Review TRENDS in Neurosciences Vol.29 No.
7 July 2006
INMED/TINS special issue
Viral infections in the developing
and mature brain
Anthony N. van den Pol
Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
A number of different RNA and DNA viruses can invade
the brain and cause neurological dysfunction. These
range from the tiny polio picornavirus, which has only
7 kb of RNA genetic code that preferentially infects
motor neurons, to the relatively large cytomegalovirus,
which has O100 genes in its 235 kb DNA genome and
causes various neurological problems in the developing
brain but is comparatively harmless to adults. This brief
overview of some aspects of neurovirology addresses
the complex problems that underlie an appreciation of
the contribution of viral infections to brain disease. [This
review is part of the INMED/TINS special issue Nature
and nurture in brain development and neurological
disorders, based on presentations at the annual
INMED/TINS symposium (http://inmednet.com/).]
Introduction
Despite years of study, and a clear view of which regions in
the brain are involved, we still do not know what causes
most neurological and psychiatric diseases. The specific
characteristics and symptoms for different CNS diseases
are for the most part determined by the identity of the
brain cells or pathways that are damaged or lost. Several
potential factors have been identified that contribute to
CNS disease, including environmental neurotoxins,
genetic substrates, developmental trauma and nutrition.
Viruses that invade the brain have been postulated to
cause some CNS diseases, but the evidence to support this
view is complicated, and the data are sometimes based
more on correlation than on causation. One problem that
underlies any hypothesis about viral mechanisms of brain
dysfunction relates to the large number of different
viruses that can infect the brain, each with a unique
mechanism of entry, replication, defense against the
immune system, and dissemination, and each with
preferred target cells and developmental stages of
infection [1,2] (Table 1). Some viruses are common (e.g.
herpes simplex or influenza), and although the majority of
humans have been infected by them only a small
percentage show serious neurological symptoms due to
these infections. Other viruses are rare, and might be
encountered only in discrete or isolated regions of the
world (e.g. viruses with exotic names such as Kemerova,
Lebombo, Bluetongue, Nyabira, Pootvoot, Kenai, Nipah
and Changuinola), but on occasion have been found to
Corresponding author: van den Pol, A.N. (anthony.vandenpol@yale.edu).
www.sciencedirect.com 0166-2236/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2006.06.002
infect the brains of humans or animals and cause
neurological dysfunction.
With increasingly open trade in food, animal products
and pets, and faster human transportation in the
shrinking world, exotic viruses can potentially move into
new geographical locations and expand both their
geographical range and host species, as has happened
with human immunodeficiency virus (HIV) in the past
three decades from Africa, with West Nile virus (WNV) in
the past decade from the middle east, and with H5N1
avian influenza from east Asia currently. HIV and WNV
can cause neurological problems in humans, and H5N1
can do so in animals [3]. These three viruses have each
passed to humans from non-human species: HIV from
chimpanzees or other non-human primates, WNV from
birds via mosquitoes, and H5N1 from birds directly. If we
look at the demographics for HIV, the virus was unknown
30 years ago, and now the world count of infected humans
is approaching 40 million (http://www.cdc.gov/hiv/
resources/factsheets/index.htm); HIV infections that pro-
gress to AIDS have a 50% probability of inducing
neurological dysfunction, ranging from neuropathy to
full dementia.
Viruses can cause neurological problems not only by
cytolytic actions on neurons or glia, but also by inducing
apoptosis, damaging the blood–brain barrier, initiating
autoimmune attack on specific cells, expressing viral
genes and repressing cellular genes, causing fusion of
cells, altering neuronal migration, attenuating neural
progenitor replication, and blocking cerebrospinal fluid
generation and flow. The multiple mechanisms of viral
induction of CNS dysfunction further complicate an
understanding of viral agents in brain disease.
Genetic predisposition to viral infection
It is difficult to divorce viral infections of the brain from
potential genetic sensitivity to such infections. A crucial
factor in whether a virus gets into the brain relates to
how efficient the immune system is in eliminating the
virus from the whole body. A virus that is rapidly
controlled by the immune system is less likely to gain
access into the CNS. Examples in studies with rodents
underline the crucial importance and interaction of the
genetic background with specific viruses. Cytomegalo-
virus (CMV) is an enveloped (i.e. external lipid
membrane) double-stranded DNA virus in the herpes
family that can cause substantial damage to the
 Review TRENDS in Neurosciences Vol.29 No.7 July 2006 399

Table 1. Properties of seven viruses that infect the nervous system and cause neurological dysfunctiona,b

Name CMV HSV Rabies HIV Polio WNV LCMV

Virus family Beta herpesvirus Alpha herpesvirus Rhabdovirus Retrovirus Picorna virus Flavivirus Arenavirus
Genome (C) DNA (C) DNA (–) RNA (C) RNA (C) RNA (C) RNA (C/–) RNA
Double- Double- Single- Single- Single- Single- Ambisense
stranded stranded stranded stranded stranded stranded single-stranded
linear linear linear linear (2x) linear linear circular

Genome size 235 kb 152 kb 11 kb 9.2 kb 7.5 kb 11 kb 3.5C7 kbc

Number of genes O100 w100 5 9 1d 1d 2C2c
Virus size w200 nm w200 nm 75!180 nm 100 nm 28 nm 45 nm 50–200 nm
Envelope Yes Yes Yes Yes No Yes Yes
Route of Cell-mediated Trigeminal nerve Retrograde Cell-mediated Retrograde Direct BBB BBB crossing
brain entry BBB crossing Olfactory nerve axonal BBB crossing axonal crossing
BBB crossing
Neurological Deafness Encephalitis Guillain–Barre- Dementia Paralysis Encephalitis Developmental
Developmental Herpetic neuralgia like syndrome Encephalitis Respiratory Meningitis brain defects
brain defects Meningitis Progressive Myelitis arrest Myopathy Encephalitis
Encephalitis Myelitis encephalitis Neuropathy Hydrocephalus
Epilepsy Paralysis Meningitis
Guillain–Barre
syndrome
Retinitis
a
Major routes of entry are listed, but as for most viruses, other routes are not excluded. Similarly, the list of symptoms is not exhaustive, and many other symptoms can be
produced by infection of the CNS by each virus [1,2,23,31,62].
b
Abbreviations: BBB, blood–brain barrier; CMV, cytomegalovirus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; LCMV, lymphocytic choriomeningitis
virus; WNV, West Nile Virus. DNA genomes are blue, negative-stand RNA is pink, and positive-strand RNA is green.
c
Short and long segments.
d
Encoding a single large polyprotein. Protease cleavage yields as many as 11 (polio virus) or 10 (WNV) virally encoded proteins

developing brain. Different strains of mice show strik-
ingly different responses to viral infections. For instance,
the C57Bl/6 strain is resistant to CMV infections,
whereas Balb/c mice are susceptible; a difference in a
single mouse gene that regulates natural killer cells
seems to be responsible [4,5]. The difference in genetic
sensitivity to a virus is not simply due to generally weak
immune surveillance by Balb/c mice, because when
infected by a different virus the tables are reversed.
For instance, when infected by intranasal application of
a neuro-adapted Sindbis virus, a positive-strand RNA
virus, 100% of the C57Bl/6 mice died from fatal
encephalitis; by contrast, all of the Balb/cBy mice
infected by the virus in this way survived [6]. Similar
sensitivities are found in human viral infections.
Humans with a mutated chemokine receptor CCR5, a
co-receptor for HIV, show a substantial reduction in the
probability of developing AIDS; by contrast, there is a
higher incidence of West Nile encephalitis associated
with the mutated receptor [7]. Although outside the
scope of the present review, minor shifts in viral genomes
can also have an important role in neurovirulence: for
example, a single amino acid shift from cysteine to serine
at position 102 of WNV substantially attenuated
neurovirulence [8]. A single nucleotide mutation at
position M51 in vesicular stomatitis virus (VSV,
Figure 1), a bullet-shaped RNA virus, reduced the ability
of the virus to infect normal interferon-responsive cells,
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but the virus remained highly infective for most human
tumor cells [9].
Many neurological or psychiatric diseases, including
Parkinson’s disease, schizophrenia, autism, obsessive
compulsive disorder, Tourette’s syndrome and narcolepsy,
show a genetic contribution [10–12] (Persico and Bour-
geron, in this issue). However, the genetic substrate
appears to have only a partial, sometimes minor, role in
the manifestation of many of these diseases, indicating
other factors, probably environmental and sometimes
viral, have crucial roles in concert with an underlying
genetic substrate. A genetic contribution to neurological
dysfunction might generate mistakes in brain develop-
ment or wiring for instance, but could also alter sensitivity
to viral infections within the brain that might lead to
destruction of select cell types.
Many infected, few show symptoms
One of the biggest complications in trying to understand
the role of viruses in human neurological dysfunction is
the striking difference in symptoms of those infected.
This is perhaps best exemplified by polio virus, a small,
non-enveloped positive-strand RNA virus. Although
eliminated in many parts of the world today by
immunization, there are geographical pockets where
polio still exists. Unfortunately, polio seems to be
returning into regions in which it had been eradicated,
in part because of regional political instability leading to
400 Review TRENDS in Neurosciences Vol.29 No.7 July 2006
Figure 1. Electron micrograph of neurons infected by vesicular stomatitis virus (VSV). Bullet-shaped VSV is shown infecting hippocampal neurons in vitro; rabies in the same
family of rhabdoviruses has a similar ultrastructural morphology. The long arrow points to VSV being taken up in clathrin coated pits in a dendrite. Short arrows point to
viruses that are outside the cell, with one arrow showing the shape of the virus in a longitudinal dimension and the other showing the virus cut in cross-section. Scale bar,
200 nm.
impaired immunization programs. Similar to smallpox,
the possibility of eradicating polio virus completely is
greatly increased by the absence of an animal reservoir
for the virus. An important take-home message from
polio is that the typical neurological symptoms of full or
partial motor paralysis are generally found in !1% of
non-immunized humans infected with the virus. In other
words, the great majority of those infected seldom even
know that they are, or have been, infected with this
potentially paralyzing virus [13]. Similar to most other
viruses that can infect the brain, polio virus is not
restricted to brain cells and can infect other cell types
outside the CNS. Polio is primarily a virus of the
gastrointestinal tract. Although the receptor for polio
virus has been identified as a member of the immu-
noglobulin superfamily [14,15], the crucial mechanism
that enables polio to spread into and replicate within the
motor neuron system in the spinal cord has not yet been
determined. An emerging virus that can cause neuro-
logical symptoms similar to polio is enterovirus 71
(which causes hand, foot and mouth disease) [16,17],
another small RNA virus from the same family. Similar
to polio virus, only a small percentage of humans
infected with WNV show neurological symptoms (http://
www.cdc.gov/ncidod/dvbid/westnile/).
In contrast to polio and WNV, infections by rabies
virus, a negative-strand RNA virus, are much more likely
to be dangerous. Although the probability of infection
with rabies virus is only 15% after a bite from a rabid dog
[2], humans with symptomatic rabies rarely survive. The
crucial event here is whether the rabies virus is taken up
by motor axons and retrogradely transported back into
the spinal cord. Three possible neuronal receptors for
rabies have been identified: the ACh receptor [18], neural
cell adhesion molecule (NCAM) [19] and the low-affinity
nerve growth factor (NGF) receptor P75 [20]. Either
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cutting the axons that innervate rabies-infected muscles
or using colchicine to stop axonal transport blocks
movement of the virus into the brain, and neurological
illness is prevented [21,22] (Figure 2). Once within the
CNS, rabies spreads rapidly (Figure 3). Unlike many
other viruses, rabies might not cause cytolytic death of
the infected neurons; rather, it takes command of the
translational pathways in neurons, blocks the synthesis
of proteins that neurons normally make, and conscripts
these pathways into synthesizing proteins encoded by the
viral RNA genome. This renders the neuron unable to
carry out its normal signaling function, because it cannot
generate neuronal molecules [23]. Remarkably, neuro-
pathological examination of a rabies-infected brain might
show little tissue necrosis or cellular loss, whereas
immunocytochemical detection of viral antigens will
reveal widespread viral infection of neurons [18].
Similarly, lymphocytic choriomeningitis virus (LCMV)
and Borna disease virus (BDV) can infect glia and
neurons without killing them, and can lead to long-term
infections; BDV causes severe behavioral disturbances in
many animal species, and has been associated with
increased incidence of psychiatric disease, including
schizophrenia and bipolar disorder, in humans [24,25].
In humans, LCMV fetal infection can lead to serious
neurological complications; infections in adults generally
do not. In a rodent brain exposed to LCMV, the virus
infects cerebellar neurons and periventricular neurons,
but only the cerebellar neurons die [26]. Interestingly,
one mechanism for cell death is a direct attack on
infected cerebellar cells by CD8CT cells; in rodents
with a weakened T-cell immune response, cerebellar
cells are spared [27]. This is another example of the
genetic substrate for immune surveillance having a
crucial role in neurological damage resulting from viral
infections; in this case, a mouse with a vigorous T-cell
 Review TRENDS in Neurosciences Vol.29 No.7 July 2006 401

(a) Anterograde transport into brain from (c) Direct BBB crossing
peripheral cell body via olfactory nerve e.g. WNV, EEE
e.g. VSV, HSV, influenza

(d)
‘Trojan Horse’ crossing
e.g. HIV, CMV
(b) Axon terminal uptake and transport
back to cell body in CNS or PNS

DRG neuron Motorneuron

e.g. VZV, HSV e.g. Rabies

Figure 2. Virus entry into nervous system. (a) Several viruses (VSV, herpes, influenza, pseudorabies virus) can enter the brain by traveling in an anterograde direction along
the olfactory nerve into the olfactory bulb [47,53,63]. (b) Herpes viruses such as varicella zoster virus (VZV) and herpes simplex virus (HSV) commonly enter the trigeminal
nerve or dorsal root ganglion sensory nerves, traveling toward the cell body during primary infection and, if awakened from latency in the cell body, back to the periphery
[62]. Some viruses such as rabies, and in some cases polio, enter the brain after retrograde axonal transport from muscles or other tissue. (c) West Nile virus (WNV) and
eastern equine encephalitis (EEE) can cross the blood–brain barrier (BBB) directly, or can infect endothelial cells and subsequently cross the BBB. (d) Human
immunodeficiency virus (HIV) and cytomegalovirus (CMV) cross the BBB hidden in ‘Trojan Horse’ macrophages or monocytes, and subsequently are released to infect other
cells within the brain. All viruses in this diagram are illustrated as small green hexagons.

response to LCMV might lose more CNS neurons than
one with a weak immune response.
One virus, multiple neurological syndromes:
developmental perspective
Several viruses that can cause neurological dysfunction
show development-dependent preferences. CMV is a
member of the herpes family, with a genome of w235 kb
that encodes O100 genes. Similar to the other seven
members of the herpes family that infect humans,
infection can lead to viral latency, both within [28] and
outside the brain. In latency, the viral genome remains
within the nucleus of infected cells, and can be reactivated
to produce replication-competent virus (Figure 4). As with
other herpes viruses, CMV can remain latent for a human
lifetime. CMV is particularly dangerous to the developing
human or mouse fetus, and has been suggested as the
number one infectious agent causing birth defects and
neurological dysfunction in the developing human brain
[29–31]. CMV can cause various neurological problems
including epilepsy, blindness, deafness, polymicrogyria,
microcephaly, hydrocephalus and mental retardation [32–
34]. The probability of CMV-mediated neurological pro-
blems has been estimated at 0.1% of births, with a
possibility of additional subtle problems such as learning
deficits in infected children [2,33]. As with some of the
other examples described here, only a fraction (!10%) of
intrauterine CMV infections result in neurological dys-
function. Why some fetuses show no CNS debilitation is
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not clearly understood, although it might relate in part to
the developmental period of infection, with infections in
the first trimester being the most problematic. In contrast
to its effects on the developing brain, although CMV
infection is fairly common in adults it causes relatively
little neurological problem, except in immunocompro-
mised individuals such as AIDS patients. It is one of the
opportunistic viruses that invade the brain when the
immune system is weakened [31,35].
This raises the question of why CMV is a problem in
the developing brain but not in the mature brain. One
reason is that in early development, the systemic immune
system is not fully functional, and the T and B
lymphocytes, natural killer cells and macrophages/mono-
cytes are not mature enough to eliminate a viral infection
effectively and rapidly [29,36–38]. The developing brain
also has a poor blood–brain barrier, so if a virus enters
the developing fetus its passage into the brain is not
impeded as it would be in the adult brain. CMV appears
to have an intrinsic preference for developing brain cells
[39,40], perhaps related to the inability of developing
neurons or glia to effect an efficient cellular immune
response. When a CMV promoter such as CMV ie1 is used
to drive reporter genes, transgenic mice show greater
expression during early brain development, suggesting
that transcriptional activation of some of the viral genes
is selectively enhanced in the developing brain [41,42].
Depending on which part of the brain is infected, CMV
causes different neurological syndromes [39,43].
402 Review TRENDS in Neurosciences Vol.29 No.7 July 2006

(a)
Rabies, PRV (Bartha strain):
Retrograde trans-synaptic transmission

2 3
1

(b)
PRV:
Anterograde trans-synaptic transmission

2
1

(c)
CMV, VSV:
Cell-to-cell diffusion
2

2
2

Figure 3. Virus spread within the nervous system. Viruses (red shading) are disseminated by various mechanisms. (a) Some viruses such as pseudorabies virus (PRV Bartha
strain; a pig herpes virus that can infect several mammalian species) and rabies (a rhabdovirus) can be transported retrogradely by the axon and released by the cell body and
dendrites to be subsequently taken up and transported by synaptically coupled neurons. (b) Some viruses (e.g. PRV) are transported anterogradely from the cell body to the
axon terminal where the virus is released (i.e. wild-type PRV is transported along the axon in both retrograde and anterograde directions). (c) Other viruses such as CMV and
VSV are spread to a large degree by local diffusion from one cell to another, or by long distance by diffusion through the cerebrospinal fluid [1,2,25,31,39,62,64].

Although at the cellular level the mechanisms of cytolytic
infection might be the same in different regions of the
brain, completely different symptoms will be generated
by infections of different brain regions, with motor
deficits from infections of motor regions of the brain
and sensory loss from infection of either the sensory
receptors or central sensory processing regions of the
brain. Some viruses such as polio show a high degree of
selectivity in which regions of the brain are infected,
whereas others such as CMV can and do infect many
regions of the brain. Which region of the developing brain
is damaged by CMV may depend on the stage of
development during which CMV first enters the brain.
In addition to CMV, three other viruses that are
transmitted from mother to fetus are rubella (German
measles), HIV and LCMV. Although most people are now
vaccinated against rubella, in the non-vaccinated, fetal
infection with rubella or LCMV, particularly in the first
trimester (a window of increased vulnerability to viral
damage) can lead to microcephaly, reduced mitosis of
developing brain cells, deafness and motor or mental
retardation [2]. Maternal transmission of HIV is not
uncommon in infected mothers; estimates of the rates of
transmission vary, but 25% transmission is probable in
mothers not receiving antiviral therapy. Children born
with HIV show various neurological symptoms, due both
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to HIV and to secondary opportunistic infections. The
destructive actions of HIV on the brain are complicated.
The current view is that neurological dysfunction is
largely due to invasion of the brain by HIV-infected
monocytes; this leads to infection of microglia or
pericytes, and with the monocytes these cause secondary
damage to the blood–brain barrier or release cytotoxic
molecules that evoke secondary damage in neurons and
glia [44,45].
Several other viruses, including positive-strand RNA
alpha viruses such as Sindbis [46] and the negative-
strand RNA VSV [40,47], show a preference for infecting
and replicating in developing rodent brain cells. Some
viruses selectively infect dividing neuronal precursors.
For instance, feline panleucopenia virus (FPV) is an
autonomous parvovirus, related to B19 that infects
humans. FPV and related rodent parvoviruses infect
replicating granule cells in the developing cerebellum,
leading to cerebellar ataxia [48]. Other viruses such as
LCMV also preferentially infect replicating cells within
the brain [26].
Childhood infection, adult manifestations
Some viruses can infect us at a young age and cause
minor discomfort, and then reappear from a latent
genome that has been quiet for years or even decades.
 Review TRENDS in Neurosciences Vol.29 No.7 July 2006 403

(a) (b)
CMV VSV
DNA genome RNA genome
replication in nucleus replication in cytoplasm

Transcription Transcription Replication

mRNA

Translation
mRNA
Replication

Figure 4. Replication of CMV and VSV. This diagram shows the replication pathways of two unrelated viruses: a DNA virus in the herpes family (CMV) and a negative-strand
RNA virus in the rhabdovirus family (VSV). The temporal sequence in both panels is top to bottom, with the free virus attaching to the cell at the top, and the progeny virus
exiting the cell at the bottom of the figure. (a) CMV attaches to a cell, and its lipid envelope fuses with the plasma membrane, enabling the virus nucleocapsid to enter the
cytoplasm. At the nuclear envelope, the linear double-strand DNA enters the nucleus, and circularizes, and the genome replicates. The origin of the CMV envelope and how
the nucleocapsid moves from the nucleus is still being studied, but one current view is shown here. The final virus is contained in an endosome-like organelle that releases
the progeny virus after fusion of the organelle to the cell plasma membrane. CMV expresses many genes that counteract attempts by the cell to block viral replication. (b) VSV
binds to its cellular receptor, and then is brought into the cytoplasm by endocytosis. The single negative-strand RNA escapes the vacuole after acidification, and is copied into
a positive-strand RNA. This RNA serves as a template for additional negative-strand viral genomes, and initiates protein synthesis. The virus captures its envelope from the
cell plasma membrane, in which viral proteins such as the VSV G protein are already positioned. Viruses such as VSV that have RNA genomes show high mutation rates; that
for VSV is 1 in 10 000 nucleotides, or w1 mutation per viral genome [23,65]. Mutation rates of DNA viruses are lower.

The most well-known example is varicella zoster virus
(VZV or chicken pox). Prior to immunization, 95% of the
US population was infected in early childhood. VZV is in
the herpes family, and during the initial 1–2-week long
illness, often occurring in young children, a fever and
itchy dermal lesions might be the primary symptoms.
Transport of herpes from the skin back to the dorsal root
ganglia (DRG) might occur at the time of primary
infection. But 30 or 40 years later, a replication-
competent virus re-emerges from the viral genome that
has waited dormant in the nucleus of neurons in the
DRG. The virus then travels back out the axon to the
axon terminal, where it is released to again infect other
cells in the skin, leading to dermal discomfort or pain
(post-herpetic neuralgia) that can last for long periods
(herpes zoster or shingles) [49]. The post-herpetic pain
might be due directly to skin infection, or in some cases
might relate to central reorganization of pain pathways
in the spinal cord as DRG cells and their centrally-
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projecting axons are lost. Because the virus emerges
from select ganglia, the appearance of the VZV-induced
skin lesions are restricted to select dermatomes inner-
vated by the infected ganglia, and often occur on only
the left or right half of the body.
Polio is another virus that can cause secondary
problems decades after the primary infection, a condition
know as post-polio syndrome. In this syndrome, those
regions of the body that showed weakness or paralysis
during the primary infection show a further decline of
function decades later. Unlike VZV, most reports have
failed to localize infectious virus during the post-polio
syndrome [13]. The mechanism for the late decline in
function is not clear, but it might relate to the plasticity of
surviving motor neurons that reinnervated the virally
denervated muscles, or to the fact that normal neuron loss
in old age might take a larger toll when many motor
neurons have already been killed by the polio virus.
Alternately, an autoimmune cause has been suggested.
404 Review TRENDS in Neurosciences Vol.29 No.7 July 2006
Not all viruses cause problems primarily during early
development. WNV, for instance, is more likely to cause
neurological problems in the elderly [3]. The mechanism
for this is not clear, but it might be based on a reduced
immune response to WNV.
Altered viral targets dependent on brain development
Some viruses have specific targets within the CNS. For
instance, polio shows a cellular preference for the motor
system. Some viruses show a developmental shift in which
cells are infected. Intranasal inoculation of VSV causes
widespread lethal encephalitis in neonatal mice and rats.
In rodents 2–3 weeks old, it can selectively infect the
noradrenergic neurons of the locus coeruleus and the
serotonergic neurons of the dorsal raphe, after which the
virus is eliminated from the CNS by the immune system;
this leads to a permanent reduction in brain serotonin and
noradrenaline levels, and long-term changes in behavior.
In adult rodents, VSV inoculation of the olfactory nerves
can lead to infection of the GABAergic neurons of the
olfactory bulb, particularly the periglomerular and gran-
ule cells. But the excitatory projection neurons, the mitral
cells, appear resistant to infection, and in most cases the
virus does not proceed caudally from the olfactory bulb to
the rest of the brain [47,50–54].
It is not clear what crucial differences in developing and
mature brains cause a shift in the cell preference of VSV
infection. It is probably not a change in the viral receptor,
possibly phosphatidyl serine, a molecule found on the
surface of most developing and mature cells [23]. More
likely, the difference relates to the ability of cells within
the brain to resist or block VSV replication through a host
of mechanisms including activation of interferon
pathways, Toll-like receptors, interleukin-12, or nitric
oxide [47,55,56]. Although VSV poses little threat to
humans [57], VSV studies are potentially important
because they demonstrate that a virus can invade the
brain, selectively destroy specific groups of cells depending
on the stage of brain development, and then disappear
from the brain after only a few days, leaving no genomic
trace but causing a permanent attenuation of transmitter
levels and alteration in behavior. These VSV studies might
reflect parallel events in the human brain, in which a
virus can infect a subset of neurons or glia, and then be
eliminated, leaving a neurological or psychiatric disease
with no detectable cause.
One disease, many viruses
Multiple sclerosis (MS) is characterized by the loss of
axonal myelination over time, leading to impairments in
neuronal signaling and function. It is generally associated
with an autoimmune imbalance involving an immune
attack on the myelin-forming oligodendrocytes. Could the
autoimmune targeting be initiated by a virus? This is a
complicated question, and numerous viruses have been
isolated from MS patients, including herpes simplex,
measles, CMV, Epstein–Barr, rhabdovirus and human
herpes 6 [2]. But a substantial problem is that correlation
does not mean causation. Particularly when many of these
viruses are commonly found in humans who show no sign
of neurological problem. A further complicating factor is
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that, contrary to Koch’s postulate that an infectious agent
should cause the disease in all those infected, not everyone
infected with a particular virus (e.g. polio) shows
symptoms. This is where animal models are particularly
valuable, because the genetic background, developmental
stage of exposure and type of virus can be controlled.
In experimental animal models, viruses can initiate
MS-like symptoms. But which virus might cause MS?
Interestingly, several viruses can induce MS-like symp-
toms in animals, including VSV, measles, vaccinia, mouse
hepatitis, Theiler’s, Chandipura, Semliki Forest (SFV)
and Venezuelan equine encephalitis (VEE) [2]. When mice
lacked CD8CT cells, SFV-induced demyelination was
prevented [58]; similarly, the use of immunocompromised
mice prevented VEE-induced demyelination [59], indicat-
ing that the demyelination was due to the host auto-
immune response to viral infection and not to viral
cytolysis. That many different viruses can precipitate
MS-like symptoms in rodents suggests that it might be
difficult to identify which virus (or viruses) have a similar
role in the human disease. But if MS can be caused by an
infection, it raises the question of whether MS in humans
must be restricted to a single virus. If an autoimmune
response can be initiated by infection of oligodendrocytes
in rodents, multiple viruses might similarly precipitate
such an immune response in humans. As already noted
here for other viral syndromes, a genetic predisposition is
important in models of virally induced MS-like symptoms.
For instance, measles virus caused Lewis rats to show
substantial lesions in the brain similar to those induced by
injection of myelin basic protein to generate experimental
allergic encephalitis, an animal model of MS; lesions
continued even in the absence of the replicating virus,
suggesting an autoimmune response had been initiated.
By contrast, brown Norway rats treated similarly showed
little evidence of brain lesions [60,61]. MS is more
prevalent in certain geographic regions of the world, for
instance in higher latitudes. That this prevalence is not
solely based on genetic predisposition is suggested by
indications that immigrants take on the MS risk of the
area into which they move (http://www.nationalmssociety.
org/Sourcebook-Epidemiology.asp). It is important to note
that, although viruses might cause some cases of MS,
other cases of MS might be entirely independent of viral
induction. As with other neurological disease, there is no
reason that every case must have the same exact cause,
although some general similarity in induction might
be expected.
Concluding remarks
Our view of viral causes of CNS dysfunction has evolved
from a simple cause-and-effect paradigm into one that
recognizes multiple factors that influence the final
neurological outcome. The presence of a neurotropic
virus in the brain might be brief, but can result in long-
lasting effects. Depending on which region of the brain is
infected, a single virus can generate different neurological
or psychiatric symptoms; or a single set of symptoms
might be generated by multiple viruses that share a
common target. Together, these factors underline the
complexity of determining a clear viral responsibility for a
 Review TRENDS in Neurosciences Vol.29 No.7 July 2006
brain disease that might manifest at substantial time
after the initial infection is resolved. Given the many
variables that can have a role in whether a viral infection
leads to CNS involvement and dysfunction in humans, the
use of carefully controlled animal models is crucial for
understanding and combating viral infections that
underlie CNS dysfunction.
Acknowledgements
I thank Dr G. Wollmann for suggestions and artistic contribution to the
schematic figures.
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5th INMED/TINS Conference

September 9–12 2006, La Ciotat, France

Physiogenic and pathogenic oscillations: beauty and the beast

Neuronal networks generate a variety of oscillations and patterns that are involved in sensory integrative processes as well as
memory processes. Thus, sensory binding is thought to involve the generation of oscillations in different parts of the brain that are
related to various sensory modalities and somehow help in reconstructing the image. Oscillations are also involved in a wide range
of pathogenic patterns and provide a signature of the neurological disorder. For example, in Parkinson’s disease, abnormal
patterns are likely to be involved in akinetic disorders, and epilepsies are associated with high-frequency oscillations that also
transform a naive structure to one that generate seizures, on the principle that ’seizures beget seizure’.

Using a wide range of recordings and preparations, imaging techniques and mathematical models, we are beginning to
understand how the brain generates these patterns and which neuronal population is dominant in the generation of a given
pattern. What is now needed is to confront the various results and concepts and to generate an organised model of the physiogenic
and pathogenic patterns: what are the similarities and differences in terms of mechanisms, of generators, etc? We shall invite to the
meeting experts in the clinical, physiological, imaging and theoretical aspects of this question. We expect attendees to include
students and senior researchers in neurology and neurobiology, as well as in mathematics and modelling.

Past INMED/TINS conferences

4th INMED/TINS Conference: Nature and nurture in brain development and neurological disorders
3rd INMED/TINS Conference: Multiple facets of GABAergic synapses
2nd INMED/TINS Conference: Nature and nurture in brain development
1st INMED/TINS Conference: Nature and nurture in neuroscience

More information: http://inmednet.com/2006-conference.html

www.sciencedirect.com