JOURNAL OF VIROLOGY, June 2002, p. 5797–5802
Copyright © 2002, American Society for Microbiology. All Rights Reserved.
Vol. 76, No. 11
Enhanced Expression of Proinflammatory Cytokines in the Central
Nervous System Is Associated with Neuroinvasion by Simian
Immunodeficiency Virus and the Development of Encephalitis
Marlene S. Orandle,† Andrew G. MacLean,† Vito G. Sasseville,‡ Xavier Alvarez,† and
Andrew A. Lackner*
New England Regional Primate Research Center, Southborough, Massachusetts 01772-9102
Received 19 November 2001/Accepted 21 February 2002
Inflammatory cytokines are believed to play an important role in the pathogenesis of human immunodefi-
ciency virus type 1-associated encephalitis. To examine this in the simian immunodeficiency virus (SIV)-
infected macaque model of neuroAIDS, inflammatory cytokine gene expression was evaluated in the brains of
macaques infected with pathogenic SIVmac251by reverse transcriptase PCR. Interleukin-1 beta was readily
detected in the brains of all animals evaluated, regardless of infection status or duration of infection. Tumor
necrosis factor alpha (TNF-?) and gamma interferon (IFN-?) transcripts were undetectable in the brains of
uninfected control animals but were upregulated at 7 and 14 days postinoculation. At the terminal stage of
infection, TNF-? and IFN-? transcripts were coexpressed in the brains of four of five animals with SIV
encephalitis (SIVE). Within an encephalitic brain, TNF-? and IFN-? transcripts were detected in six of seven
regions with histologic evidence of SIVE, suggesting a direct relationship between neuropathology and altered
cytokine gene expression. With combined fluorescent in situ hybridization and immunofluorescence, TNF-?-
expressing cells were frequently identified as CD68-positive macrophages within perivascular lesions. These
observations provide evidence that cytokines produced by activated inflammatory macrophages are an impor-
tant element in the pathogenesis of SIVE.
Approximately 25% of human immunodeficiency virus type
1 (HIV-1)-infected adults develop a debilitating neurological
disorder termed AIDS dementia complex (ADC) (18, 22, 23).
The pathological substrate of ADC, termed HIV encephalitis
(HIVE), is characterized by perivascular accumulation of mac-
rophages and multinucleated giant cells in the central nervous
system (CNS) and abundant infection and activation of brain
macrophages (1, 14, 43). Early reports suggested that the level
of virus replication within the CNS was correlated with the
presence of ADC (43). However, more recent data have dem-
onstrated that the number of activated inflammatory macro-
phages in the CNS was more closely correlated with dementia
in people with AIDS (8). Since HIV-1 does not productively
infect neurons, the causes for CNS dysfunction in people with
AIDS remain uncertain. Neurological impairment is thought
to result from the release of cytokines and other neurotoxins
from activated macrophages/microglia in inflammatory infil-
trates, some of which are infected with HIV.
Inflammatory cytokines, including tumor necrosis factor al-
pha (TNF-?), interleukin-1 beta (IL-1?), and gamma inter-
feron (IFN-?), have been shown to induce neuronal apoptosis
and death in vitro (7) and also function to mediate the activa-
tion of monocytes/macrophages, the primary cell type infected
with HIV or simian immunodeficiency virus (SIV) in the CNS
(44). These cytokines also activate brain endothelial cells (17),
thereby facilitating leukocyte recruitment to the CNS. A num-
ber of cytokines, including IL-1? and TNF-?, are dysregulated
in encephalitic brains of patients with AIDS (30, 31, 34, 38, 39).
It is therefore likely that cytokines produced by inflammatory
mononuclear cells (29, 31, 40) play a significant role in the
neuropathogenesis of AIDS.
We and others have extensively characterized changes in the
CNS of macaques infected with pathogenic SIV. From this
body of work, it has been well documented that viral neuroin-
vasion occurs early following SIV infection. Virus is routinely
detected in the CNS by 7 to 14 days after infection (2, 6, 11, 15,
44). Neuroinvasion is correlated with increased numbers of
perivascular macrophages, enhanced endothelial expression of
vascular cell adhesion molecule 1 (VCAM-1), and evidence of
intrathecal immune activation (12, 15, 25, 32, 44). During both
acute and terminal infections, most SIV-infected cells are
perivascular macrophages (12, 44), suggesting that infected
cells enter the CNS from the periphery. During the asymptom-
atic stage of infection, viral load in the CNS decreases, only to
rebound again as immunodeficiency develops (32, 44). Similar
to what has been described for HIV infection, approximately
25% of SIV-infected macaques develop encephalitis (21, 41).
Encephalitis in SIV-infected rhesus macaques is associated
with blood-brain barrier disruption (16), enhanced CNS ex-
pression of chemokines (28) and chemokine receptors (42),
and increased endothelial expression of VCAM-1 (27). Since
many of the changes described above can be modulated by
proinflammatory cytokines, we were interested in investigating
the expression of CNS cytokines during the acute stage of
infection, concurrently with HIV or SIV neuroinvasion, and in
animals with AIDS, with and without encephalitis.
* Corresponding author. Present address: Tulane University Health
Sciences Center, Tulane Regional Primate Research Center, 18703
Three Rivers Rd., Covington, LA 70433. Phone: (985) 871-6201. Fax:
(985) 893-1352. E-mail: firstname.lastname@example.org.
† Present address: Tulane Regional Primate Research Center, Cov-
ington, LA 70433.
‡ Present address: Bristol-Myers Squibb, Princeton, NJ 08543-5400.
CNS tissues from 22 juvenile or adult rhesus macaques (Ma-
caca mulatta) were evaluated retrospectively in the present
study. The 20 SIV-infected animals were inoculated intrave-
nously with uncloned SIVmac251. Virus stocks and doses were
the same as those used previously (15, 36, 45). The remaining
two animals were uninfected, age-matched controls. The ex-
pression of IL-1?, TNF-?, and IFN-? transcripts was evaluated
by reverse transcriptase PCR in the CNS of macaques during
both acute and terminal SIV infection essentially as described
previously (21). The optimal number of PCR cycles was deter-
mined initially by using a variable number of cycles to identify
a linear range of amplification for each transcript. When sam-
ples were determined to have comparable cDNA based on the
intensity of the ?-actin PCR product (24), cytokine cDNAs
were amplified with published primer sequences (37).
Ten SIV-infected animals were euthanized at timed intervals
during the acute stage of infection: five animals were evaluated
at 7 days postinoculation (dpi), three animals at 14 dpi, and
two animals at approximately 1 month postinoculation (mpi).
IL-1? mRNA was readily detected in the brains of all animals
evaluated, regardless of infection status or time postinfection.
In contrast, TNF-? and IFN-? could not be detected in the
brains of uninfected controls (Table 1). However, by 7 dpi,
TNF-? and IFN-? were present in five of five and four of five
infected animals, respectively. Both cytokines were still present
in two of three animals evaluated at 14 dpi. However, by 1 mpi,
IFN-? transcripts could no longer be detected in the CNS of
either of the two animals evaluated, while TNF-? was detected
in the CNS of only one animal.
TNF-? and IFN-? can induce VCAM-1 expression in cul-
tured brain endothelial cells in a variety of species, including
rhesus macaques (17). Increased endothelial expression of
VCAM-1 in the CNS occurs by 14 dpi with pathogenic SIV,
concurrent with viral neuroinvasion (25). Endothelial cell ad-
hesion molecules have been shown to be involved in the ad-
hesion of monocytes to activated brain endothelium in HIV
and SIV infections (19, 26). Thus, based on our observations
and those of others, we speculate that increased levels of
IFN-? and TNF-? in the CNS of macaques during acute SIV
infection play an important role in facilitating the initial entry
of mononuclear cells, some of which are infected with SIV,
into the CNS via activation of brain endothelium.
Cytokine abnormalities, including increased TNF-?, have
been noted in the CNS of HIV-infected patients with ADC (9,
38, 39), suggesting that indirect mechanisms, such as abnormal
cytokine expression, may contribute to the pathogenesis of
neurological disease. However, it is not clear from these re-
ports whether the observed cytokine changes were directly
associated with neuropathology in demented individuals. We
TABLE 1. Cytokine changes in the brains of macaques during the
acute stage of SIV infection
Presence (?) or absence (?) of
aAnimals are designated by their animal identification numbers.
bTC, temporal cortex; FC, frontal cortex; PC, parietal cortex; OC, occipital
TABLE 2. Cytokine gene expression in encephalitic and
nonencephalitic brains of adult macaques terminally infected with
Presence (?) or absence (?)
of indicated cytokine
SIV without encephalitis
aAnimals are designated by their animal identification numbers.
bTC, temporal cortex; FC, frontal cortex; PC, parietal cortex; C, cortex.
TABLE 3. Expression of proinflammatory cytokines and presence
of SIVE in multiple brain regions from a macaque with encephalitis
Presence (?) or
absence (?) of
aSeverity scoring system: 0, none; 1, minimal; 2, mild; 3, moderate; 4, severe.
bDistribution scoring system: 1, focal; 2, multifocal; 3, diffuse; N/A, not ap-
plicable (no lesions).
5798NOTES J. VIROL.
therefore sought to investigate the association between cyto-
kine abnormalities and neuropathology by comparing cytokine
profiles in the CNS of SIV-infected macaques with and without
encephalitis. We evaluated CNS tissues from 10 additional
animals that were similarly infected with SIV but were allowed
to progress until they were moribund with AIDS. Five animals
with AIDS and histologic evidence of SIV encephalitis (SIVE)
and five animals with histologically normal brains were se-
lected from a larger group of SIV-infected animals for evalu-
ation of cytokine gene expression. None of the selected ani-
mals had histologic evidence of CNS opportunistic infections.
The diagnosis of SIVE in animals with AIDS was based on the
presence of perivascular accumulations of macrophages and
multinucleated giant cells and the presence of SIV demon-
strated by in situ hybridization. Riboprobes and methods for
SIV localization have been described elsewhere (10, 21). Sim-
ilar to observations during acute SIV infection, IL-1? was
detected in all tissues, regardless of neuropathological status.
Both TNF-? and IFN-? were detected in the brains of four of
five animals with SIVE (Table 2), whereas TNF-? or IFN-?
alone was detected in the brains of two of five or one of five
animals without encephalitis, respectively (Pz ? 1.25? 0.89; Z
It has been suggested that CNS expression of cytokines in
HIV-infected patients with AIDS may reflect a generalized
CNS immune activation with terminal disease (34). We there-
fore sought to investigate whether the expression of IFN-? and
TNF-? in the CNS of animals with SIVE was generalized or
associated with areas of neuropathology. TNF-? and IFN-?
gene expression was evaluated in multiple regions within the
brain of an animal with SIVE and then correlated with the
presence and severity of lesions within each region. The sever-
ity and distribution of lesions were scored as described previ-
ously (28) and outlined in Table 3. As with our observations
when comparing cytokines in encephalitic versus nonencepha-
litic brains, there was coordinate expression of both TNF-?
and IFN-? in six of seven CNS regions with histologic evidence
of SIVE (Table 3). By evaluating multiple regions within an
encephalitic brain, we were able to clearly demonstrate a direct
association (Pz ? 5.99? 0.99; Z test) between altered cytokines
and the presence of characteristic lesions within these regions.
Thus, we can conclude that the enhanced expression of TNF-?
FIG. 1. Demonstration of TNF-? transcripts in paraffin-embedded sections of brain from an SIV-infected macaque with SIVE. Many TNF-??
cells are CD68?macrophages (colocalized as yellow) located within a focus of inflammation. TNF-? transcripts are also evident within endothelial
cells adjacent to the lesion and other cells within the neuropil. Bar ? 10 ?m.
VOL. 76, 2002NOTES 5799
and IFN-? in the CNS of macaques with SIVE is directly
associated with areas of neuropathology and does not reflect a
generalized phenomenon of CNS immune activation.
Our observation that TNF-? and IFN-? were coordinately
expressed in the CNS of acutely infected macaques and in
macaques with SIVE suggests that these two cytokines may be
functioning synergistically. In human cell lines, TNF-? and
IFN-? have been shown to synergistically regulate the expres-
sion of inflammation-associated genes such as those encoding
major histocompatibility complex class I, intercellular adhesion
molecule 1, and VCAM-1 (4). TNF-? and IFN-? have also
been shown to synergistically enhance fractalkine expression in
cultured astrocytes (46). Fractalkine plays an important role in
the recruitment and adhesion of monocytes to human endo-
thelial cells (3) and is markedly upregulated in the brains of
pediatric patients with HIVE compared to those without
HIVE (33). Thus, it is possible that TNF-? and IFN-? operate
synergistically in the CNS to enhance the recruitment and
adhesion of monocytes from the peripheral blood into the
It is believed that neurotoxins produced by inflammatory mac-
rophages contribute to the development of neurologic impair-
ment in ADC. TNF-? is a potent neurotoxin, and its expression
has been described in both endothelial cells and macrophages/
microglia in tissues from patients with ADC (20, 29, 35, 40). To
determine the cellular source of TNF-? and IFN-? in tissues from
macaques with SIVE, we developed a novel fluorescent in situ
hybridization technique combined with immunofluorescence. In
situ hybridization was performed essentially as described previ-
ously (21, 44). Sections were hybridized overnight with antisense
cytokine riboprobe. Digoxigenin-labeled riboprobes specific for
rhesus macaque TNF-? and IFN-? genes were synthesized in
vitro from T7 RNA polymerase promoter-tailed DNA templates
generated by a PCR-based system (5). Bound probes were de-
tected with sheep antidigoxigenin antibodies. Detection was per-
formed with either nitroblue tetrazolium/5-bromo-4-chloro-3-in-
dolylphosphate (NBT/BCIP) for light microscopy or HNPP (2-
hydroxy-3-naphthoic acid-2?-phenylanilide phosphate) and Fast
Red TR for fluorescent microscopy (Roche Molecular Biochemi-
cals, Indianapolis, Ind.). This was followed by two-color immuno-
fluorescent staining and subsequent confocal imaging as de-
scribed previously (13, 44). Briefly, tissue sections were
sequentially incubated with a polyclonal antibody specific for
brain endothelial cells (GLUT-1; Chemicon, Temecula, Calif.)
and a monoclonal antimacrophage antibody (CD68, clone KP1;
DAKO Corporation, Carpinteria, Calif.), followed by secondary
antibodies conjugated either with Alexa Fluor 488 for CD68 de-
tection or with Cy5 for GLUT-1 detection (Molecular Probes,
In accordance with data from HIV dementia cases, we dem-
onstrated that CD68?macrophages within perivascular lesions
are a significant source of TNF-? transcripts in the brains of
macaques with SIVE (Fig. 1). Other cell types, including brain
endothelial cells within lesions (Fig. 1) and ependymal cells
(data not shown), were identified as additional sources of
TNF-? in encephalitic brain. Other unidentified cells adjacent
to lesions also expressed TNF-?. The identification of endo-
thelial cells as a source of TNF-? provides additional evidence
for the key role of endothelial activation in the pathogenesis of
SIVE. In comparison, IFN-? transcripts were restricted to iso-
FIG. 2. Demonstration of IFN-? transcripts by in situ hybridization on paraffin-embedded sections of brain from an SIV-infected macaque with
SIVE. Isolated, intensely positive mononuclear cells, consistent with lymphocytes, are evident adjacent to small blood vessels (indicated by the
letter V) (A) and within the subependyma (B).
5800 NOTESJ. VIROL.
lated mononuclear cells typically adjacent to small blood ves-
sels (Fig. 2). Hybridized cells, which are morphologically com-
patible with lymphocytes, were intensely positive for IFN-?.
These cells did not appear to be directly associated with in-
flammatory lesions. Evaluation of the brains of patients with
HIVE showed a similar association between macrophage in-
filtration, increased expression of endothelial adhesion mole-
cules, and increased expression of proinflammatory cytokines
(19), suggesting a common role for cytokines in HIV and SIV
We thank the pathologists and staff within the Division of Compar-
ative Pathology at the New England Regional Primate Research Cen-
ter for performing necropsies and histology. We also thank Robin
Rodriguez and Pyone Pyone Aye at the Tulane Regional Primate
Research Center for graphical and statistical assistance, respectively.
This work was supported by Public Health Service grants NS35732,
NS30769, MH61192, RR000164, and RR000168. A. A. Lackner is the
recipient of an Elizabeth Glaser Scientist award.
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