogenesis of neuropsychiatric manifestations of
HIV-1 infections C9I. To assess the role played by
alpha-TNF in the pathogenesis of CNS disorders occurring during HIV-1 infection, we measured its level
in sera and cerebrospinal fluid (CSF) from patients infected with HIV-1, with and without CNS involve-
Materials and Methods
Patients and Samples
Paired CSF and serum samples were obtained from 45 HIV1 seropositive patients (37 males, 8 females) at different
stages of HIV-1 infection. Their ages ranged from 20 to 70
years (mean, 30.4 years). Thirty-eight patients were intravenous drug abusers (30 males, 8 females), 5 were homosexual,
and 2 had both risk factors. Samples from symptomatic patients were obtained at the time of the first clinical evaluation. N o patients were under specific treatment for opportunistic infections nor were on zidovudine at the time of
sample collection.
Patients were classified according to the guidelines of the
Centers for Disease Control [lo} in the following way: group
II/III (10 patients), group IV A ( 5 patients), group IV B (10
patients), and group IV C-1 (20 patients). Group IV B patients, including patients with cognitive, motor, and behavioral abnormalities but no myelopathy or peripheral neuropathy { 111, were studied before the appearance (or still in the
absence) of major systemic opportunistic infections, as inferred by negative serum and CSF antigen or antibody studies for common opportunistic agents, computed tomography, and magnetic resonance imaging of the CNS, or any
combination of these studies and scans. Diffuse CNS demyelination was found at autopsy (performed 1 to 8 weeks after
CSF removal) in 3 of 4 patients in group IV B.
To study the variation of alpha-TNF levels in relation to
the occurrence of opportunistic infections within or outside
the CNS, we subclassified group IV category C-1 into subcategories C-la and C-lb (Table). Patients in group IV C-la
suffered from opportunistic infections within the CNS, including cerebral toxoplasmosis (5 patients) and cryptococcal
meningitis (6 patients). Patients in group IV C-lb suffered
from opportunistic infections outside the CNS includingPneumaystis cariniz pneumonia (7 patients), cryptococcal pneumonia (I patient), and esophageal candidiasis ( I patient).
Neurosyphilis, frequently associated with HIV infection and
with alpha-TNF elevation [121, was routinely ruled out in all
patients by Venereal Disease Research Laboratory, microhemoagglutination-treponema pallidum (MHA-TP), and
fluorescent treponemal antibody absorption (FTA-ABS)tests.
Control specimens from HIV- 1 seronegative patients included 10 sera from healthy individuals, as well as paired
serum and CSF samples from 14 orthopedic patients, 5 patients with tension headache, and 3 patients with lumbar disk
disease. Serum samples from 10 HIV-1 seronegative intrave-
Annals of Neurology
Vol 29
No 1 January 1991
Classifcution System for Human
lnzmunodeficiency Virus Infiction"
Group I. Acute infection
Group 11. Asymptomatic infection
Group 111. Persistent generalized lymphadenopathy
Group IV. Other diseases
Subgroup A. Constitutional disease
Subgroup B. Neurological diseases
Subgroup C. Secondary infectious diseases
Category C-1. Speched secondary infectious
diseases listed in the CDC
surveillance for AIDS [lo)
Subcategory C-la. Secondary infectious diseases
within the central nervous
Subcategory C- 1b. Secondary infectious diseases
outside the central nervous
Category C-2. Other specified secondary infectious
Subgroup D. Secondary cancers
Subgroup E. Other conditions
"Modified from [lo].
CDC = Centers for Disease Control; AIDS
immunodeficiency syndrome.
nous drug abusers were also studied to exclude that an alteration of alpha-TNF production was not specifically associated
with the altered immunity frequently found in these patients
Enzyme-linked Immunosorbent Assay f i r Alpha-TNF
Alpha-TNF levels were measured in all samples by an
enzyme-linked immunosorbent assay (ELISA) test (T-cell
Science, Cambridge, MA) able to detect alpha-TNF levels
greater than 10 pg/ml (or 0.2 Uiml). The obtained standard
curve was tested with a different brand of rHuTNF (Genzyme, Boston, MA), showing a specific activity of 2 X lo7
U/mg. Results were compatible with the expected values.
Sera and synovial fluid from 3 patients with rheumatoid
arthritis showing elevated alpha-TNF levels El41 were used
as positive clinical controls.
Sera and synovial fluid were opportunely diluted (1: 10 to
1 : 100 {volivol)) before testing; CSF was tested undiluted.
All samples were run in duplicate, and results were confirmed on repeated testing.
The mean of alpha-TNF levels was calculated by attributing an arbitrary value of 5 pgiml to samples with an alphaT N F level greater than 10 pgiml. By attributing values of 0
and 10 pgiml to the samples with an alpha-TNF level of
greater than 10 pgiml, we considered all possible fluctuations
of the mean value in the 0 to 10 pg/ml range.
Other Humoral Studies
Serum and CSF albumin and IgG levels were measured by
nephelometric methods in all but 4 HIV-1 seropositive patients. Blood-brain barrier damage was evaluated according
to Thompson's criteria [ l 5 ] . Intrathecal immunoglobulin G
(IgG) production was measured by calculating the IgG index
116) or determining the presence of CSF oligoclonal bands
Fig I . Alpha-tumor necrosis factor lenels i n sera and cwehospinal fluid samples from control patients with other neurological
diJeases, intravenous drug abusers, and HIV-I -injicted patients
cla.w$ed as group IIIIII, group IV A, group IV B, group IV
C-la, and group IV C-Ib (see Table). TNF = alpha tumor
necrosisfactor; ser = serum; CSF = cerebrospinaljuid; IVDA
= intravenous drug abusers.
Fig 2. Cerebmrpinalj a i d versus serum alpha-tumor necrosis factor levels in symptomatic HIV-I -infictedpatients with (group
IV B {open circles}, group IV C-la {open squares}). and
without (group IV C-lb {filled circles)) central nerwous system
involvement. Dotted lines represent the lower limit of detection
(10 pglmli of the assay. TNF = alpha-tumor necrosir factor;
CSF = cerebrospinaljuid.
C17). The CSF and serum levels of HIV-1 p24 antigen were
also measured by an ELISA (Cellular Product, Buffalo, NY)
in 29 of 45 HIV-1 seropositive patients.
All data were statistically correlated by using the x2 test
and the Mann-Whitney U test.
patients in group IV C-1) had measurable levels of
alpha-TNF. Patients in group IV B had an alpha-TNF
mean value of 2 1.5 pgiml (fluctuations of the mean
value, ? 2.5) in serum and of 50 pgiml in CSF; patients in group IV C-la had a mean of 20 pgiml (fluctuations of the mean value, -t 2.7) in serum and of 35
pgiml (fluctuations of the mean value, t 1.4) in CSF;
patients in group C-1b had a mean of 38.3 pgiml (fluctuations of the mean value, zk 1.1) in serum and of 15
pgiml (fluctuations of the mean value i 2.8) in CSF.
The mean of alpha-TNF levels for the patients in combined groups IV B and IV C-la was 20.7 pg/ml (fluctuations of the mean value, ? 2.6) in serum and 42 pgl
ml (fluctuations of the mean value,
0.7) in CSF.
Alpha-TNF levels that were higher in CSF than in
serum were found in 15 of 19 (79%) patients from the
combined groups IV B (9 of 10 patients, including the
3 patients with evidence of CNS demyelination and a
demented patient without evidence of CNS demyelination at autopsy) and IV C-la (6/9 patients); alpha-TNF
levels higher in serum than in CSF were found in 6 of
7 patients (8676) belonging to the IV C-lb group of
patients with opportunistic infection without CNS
involvement (Fig 2). Overall, alpha-TNF levels significantly correlated with localization of the inflammatoryiinfectious process Cp < 0.002).
N o significant differences were found between the
alpha-TNF levels in samples from patients belonging
to the groups IV B and 1V C-la.
Alpha-TNF Quantitation
Results of alpha-TNF quantitation are shown in Figure 1.
Control Patients
Only 5 of 32 sera (15.65%) and 1 of 22 CSF (4.596)
samples from healthy control patients and orthopedic
or neurological control patients, and 1 of 10 (10%)
sera from intravenous drug abusers showed detectable
levels of alpha-TNF.
HIV- 1 Seropositive Patients
Alpha-TNF was detected in 20 of 45 (4496) sera and
in 25 of 45 (55%) CSF samples from HIV-1 seropositive patients. The majority (72%) of the 25 HIV-1
seropositive patients with detectable CSF alpha-TNF
levels belonged to the groups of patients with CNS
clinical involvement (groups IV B and IV C-la) (a <
Two of 10 patients from group IIiIII (2096) and 1 of
5 patients from group IV A (2076) showed detectable
levels of alpha-TNF in their paired CSF and serum, a
result comparable with control patients. Among the
samples obtained from patients at more advanced
stages of HIV-1 infection (groups IV B and JV C-l),
17 of 30 (57%) sera (5 from patients in group IV B, 12
from patients in group IV C-1) and 22 of 30 (73%)
CSF samples (10 from patients in group IV B, 12 from
Other Humoral Studies
Twenty-four of 42 (57%) HIV-1 seropositive patients
showed a slight increase of blood-brain barrier permeability (percentage of albumin transfer from serum to
Grimaldi et al: Alpha-TNF in CSF from HIV-1 Patients
CSF, ranging from 0.7% to 2.0%). Intrathecal I@
synthesis was present in 21 of 42 (50%) HIV-1
seropositive patients. No statistical correlation was
found between these evaluations and detectable CSF
levels of alpha-TNF.
HIV-1 p24 antigen was detected in 3 of 11 (27%)
sera and 1 of 11 (9%) CSF samples from patients in
group II/III and group IV A; in patients from groups
IV B and IV C-1, HIV-1 p24 antigen was detected in
13 of 18 (72%) sera and 3 of 18 (17%) CSF samples.
Among samples positive for HIV-1 p24 antigen,
alpha-TNF was detected in 7 of 13 (54%) sera and all
3 CSF obtained from patients in group 1V B and group
IV C-1 but not in samples from patients in groups II/
111 and IV A. The detection of HIV-1 p24 antigen (an
index of HIV-1 replication) was thus more frequent in
samples with measurable alpha-TNF levels.
The hypothesis that an elevation of alpha-TNF levels
could explain the demyelination or the dementia seen
in patients with CNS localization of HIV-1 infection is
supported by the following observations: (1)astrocytes
are activated by demyelinating viruses 111 and express
CD4, the cell surface receptor for HIV-I [l8), (2)
HIV-1 particles are detected in astrocytes from patients with HIV-1 encephalopathy C191, (3) astrocytes
activated in vitro by inflammatory or viral stimuli produce alpha-TNF [20], and reactive astrocytes participate in white matter inflammation in HIV-1 infected
brains [81, (4) rHuTNF is able to damage rat [5) and
mouse [GI oligodendrocyte cultures, and ( 5 ) CSF
alpha-TNF levels are reported to be more elevated in
patients with HIV-1 encephalopathy than in healthy
patients who are HIV-1 seropositive 121).
We actually found higher alpha-TNF levels in CSF
than in serum, suggesting intrathecal production of
alpha-TNF, in HIV-1 seropositive patients with dementia (group IV B), including our 3 patients with
autopsy evidence of CNS demyelination; however, a
similar elevation was also seen in iiondemented patients with CNS opporrunistic infections, such as cryptococcal meningitis and cerebral toxoplasmosis, not
usually accompanied by overt demyelination 1221. Our
results do not support a specific role for alpha-TNF in
causing HIV- 1-associated CNS demyelination or dementia, but an alpha-TNF involvement in these CNS
complications of HIV-1 infection certainly cannot be
ruled out.
Although the amount of rHuTNF (500-10,000 U/
ml) able to cause demyelination in vitro 15, 6) and
biologically active in vivo {23] is ?-fold to 200-fold
more elevated than alpha-TNF levels measured in our
group of HIV-1-infected patients, the short half-life
of alpha-TNF and the widespread distribution of its
receptors throughout the body may hamper its avail-
24 Annals of Neurology Vol 27 No 1 January 1971
ability for antibody detection. Furthermore, CSF may
not accurately reflect alpha-TNF levels in the CNS
parenchyma, as demonstrated by the presence of high
levels of alpha-TNF on the surface of CNS astrocytes
and macrophages in patients with multiple sclerosis, in
the absence of significant levels of CSF-free alpha-TNF
[14, 24). Finally, alpha-TNF elevation observed during
acute opportunistic infections is probably the shortlasting result of acute inflammatory cell responses. We
cannot exclude that chronic exposure to alpha-TNF
does not cause demyelination or dementia. It remains
to be established if alpha-TNF causes CNS demyelination or dementia during HIV-1 infection.
We also observed that patients with CNS opportunistic infections (group IV C-la) showed more elevated alpha-TNF levels in CSF than in serum, whereas
patients with systemic opportunistic infections without
CNS involvement (group IV C-lb) showed the opposite. Alpha-TNF production was similar in patients
with HIV-1 encephalopathy (group IV B) and patients
with opportunistic infections of the CNS (group IV Cla). In this clinical setting, alpha-TNF levels strongly
correlate with the localization of infection and may
represent a marker of inflammatory/infectious activity
within the CNS. The results of this study support the
validity of our modification of the Centers for Disease
Control classification system for HIV infection (see
Materials and Methods).
Alpha-TNF can stimulate HIV-1 replication 1251.
The levels of alpha-TNF ( 5 2 U / d ) that we measured
in serum and CSF samples from patients in group IV B
and group C, but not in asymptomatic patients or in
patients in groups 111 and IV A, are of a magnitude
comparable with those needed to enhance HIV-1 replication in chronically infected cell cultures [261. We
found the most elevated alpha-TNF levels in samples
from patients with active HIV-1 replication, as inferred from the presence of HIV-1 p24 antigen. This
observation, similar to that made by Jackson and colleagues [27), suggests that circulating alpha-TNF could
contribute to enhance HIV- 1 replication in HIV-1
seropositive patients and provides an in vivo support
for the concerns expressed by Matsuyama and coworkers {28) on the clinical use of TN F in patients
with acquired immunodeficiency syndrome.
Does alpha-TNF play a role in the pathogenesis
of HIV- 1-related imrnunodysregulation? Alpha-TNF
enhancement of HIV-1 expression is mediated by nuclear factor KB,a protein that binds in the nucleus to
a cis-acting DNA sequence called KB 1291. KB functions as an enhancer for the kappa light chain gene in B
lymphocytes 1297, and as a promoter of interleukin-2,
interleukin-2 receptor alpha, and beta-2 microglobulin
genes in T lymphocytes (for review, see 1301). It has
been hypothesized that alpha-TNF, released in response to H IV infection, causes an undesired effect by
enhancing HIV production and, at the same time,
stimulates the production of several other nuclear factor KB-controlled immunologically relevant molecules
from B and T lymphocytes (for review, see C311). A
study that endeavors to correlate circulating levels of
alpha-TNF, beta-2 microglobulin, interleukin-2, interleukin-2 receptor alpha, kappa and lambda light chain
immunoglobulins, and clinical findings in HIV-1 infected patients is presently underway.
Dr Grimaldi is recipient of a fellowship from ARIN (Associazione
per la Promozione delle hcerche Neurologiche).
We thank Professors G.V. Melzi DEril and L. Minoli for their
scientific support. We want to express gratitude to Professor C.
Rugarli, Professor P. Micossi, and K. Winter Beatty for reviewing
the manuscript. We also thank L. Galli for her help in performing
statistical analyses.
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