Viral infection and neural stem/progenitor cell’s fate: Implications in brain
development and neurological disorders
Sulagna Dasa,b,*, Anirban Basua
aNational Brain Research Centre, Manesar, Haryana 122050, India
bCenter for Cell Analysis and Modeling, University of Connecticut Health Center, CT 06032-3105, USA
The Central nervous system (CNS) is in a dynamic state of brain
development during intrauterine life and also during childhood.
CNS developmental abnormalities are one of the most common
forms of birth defects and many of them are associated with viral
infections during the intrauterine period or in postnatal stages.
Perinatal exposureto variousinfectiousagents andtoxinshas been
proposed as one of the key contributors in the pathogenesis of
neuropsychiatric disorders (Hornig et al., 1999; Wyatt, 1996).
However, the mechanism of how these viruses interact with the
immune system and the developing neural elements is poorly
Neurotropic viruses causing chronic CNS infections include
DNA viruses like Cytomegalovirus (CMV) (Bray et al., 1981), RNA
viruses like measles virus and few Retroviruses like Human
Immunodeficiency virus (HIV) and Human T-lymphotropic virus
(Kaul et al., 2005; Lipkin and Hornig, 2004; van den Pol, 2006). In
this review, we discuss about some of the characteristic features
associated with these neurotropic viral infections in the postnatal
brain. Neuroinvasion (ability to enter the CNS), neurotropism
(ability to infect cells of CNS), neurovirulence (capacity to cause
disease within the CNS) and neurosusceptibility (vulnerability of
the host to the virus induced neurological disease) are the four
strategies or four ‘‘N’’s of neurotropic viral infections (Patrick et al.,
2002; Schultz, 1948). Since the brain is composed of different cell
populations (mainly the neurons, glial cells, neural stem/progeni-
tor cells, endothelial cells, pericytes, etc.), the permissiveness of
these cells to a specific viral strain depends on the receptors
molecules that allow viral entry and whether the host machinery
supports the viral replication. How the virus modulates the cell
machinery post infection is still an intriguing question, and in this
review we have laid special emphasis on the modulation of NSPC
fate by these viruses.
It now established that neurogenesis and CNS development
continues beyond embryonic life, though confined in specific
niches in the brain, mainly the subventricular zone (SVZ) and
subgranular zone (SGZ) of hippocampus (Ming and Song, 2005).
The entire concept of postnatal neurogenesis revolves around the
Neurochemistry International 59 (2011) 357–366
A R T I C L E I N F O
Received 14 October 2010
Received in revised form 16 February 2011
Accepted 17 February 2011
Available online 24 February 2011
Neural stem cells
A B S T R A C T
Viral infections in the prenatal (during pregnancy) and perinatal period have been a common cause of
brain malformation. Besides the immediate neurological dysfunctions, virus infections may critically
affect CNS development culminating in long-term cognitive deficits. Most of these neurotropic viruses
are most damaging at a critical stage of the host, when the brain is in a dynamic stage of development.
The neuropathology can be attributed to the massive neuronal loss induced by the virus as well as lack of
CNS repair owing to a deficit in the neural stem/progenitor cell (NSPC) pool or aberrant formation of new
neurons from NSPCs. Being one of the mitotically active populations in the post natal brain, the NSPCs
have emerged as the potential targets of neurotropic viruses. The NSPCs are self-renewing and
multipotent cells residing in the neurogenic niches of the brain, and, therefore, hampering the
developmental fate of these cells may adversely affect the overall neurogenesis pattern. A number of
neurotropic viruses utilize NSPCs as their cellular reservoirs and often establish latent and persistent
infection in them. Both HIV and Herpes virus infect NSPCs over long periods of time and reactivation of
the virus may occur later in life. The virus infected NSPCs either undergoes cell cycle arrest or impaired
neuronal or glial differentiation, all of which leads to impaired neurogenesis. The disturbances in
neurogenesis and CNS development following neurotropic virus infections have direct implications in
the viral pathogenesis and long-term neurobehavioral outcome in infected individuals.
? 2011 Elsevier Ltd. All rights reserved.
* Corresponding author at: Center for Cell Analysis and Modeling, University of
Connecticut Health Center, CT 06032-3105, USA.
E-mail addresses: email@example.com, firstname.lastname@example.org (S. Das).
Contents lists available at ScienceDirect
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existence of self-renewing, multipotential cells called the neural
stem/progenitor cells (NSPCs) in neurogenic areas (Brazel et al.,
2003; Gage, 2000). These cells have potential for brain repair
following any injury or insult owing to their ability to generate any
of the three cell types—neurons, astrocytes, or oligodendrocyte
(Romanko et al., 2004). Therefore, disrupting the proper develop-
ment of these cells may culminate in impairment of the overall
neurogenesis pattern in the brain. The functional role of post-natal
neurogenesis in proper CNS development in children as well as in
learning and memory and neurobehavioral aspects has been
proven (Kempermann et al., 2004; Zhao et al., 2008). Viral
infections in the perinatal and postnatal period may modulate
the neurogenesis process, possibly contributing to the onset of
neurobehavioral abnormalities and neurological sequelae.
The direct causal relationship between virus infection and
neurological sequelae is difficult to establish because of the
interplay of a number of host and environmental factors and the
lack of animal model which exhibit the neurobehavioral syndrome
(Lipkin and Hornig, 2004). However, the virus-induced neuro-
pathological changes depend on the cell tropism, viral replication,
inflammatory responses and the areas of the brain affected. We
have tried to provide a comprehensive overview of the various
neurotropic viruses, their cellular tropism, and the neurobeha-
vioral disturbances that these infections cause (Table 1). While it is
of neurotropic virus infections, however, how these infections in
NSPCs contribute to the viral pathogenesis is still unknown. This
review mainly emphasizes the role of NSPCs in viral disease
progression and the development of long-term neurological
sequelae in the infected individuals.
2. Etiology of virus induced neurodevelopmental and
neurobehavioral disorders: evidence from epidemiological
studies and rodent models of viral infection
Most of the neurobehavioral disorders do not have well defined
etiology, however, viral infection has emerged as a potential
environmental factor causing neurophysiological disturbances,
which culminates in behavioral abnormalities. One hypothesis
proposes that alterations in behavior and cognitive functions can
be attributed to virus induced neuronal loss or functional
impairment of neurons (Kaul and Lipton, 2006). The virus besides
directly killing the neurons can impair neuronal functions via an
indirect pathway involving toxic factors from activated glial cells
or infiltrating immune cells. The other hypothesis advocates glial
cell loss and glial cell dysfunction as one of the major
pathophysiological feature in psychiatric disorders like major
depressive disorder (MDD) and bipolar disorders (BPD) (Cotter
et al., 2001). One of the consequences of reduced astrocyte
population and/or their functional activity would be deficits in the
glutamatergic neurotransmission and subsequent NMDA receptor
hypofunction, reduced metabolic and trophic factor support to the
neurons and subsequent deterioration of neuronal health and
synaptic functions (Cotter et al., 2001; Haydon and Carmignoto,
A number of viruses causing acute encephalitis also have
psychiatric manifestations, sometimes dependent on the brain
areas which are primarily affected. Since the virus is present in
high titers in the brain during the disease manifestation, the role of
viral agents in causing psychological disturbances in acute viral
encephalitis can be readily implicated. In case of Herpesvirus
Characteristic features of some of the prominent neurotropic viruses and their effects on the CNS.
NameVirus familyGenome Route of entryTarget cells Effect on NSPCs Long term Neurological
(+) DNA Double-
No cell death, inhibits
neuronal and glial
Kosugi et al. (2000),
Luo et al. (2008) and
Tsutsui et al.
Dickerson et al. (2004)
and Gilden et al. (2007).
(+) DNA Double-
Learning and memory
Feuer et al. (2003, 2005).
HIV-1 Retrovirus(+) RNA single
mediated BBB crossing
gp120/HIV do not cause
cell death, inhibits
JEV causes no significant
cell death but inhibition
Kaul et al. (2001, 2005)
and Lawrence et al. (2004).
WNV/JEVFlavivirus (+) RNA single
Direct BBB crossing
Swarup et al. (2007)
and Das and
LCMVArenavirus(+/?) RNA single
Direct BBB crossing
Bonthius et al. (2007a,b)
and Sharma et al. (2002).
BDVBornavirus(?) RNA single
Not known Bipolar disorders, Acute
Learning and memory
Human reovirus mostly
Kamitani et al. (2003)
and Pearce (2001).
Alphavirus(+) RNA single
Hematogenous routeNeuronsNot known
Lewis et al. (1996) and
Daley et al. (2005).
Picornavirus(+) RNA single
Retrograde axonal BBB
Neurons Not known
Rabiesvirus Rhabdovirus(?) RNA single
Retrograde axonal NeuronsNot known Fu and Jackson
et al. (2002).
ReovirusNeural route via vagal
Neurons Not known
S. Das, A. Basu/Neurochemistry International 59 (2011) 357–366
infection, the tropism of limbic structures for HSV-1 may cause
psychosis, abnormalities in cognitive and social abilities, and
symptoms similar to autism (Caparros-Lefebvre et al., 1996;
Dickerson et al., 2004). Sporadic case reports of acute encephalitis
with behavioral disturbances have been reported in Flavivirus
(WNV, JEV) and influenza A virus encephalitis (Monnet, 2003;
Retrospective epidemiological analyses of human psychiatric
illnesses have shown that that development of psychological
disturbances is predominant in chronic/persistent viral infections.
However, only indirect evidence like serology is available to
support these observed correlations between behavioral altera-
tions and viral infections in humans. In chronic infections, like HIV,
the neurocognitive impairment and neurological disorders are
(HAND), characterized by cognitive, motor and behavioral
abnormalities. The severe form of HAND refers to HIV Associated
Dementia (HAD) (Grant et al., 1995; Lindl et al., 2010; Lopez et al.,
1998). The severity of the cognitive dysfunction may increase with
age, higher viral load and reduced CD4+cell counts. Patients with
early asymptomatic HIV infection also exhibit neuropsychological
impairment (Albert et al., 1995; Wilkie et al., 2003), and at later
infection stages development of HAD occur but its pathogenesis is
still in exploratory stages (Kaul et al., 2001). Interestingly, a
spectrum of neurological deficits including acute encephalitis, and
neuromotor and cognitive impairment is observed in infections by
certain murine Retroviruses like murine leukaemia viruses
(MuLV). A high level of infection in the cerebellar granule neurons
is a prominent feature (Lynch et al., 1991). Like human retroviral
infections, microglial cells, rather than neurons are the primary
sites of infection and neurological damage results from indirect
effects of microglia on the neighbouring neurons (Poulsen et al.,
One of the best studied animal models of virus infection
exhibiting neurobehavioral changes is Borna disease virus (BDV)
infection in rodents. Whether BDV cause infection in humans is
still an unresolved issue, however, its broad host range among
warm-blooded animals suggests that humans are a likely target.
Moreover, increased serum immunoreactivity to BDV and detec-
tion of BDV RNA in various psychiatric populations like patients
with major depression, bipolar disorders and schizophrenia like
symptoms have been reported (Nunes et al., 2008; Rott et al.,
1985). BDV infection, particularly of neonatal rats generates
persistent infection and induces a range of neurodevelopmetal
abnormalities and complex behavioral and socio-emotional
changes, similar to those observed in autism, schizophrenia and
affective disorders (Briese et al., 1999; Lipkin et al., 2001).
Moreover, this neonatal model exhibits minimal immune cell
infiltration, thereby ruling out the contribution of the inflamma-
tory mediators in the etiology of the behavioral sequelae.
Cerebellar and hippocampal dysgenesis is a prominent feature
in these infected animals and have been linked to deficits in spatial
learning and memory. Since, cerebellum and hippocampus
continue to develop even after birth in rodents, a direct effect of
virus infection on the morphogenesis of these two structures can
be established. Thus, this model shows that virus infection during
CNS developmental stage may influence the onset of neurobeha-
vioral changes later in life (Hornig et al., 1999).
The neonatal rat infected with LCMV is a good model system for
congenital LCMV infection, showing all the neuropathological
changes like microcephaly, encephalomalacia, disturbances in
neuronal migration, periventricular infection with cerebellar
hypoplasia (Gilden et al., 1972; Monjan et al., 1971). The late
onset of symptoms of LCMV infection like abnormal hippocampal
development and reduced hippocampal volume has popularized
the use of this model in understanding the etiology of psychosis
like schizophrenia where the hippocampal connections are
presumed to be haywire (Pearce, 2001). However, most neuro-
pathological changes in LCMV infection are both virus- and
immune-mediated, and hence, this model do not provide a direct
correlation between neonatal virus infection and neurobehavioral
changes. Neonatal LCMV infection in rats, however, leads to
compromised adult neurogenesis later in life and manifests in
model with persistent LCMV infection exhibit impaired learning
therapeutic intervention (Brot et al., 1997).
Recent years has seen considerable progress towards under-
standing of mental illness and neurobehavioral deficits from a
standpoint of virus infection. However, a unified hypothesis
integrating various genetic, environmental, and neurodevelop-
mental factors of these complex heterogeneous mental disorders
need to be formulated. Simultaneously, the virus infection as an
environmental factor may influence the disease outcome depend-
ing on the timing of infection, host age and also the brain areas
3. Virus induced damage to CNS
Neuronal death and glial dysfunctions are two of the primary
mechanismsof virus-induceddamageto theCNS.Manyof theDNA
and RNA viruses, like CVS strain of rabiesvirus (Fu and Jackson,
2005), alphavirus (SINV, SFV) (Lewis et al., 1996; Nargi-Aizenman
and Griffin, 2001), Poliovirus (Daley et al., 2005), HSV (Gilden et al.,
2007), Flavivirus (Swarup et al., 2007) and reovirus (Richardson-
Burns et al., 2002), infect neurons, replicate in them and result in
direct cytopathic effects and cell death (Fig. 1). Because of the post-
mitotic nature of the neurons, virus induced neuronal apoptosis
often turns out to be a pathological response of the host. Neuronal
death of a few neurons in a vital area may severely affect the
normal functioning, whereas in certain ‘‘non-vital’’ areas may
result in subclinical pathology (Fazakerley and Allsopp, 2001).
Impairment of astrocyte functions by virus infections cause
disturbances in synapse formation and neuronal health and
overall CNS development, eventually culminating in neurobeha-
vioral abnormalities (Cotter et al., 2001). Moreover, astrocytes
support persistent viral infection, like LCMV infection (Bonthius
and Perlman, 2007) and in transgenic mice models of BDV
infection, where long-lasting production of BDV phosphoprotein
occurs from the astrocytes (Kamitani et al., 2003). These provide
important clues in understanding the interplay of persistent virus
infections and glial dysfunctions in virus induced neurobehavioral
In recent years, NSPCs have been identified as another mitotic
CNS cell population, which have been targeted by several viruses.
The active areas of neurogenesis are along the ventricular zones in
the developing brain, which in post-natal stages become confined
to SVZ, SGZ of the hippocampus and olfactory bulb. These areas are
considered neurogenic because they harbor a population of cells
capable of self-renewal and multipotency (generating neurons,
astrocytes and oligodendrocytes) called NSPCs (Ming and Song,
4. Virus infection of neural stem/progenitor cells (NSPCs)
A number of viruses causing neurodevelopmental damage
infects NSPC population and affects their developmental fate
(Figs. 1 and 2). Mouse neurosphere cultures, which represent the
EGF-responsive neural stem cells are permissive to murine CMV
(MCMV) infection and show cytopathic effects upon progressive
infection, providing a possible explanation for the development of
brain abnormalities upon congenital CMV infections (Kosugi et al.,
S. Das, A. Basu/Neurochemistry International 59 (2011) 357–366
2000). Undifferentiated human NSPC cultures have also been
shown to be permissive to human CMV (HCMV) infection.
Experiments by Mc Carthy et al. and Cheeran et al. have
convincingly demonstrated the expression of HCMV antigens on
NSPCs, and found that these cells support exponential increases in
viral titer over 7 days post infection. Interestingly, the virus did not
alter the expression of various precursor antigens, like Nestin and
A2B5 on NSPCs, but abroagted the proliferation of NSPCs (Cheeran
et al., 2005).
The permissiveness of NSPCs to viral infections has been
elucidated in rodent models of neurotropic viruses also. LCMV
infected rats (infection during PND 4) showed a decrease in
mitotically active neural precursors, or Mash-1 positive cells in
dentate gyrus. The severe loss of Mash-1 precursors implies that
LCMV has directly acted upon these cells during the acute phase of
infection and decreased their pool (Sharma et al., 2002). The
primary areas infected by LCMV (cerebellum, olfactory bulb,
dentate gyrus and periventricular areas) overlap with the areas of
Fig. 1. Viral infection of different cell types in the brain and development of latent infection. Different cell types in the brain are permissive to different viral infections,
according to the type of cell surface receptors and their metabolic and/or cell cycle status. Some neurotropic viruses have multiplecellular targets, in which they can replicate
and survive. Besides causing acute infection and leading to cellular dysfunction and/or cell death, a number of viruses are able to integrate in the nucleus of the host cell. This
leads to the development of persistent and/or latent infection, and upon induction with various stimuli, the virus can be reactivated into its replication competent state.
Fig. 2. Viral infection impairs the developmental fate of NSPCs. Most neurotropic viruses can infect NSPCs and block different stages of neurogenesis. i.e. development of
lineage, depending of the intrinsic and extrinsic cues. A significant number of viruses may alter the differentiation signals and impair the formation of new neurons, thus
causing a deficit in neurogenesis. A handful of viruses may also affect the generation of immature astrocytes and lead to glial dysfunctions. Besides the virus, a number of
virus-induced inflammatory molecules also induce quiescence in NSPCs or block the neuronal differentiation.
S. Das, A. Basu/Neurochemistry International 59 (2011) 357–366
prominent neurogenesis (Bonthius et al., 2007a; Bonthius and
Perlman, 2007; Sharma et al., 2002). A member of the Enterovirus
group, Coxsackievirus B3 has emerged one of the prominent viral
infections in neonates. Coxsackievirus targets the actively prolif-
erating type B stem cells and the more committed type A
progenitors in the SVZ. These infected progenitors migrating via
the rostral migratory stream helps in spread of the virus to the
olfactory bulb and other cortical areas (Feuer et al., 2003, 2005).
The tropism of HIV-1 extends beyond the cells of monocytic
lineage in the CNS and several studies have documented infection
of NSPCs by different strains of HIV-1 and the viral proteins like
gp120 and Tat (Lawrence et al., 2004). Models of persistent viral
infection have also been developed using HIV infection in NSPCs,
which provide a good tool to study long-term neuropathological
changes. HIV infected Nestin-positive NSPCs produce the virus for
7 days post-infection, however beyond 10 days the virus produc-
tion diminishes. Surprisingly, upon stimulation with TNF-a, the
ability of these infected NSPCs to produce viral particles was
revived (Lawrence et al., 2004). Using in vitro studies it has thus
been shown that HIV can persist in NSPCs for a long-term and
disseminate the virus depending on the cues from the extracellular
environment (Rothenaigner et al., 2007). The persistence of HIV in
these progenitors clearly establishes multipotent NSPC population
as cellular reservoir for HIV in the brain.
5. Possible mechanisms of virus induced damage to NSPCs
The damage to the NSPCs upon infection by neurotropic viruses
of by-stander damage resulting from the production of inflamma-
tory mediators (Fig. 2). In the following sections we discuss about
how the live virus or virus proteins affect the ‘‘stemness’’ and
differentiation potential of the NSPCs. In a previous review, we
have elaborately described how microglial activation and subse-
quent release of inflammatory molecules regulates the neurogen-
esis pattern both in vivo and in NSPC culture systems (Das and
5.1. Virus induced cell death in NSPCs
One of the prominent cytopathic effects of virus infection is cell
death in infected neurons (Fazakerley and Allsopp, 2001), which is
one of the effective anti-viral strategy employed by the target cells
in a bid to curtain virus replication and spread. However, few
reports indicate virus induced cytotoxic effects on NSPCs or the
existence of lytic cycle in these cells. Findings by van Marle et al.
showed that infection of embryonic neurospheres with Sindvis
virus vectors expressing the envelope protein of neurovirulent
HIV-1 strain (SIV-HIVenv) exhibited significant cell death com-
pared to the empty vector infected cells. Aberrant neurosphere
formation and reduced nestin expression was also observed in
NSPCs with SIV-HIVenv infections (van Marle et al., 2005).
Surprisingly, in adult mouse neurosphere cultures, exposure to
gp120 (at concentrations known to effectively induce cell death in
neurons) yielded very few apoptotic and necrotic cells (Okamoto
et al., 2007). The researchers also observed very few apoptotic
TUNEL positive cells in the SGZ of gp120 transgenic mice. In
concordance with these observations, work from our group in
Flaviviral infections also report that the highly neurovirulent JEV
did not induce robust cell death in NSPCs in vitro (Das and Basu,
2008b). The percentage of cells undergoing both apoptotic and
necrotic death was not significantly higher in JEV infected NSPCs
after 7 days post-infection than uninfected ones. Similar results of
insignificant cell death were observed with HCMV infection up to
168 h post infection, as inferred from DNA fragmentation studies
(Cheeran et al., 2005).
One of the actively dividing progenitor cells with immense
potential for repair are the NSPCs. From an evolutionary
perspective, an intuitive concept support that these cells would
be endowed with certain features that make them less susceptible
to neurotoxic damage. The key pathways triggering apoptosis in
cells are the Fas–FasL (Fas–Fas ligand) pathway and the TNF
pathway. Considerable evidence indicate that the Fas–FasL
mediated cell death pathway is not prevalent in NSPC, and that
despite expressing Fas receptor, the NSPCs do not undergo
apoptosis upon exposure to its cognate ligand, Fas mAb (Ceccatelli
et al., 2004). Further experiments in NSPC line, C17.2 showed that
induction of Fas receptor signalling results in Extracellular Signal
Related Kinase (ERK) phosphorylation, which is a mitogenic signal
for the cells. Thus, the role of Fas as a signal for growth, rather than
cell death in NSPC has been strongly advocated (Ceccatelli et al.,
2004; Sleeper et al., 2002).
The other apoptotic pathway which involves Tumor Necrosis
Factor (TNF) family of ligands, specifically TNF-Related Apoptosis
Inducing Ligand (TRAIL) is also redundant in NSPCs, even though
TRAILreceptor 2 ishighly expressed inthem. It canbe attributed to
the fact that the NSPCs are equipped with certain anti-apoptotic
factors, like IAP family members (c-IAP1) which blocks TRAIL
dependent apoptotic events by inhibiting both initiator and
effector caspase activity (Peng et al., 2005). Since TRAIL pathway
is associated with viral pathogenesis (Cummins and Badley, 2009),
resistance to TRAIL-mediated apoptosis is one of the putative
defense mechanisms in the NSPCs upon infection.
It is thus a property of the NSPCs that makes them resistant to
these neurotropic virus induced cell death. Though, some of the
anti-apoptotic mechanisms have been elucidated in NSPCs that
make them resilient to apoptotic signals, however, direct evidence
of how they evade virus induced cell death is still not established.
The neurotropic viruses may also promote survival of these cells
and use them as reservoirs for developing long-term infection.
However, the virus triggers other morphological changes and
aberrations in their growth kinetics that cripple the repair
potential of these NSPCs following a viral infection to the brain.
5.2. Virus induced proliferation arrest in NSPCs
One of the characteristic features of virus induced cytopathic
effects on NSPCs is the aberrant growth and arrest in proliferative
ability of these cells (Fig. 2). The neurosphere model is an elegant
system to study the growth kinetics and proliferative potential of
NSPCs. Typically, a neurosphere is derived from single cell
suspensions of NSPCs and is a free-floating aggregate of the
Infection of mouse NSPCs with MCMV virus result in distorted
neurosphere formation and inhibition in growth and DNA
replication of these cells. Clonogenic assay showed that the MCMV
infection suppressed the ability of these single NSPC to form
spheres (Kosugi et al., 2000). Attenuated cell proliferation was also
observed in human NSPC cultures infected with HCMV, and this
was dependent on active viral replication in these cells (Odeberg
indicates an important mechanism of a switch from cellular DNA
synthesis to viral DNA synthesis (Salvant et al., 1998). Evidence
from our lab further corroborate that virus (JEV) infection leads to
decreased uptake of BrdU by NSPCs, and cell cycle arrest at G1 ! S
phase (Das and Basu, 2008b). Based on the above reports, it can be
hypothesized that an induction of cell cycle arrest in host cells by
the virus helps in development of persistent infection.
Quiescence in adult NSPCs following HIV-1 infections was
reported for the first time by Krathwohl and Kaiser (2004b) and
attributed to the chemokine receptors, C-C chemokine receptor 3
(CCR3) and C-X-C chemokine receptor 4 (CXCR4) on the NSPC
S. Das, A. Basu/Neurochemistry International 59 (2011) 357–366
surface (Fig. 3) (Krathwohl and Kaiser, 2004a; Tran and Miller,
2005). The signalling cascade initiated by binding of HIV/gp120 to
these chemokine receptors, leads to decreased phosphorylation of
ERK, resulting in loss of mitogenic signals to the NSPCs.
Interestingly, though HIV entry into cells occurs via the same
receptors, however, the pathways leading to induction of
quiescence represents a phenomenon independent and distinct
from cellular HIV entry. To extend the story further, experiments
by Tran and Miller showed that the signalling events produced by
binding of gp120 to CXCR4 antagonise those produced by Stromal
Derived Factor-1 (SDF-1) on NSPCs. SDF-1 binding to its cognate
receptor CXCR4 acts as a mitogenic signal for NSPCs, promoting
their survival and proliferation (Peng et al., 2004). Although,
several groups have shown that gp120 and SDF-1 are not receptor
antagonists for CXCR4, however, gp120 can severely interfere with
the proliferative and chemotactic functions of SDF-1, thereby
resulting in neuropathological disturbances (Kaul and Lipton,
1999; Tran and Miller, 2003). Additionally, disrupted growth
receptor signalling by HIV in terms of Insulin and Insulin-like
Growth Factor (IGF) signal transduction has been highlighted in
hippocampal NSPCs, whichmay directly impair the proliferation of
NSPCs and overall neurogenesis in patients exhibiting HAD
symptoms (Grinspoon and Bilezikian, 1992; Lindl et al., 2010).
Additional evidence by Okamoto et al. (2007) have emphasized
that HIV/gp120 forces NSPCs to undergo cell cycle withdrawal
specifically at G1, though the role of the chemokine receptors has
not been explored. The p38 MAPK pathway has been implicated in
(MAPK-activated protein kinase 2), leading to altered phosphory-
lation status of Cdc25B/C, and culminating in checkpoint arrest
(Fig. 3). Recent reports suggest that altered regulation of the
transcription factor and cell cycle protein E2F1 by HIV-1, possibly
perturb the cycling of NSPCs (Jordan-Sciutto et al., 2002; Lindl
et al., 2010).
Viral infection often do not trigger robust apoptosis, thus
suppressing the proliferative ability of the mitotically active NSPCs
might be a mechanism of neurovirulence for these viruses. It will
not be premature to hypothesize at this point that induction of cell
cycle arrest in host cells enables the virus to maintain persistent
infection. Though, virus induced cell-cycle arrest is an established
phenomena, however, how the various viral proteins interact with
the various components of the cell cycle machinery is yet to be
5.3. Virus induced inhibition of differentiation of NSPCs
The NSPCs are multipotential cells, which can give rise to both
neuronal and glial lineages upon commitment with specific
intrinsic and extrinsic cues. In petri dishes, NSPC cultures can be
of growth factors and introduction of retinoic acid and serum
respectively. The process of neurogenesis is intricately orchestrat-
ed and a number of viruses target affect the differentiation into the
proper lineages (Fig. 2).
The best illustrated example of virus induced impairment in
neuronal differentiation is in case of Cytomegalovirus (both HCMV
and MCMV) infection of NSPCs. Human NSPCs infected with
different strains of HCMV showed significant reduction in the
percentage ofb-III tubulin (immature neuronal marker) cells upon
differentiation as compared to uninfected NSPCs (Odeberg et al.,
2006). Moreover, the infected cells continue expressing nestin and
CD133, the typical markers for NSPCs, thereby indicating that they
Fig. 3. Possible mechanism of development of quiescence in NSPCs upon HIV-1 infection. HIV-1 infects NSPCs efficiently and even develops persistent infection in them.
Instead of causing death in these NSPCs, HIV-1 induces a state of quiescence or growth arrest in them. In normal NSPCs, SDF-1 is an important mitogenic signal for the
proliferation of these cells, utilizing the cognate chemokine receptor CXCR4 (a). However, upon HIV-1 infection, the surface glycoprotein gp120 utilize CXCR4 as a coreceptor,
and preventsSDF-1bindingtoitscognatereceptor.Hencegp120boundtoCXCR4blockstheSDF-1mediatedsignalling(b).Moreover,gp120 alsoinduces phospho-p38MAPK
signalling pathway and leads to induction of a checkpoint kinase Cdc25 B/C, which results in G1 ! S phase arrest in NSPCs.
S. Das, A. Basu/Neurochemistry International 59 (2011) 357–366
still remain undifferentiated. The role of late HCMV gene products
in inhibition of neuronal differentiation has been implicated, since
treatment with Focsavir (a selective inhibitor for late HCMV gene
transcription) prevented the reduction in number of new neurons
formed from infected NSPCs. In a simultaneous study by the group,
the role of the late viral genes in inhibiting astrocytic differentia-
tion was also established (Odeberg et al., 2007). Impairment of
both astrocytic and neuronal differentiation was dependent on the
active replication of the virus, since NSPCs infected with
replication deficient (UV-inactivated) virus expressedb-III tubulin
and Glial Fibrillary Acidic Protein (GFAP) at levels similar to those
virus to inhibit the differentiation pathway depends largely on the
status of differentiation of the cells. The ability of HCMV to impair
neuron and astrocyte formation declines after 3–4 days of
differentiation, further indicating that an immature differentiated
state is important for efficient infection. Interestingly, MCMV
infection of differentiating neurospheres led to decrease in both
astrocyte and neuron formation, however neuronal differentiation
was affected more severely than glial differentiation (Kosugi et al.,
2000). It can thus be inferred from both mouse and human studies
that CMV infections disturb the regulatory mechanisms of
neuronal differentiation more strongly than those of glial
In vitro studies have indicated that HIV-1/gp120 infections can
injure differentiated human neurons and astrocytes and compro-
mise neuronal dendrite and axon development. Prolonged expo-
sure of differentiating human neurospheres to gp120 selectively
decreases neuronal protein expression versus astrocytic ones,
whereasshort exposuresshownosucheffect (SchwartzandMajor,
2006). The other neurotoxic HIV protein, Tat also has deleterious
effects on neuronal differentiation as well as neuronal survival. Tat
inhibits the Nerve Growth Factor (NGF) signalling by disrupting
the NGF/Trk pathway (important for neuronal differentiation).
Since signal transduction via NGF exerts a tight regulation on early
response genes, such as inhibitors of differentiation (Ids), Tat-
induced blockade of NGF-signalling leads to dysregulated produc-
tion of Ids which play negative role in neuronal differentiation.
HIV/Tat therefore adversely affects the formation of new neurons
(Bergonzini et al., 2004).
5.4. Susceptibility of immature differentiated cells to virus
In recent years, accumulating evidence has indicated that the
progenitors are less susceptible to cell death and mostly the early
The degree of cellular infection also depends on the immature
state of differentiation, as documented in CMV infections where
differentiation into neuronal/glial phenotype rendered the cells
more permissive for infection. Furthermore, the susceptibility of
than neuronal cells (Matsukage et al., 2006). The permissiveness
cell differentiation, and a neuronal phenotype led to a marked
reduction in viral gene expression (Cheeran et al., 2005). It has
been proposed that during differentiation along a neuronal
lineage, the levels of C/EBPb transcription factors are elevated,
which, act as repressors for the CMV major immediate-early
promoter (MIEP; an important promoter in viral replication
cycle). Since C/EBPb transcription factors play crucial roles in
neuronal but not astrocytic differentiation, the suppression of
CMV replication is confined to cells of the neuronal lineage. A
recent report however indicate that infection occurs in new
neurons but the cytopathic effects develop very slowly in
neuronal phenotype compared to infected astrocyte or NSPC
population (Luo et al., 2008). In cases of human b-Herpesvirus
infections, like HHV-6, productive infection was supported by
incompletely differentiated NSPCs which express low levels ofb-
tubulin and GFAP and also retain proliferation ability (De Filippis
et al., 2006).
Accumulating evidence in HIV-1 infections indicate that
immature cells of both neuronal and glial lineage are permissive
and susceptible to the virus (Ensoli et al., 1994). Experiments with
both primary neurons and cell lines have indicated that
susceptibility to virus is largely dependent on the state of cellular
differentiation. It is now known that specific regions of HIV-LTR
promoter can be regulated by lineage- and/or differentiation
dependent factors. Thus, modulation of the transcriptional activity
of HIV-1 promoter would dictate the cellular tropism and
susceptibility of certain cells in the developing CNS (Ensoli
et al., 1997).
6. NSPCs as models of latent and persistent viral infections
To establish infective cycles in NSPCs, neurotropic viruses can
adopt either one of the two paths: (i) cause cytopathic effects by
cytolyticinfection and/or (ii) cause latent or persistent infection.In
latency, the viral genome remains within the nucleus of the
infectedcells, butdonot produce infectiousvirus particles,and can
the most well studied viruses that induce latency and often survive
life long in the host are Herpesvirus and HIV. There is still much
debate on how the host immune system tolerates these viruses
over time, or in other words, how the virus modulates the immune
response to favor its survival.
Herpesvirusrepresentsan ancient family of viruses, which have
coevolved with the host and thus natural evolution of latency is
expected in them. In HIV infection, on the other hand, the host
phase of HIV infection is associated with rapid replication of the
virus and high levels of circulating viral particles. A long
asymptomatic phase ensues during which the viral replication
This is usually the phase where HIV exists in a state of persistence
(continual replication) and latency.
HIV enters into the CNS early in infection stage and the various
sites for viral replication and the reservoirs for HIV persistence
have been extensively reviewed (Kramer-Hammerle et al., 2005).
Prolonged monitoring of human NSPC lines infected with HIV
revealed that these cells release detectable amount of Gag antigen
for over 60 days, and transcripts encoding the viral proteins, Nef,
Tat and Rev proteins till later time points. HIV proviral DNA copy
also persisted in the NSPCs for over 100 days post infection
(Rothenaigner et al., 2007). Long-term persistence of viral DNA in
NSPCs in turn led to morphological alterations, like upregulation of
GFAP production, possibly indicating commitment towards the
CMV,a memberofb-Herpesvirusgroupcanpersistlife longina
latent state and reactivation of the virus later in life often result in
brain abnormalities. This hypothesis has been tested in perinatal
and young adult mouse models of MCMV infection. After 180 days
of infection with mutant CMV (sufficient for development of latent
infection),the infectedbrainswere isolatedand transferred to slice
cultures. Cells producing mutant MCMV were observed in brain
slices following culture for 2–3 weeks. Reactivation of the mutant
virus was evident in approximately 75% of brains from both
perinatal and young adult MCMV infected mice, and localised with
NSPCs along the walls of the ventricles (Tsutsui et al., 2002). These
interesting findings led the researchers to believe that the NSPCs
are the sites of latent CMV infection, and when triggered by certain
external cues, reactivation of the virus occurs, therefore act as
models of persistent CMV infection.
S. Das, A. Basu/Neurochemistry International 59 (2011) 357–366
Recent evidence convincingly portrays NSPC as the brain cells
that efficiently support latent and persistent viral infections, but
this necessarily does not exclude other cell types in supporting
viral DNA for a long term. These findings have tremendous
implications in transplantation biology where it is imperative to
avoid the use of NSPCs latently infected with HCMV as donor cells.
7. Critical age of the host determines the extent of virus
induced CNS damage
The perinatal and postnatal stage of brain development is
particularly vulnerable to toxic insults because of the dynamic
events like pruning and synaptogenesis that occur during this
period (Hagberg and Mallard, 2005). The age of the host critically
determines the infectability by the virus and the extent of virus-
induced neurological damage, which has been well-illustrated in
Majority of the adult population are exposed to the Herpesvirus
CMV for long periods in their lifetime, which often remains latent
in infected cells without any significant neurological manifesta-
tions. In children however, CMV has been one of the leading
infectious agent causing congenital birth defects and targeting the
developing CNS (Tsutsui et al., 2005), culminating in severe and
long-term neurological problems. CMV infection in developing
brain results in epilepsy, microencephaly, microgyria, hydroceph-
alus, deafness, decreased IQ, mental retardation, motor distur-
bances, or death (Bray et al., 1981). Another interesting example of
the susceptibility of the developing CNS has been shown in
pediatric cases of HIV/AIDS. Striking clinical data show that in
children, the neurological complications are mostly the first
observed AIDS-defining illness even before the immunodeficiency
syndrome appears. In adults however, a long latent period exists
between the viral infectionsand the manifestationsofneurological
problem (Van Rie et al., 2007).
Certain animal models of CNS virus infection elegantly
demonstrate how differences in the gestational age at the time
of infection determine the viral tropism and the neuropathological
outcome. In neonatal rat models of LCMV infection, the overall
infectivity of the virus decreases multifold with the increasing age
of the developing brain (Bonthius et al., 2007a). The LCMV tropism
range fromneurons and immatureglia during infection at PND 1 to
only neurons during PND 4 infection, and no cellular targets in
cerebellar hypoplasia, and infection at PND 4/6 causes migration
defects of cerebellar neurons, infection at PND 21 causes no
cerebellar pathology at all (Bonthius and Perlman, 2007). In terms
of brain development, the first 0–6 days of rat’s postnatal life is
equivalent tothelatetrimesterofhumaninfant.This phaseisoften
referred to as ‘‘brain growth spurt’’, and is most vulnerable to the
damaging effects of various neuroteratogens (Dobbing and Sands,
1979). The inherent susceptibility of new born mouse pups to viral
infections extends to Coxsackievirus infections also, and with
increasing age the infectability drops dramatically (Feuer et al.,
2003). Neonatal Coxsackievirus B infections are associated with
choriomeningitis and encephalitis and also with onset of delayed
The enhanced susceptibility of the developing brain reflects the
increased ability of virus to enter into the cells and replicate in
the host immune system helps in viral replication in the CNS. A
competent T-cell immune response in adults is fully capable of
eliminating the viral antigens; however, in neonates the host
defense mechanism mediated by T and B lymphocytes, natural
killer cells and macrophages/microglia is not fully functional and
unable to effectively combat viral infection (Garcia et al., 2000).
Barring few studies in CMV infections, the hypothesis of an
underdeveloped immune system in neonates has not gained
Age related virulence of neurotropic virus infections has been
extensively studied in Semliki Forest Virus (SFV), a neurotropic
alphavirus that causes lethal encephalitis upon infection in
suckling mice, but not in weaning ones. The age related
neurovirulence of this virus in not dependent on the immature
immune system of the host. Instead, the transneuronal spread of
the virus to the olfactory bulb and to primary, secondary and
tertiary olfactory connections is limited by the maturity of the CNS
(Oliver and Fazakerley, 1998). The course of post-natal infection in
the cortex, cerebellum and the hippocampus indicate that as these
structures mature postnatally, they become resistant to the spread
of the virus and the pattern changes from global infection to focal
The differential expression pattern of cellular receptors utilized
by the virus to gain entry may also determine the changing pattern
of infectability with increasing age. For instance, the major
receptor for Coxsackievirus referred to as murine CAR protein, is
expressed maximally during the perinatal period and decreases
rapidly after birth (Honda et al., 2000). Thus, low levels of murine
CAR may restrict the viral tropism and hence infectability of older
Emerging studies indicate that the replication of the virus is
dependent on the cell cycle and metabolic status of the host cells.
The abundance of cell population undergoing active cell division,
migration and differentiation in the neonatal CNS provides a
plausible explanation for enhanced viral infection in the develop-
ing brain. With increasing developmental age, the mitotically
active cells are lowered in number, and hence the virus replication
is confined to some of the dividing precursors residing in specific
A classic example of how infectability of cells overlaps with the
regions of neurogenesis is in the case of LCMV infection, where
only the subependymal cells retain the ability of be infected in
adulthood. In HIV-1 infections also, the immature mitotically
active NSPCs and glial cells which populate the developing brain
are most susceptible and various lineage-dependent or indepen-
dent factors determine the levels of viral tropism and viral
replication in these cells (Ensoli et al., 1997). Based on these
findings, it seems plausible that it is primarily the brain areas
which are still undergoing postnatal maturation which are most
vulnerable to viral infections.
8. Viral infection and neurogenesis: a neurobehavioral
Most viruses causing neurological dysfunctions show prefer-
ence for the developmental stage of the brain and/or for specific
brain areas. The neurological syndromes can vary depending upon
which part of the brain is infected, like in CMV and LCMV which
infects many brain areas, and show multiple syndromes. While the
cerebellar granule neurons readily undergo apoptosis following
LCMV infection, the loss of dentate granule neurons occurs post
viral clearance. An acute destruction of the dorsal cerebellum,
migration defects in ventral cerebellum, hypoplasia of the
olfactory bulbs and delayed-onset neuronal dropout in hippocam-
pus are the variant features in different brains areas following
LCMV infections (Bonthius et al., 2007a,b). Epilepsy, polymicro-
gyria, microcephaly, hydrocephalus and mental retardation are
some of the commonly encountered neurological problems in
congenital and perinatal viral infections. Besides the immediate
neurological dysfunctions, certain viruses can infect children but
lead to long-term neurological deficits which manifest at a later
stage in adulthood. Some of the best known examples are Varicella
zoster virus (VZV or chicken pox), Poliovirus and also Flaviviruses,
S. Das, A. Basu/Neurochemistry International 59 (2011) 357–366
where the latent virus onceactivated cause problems inthe elderly
(van den Pol, 2006). In JEV, approximately 30% of the survivors
have long-term neurological deficits which include mental
retardation, learning disabilities, behavioral abnormalities and
speech and motor disorders (Misra and Kalita, 2010; Myint et al.,
The disturbances inbehavioral functionsinvolve the interplay of
a number of factors going haywire and cannot be explained by a
single direct mechanism. After reviewing most neurotropic viruses
and their targets, we hypothesize that virus induced alterations in
sequelae. Postnatal neurogenesis occurring in the SVZ and SGZ
role of neurogenesis in the development of long-term plasticity as
well as in learning processes. A surprising connection between
neurogenesis and mood disorders has also been uncovered. In
animal models of depression, neurogenesis is reduced, and
treatment with various anti-depressants has been shown to
promote neurogenesis (Becker and Wojtowicz, 2007). Thus, it
influence the ability to encode memory processes as well as have
roles in psychiatric illness. Indeed, in HIV-1 infection the develop-
ment of AIDS dementia complex has been attributed to the
significant decrement of NSPCs in the dentate gyrus of the infected
individuals. Moreover, HIV-1 induced dysfunctions of the NSPCs
functions of infected individuals (Schwartz and Major, 2006).
Neurotropic viruses like HIV and BDV have shown to have
psychiatric manifestations, which sometimes trigger mood dis-
orders in patients (Carbone et al., 2001; Gorman, 2009). A major
challenge now is to develop models of chronic viral infections in
neurogenesis, might lead to the onset of neurobehavioral abnor-
In this scientific era, viral infections of the CNS, be it
congenital or in the postnatal stages has emerged as one of the
important contributors to the development of brain anomalies
and long-term neurobehavioral impairments (Noyola et al.,
2010; Tomonaga, 2004; van den Pol, 2009). Neurotropic virus
infections represent how multiple factors come together to
influence the final neuropathological manifestation. Besides
triggering cell death and inflammation in the CNS, most of these
viruses modulate the developmental fate of NSPCs in diverse
ways. Furthermore, developing latent infection in the NSPCs is
one of the effective viral strategies to persist in the CNS for life
long and disturb the overall physiological and behavioral
Though NSPCs have been proven as cellular reservoirs for
viruses, however, studies of viral infection on the neurosphere
(which is predominantly progenitor population) model do not
explain the virus pathogenesis completely. The cellular context of
the neurospheres is completely different from the ordered and
complex environment of the CNS in which the NSPCs house,
referred to as the ‘‘stem cell niche’’. A detailed study on the cellular
interactions in this niche and the environmental cues to NSPCs is
needed to understand how virus infections would hamper
neurogenesis in the stem cell niches.
From a neuropathological standpoint, further insight into the
development of chronic viral infections, especially at a critical post
natalage and itslong-term consequenceslater inlife would help to
elucidate the role of viral infections in causing neurobehavioral
changes. Establishing a confirmed link between neurogenesis and
neurobehavioral functions would also enable us to attribute
dysregulated neurogenesis by viral infections to development of
psychiatric disorders in the infected individuals.
The work in the author’s laboratory is funded by the grant from
the Department of Biotechnology (Award#BT/PR/5799/MED/14/
698/2005 and BT/PR8682/Med/14/1273/2007), Council of Scien-
tific and Industrial Research (27(0173)/07/EMR-II and 27(0238)/
10/EMR-II), and Life Science Research Board, Defense Research &
Developmental Organization (DLS/81/48222/LSRB-213/EPB2010),
Government of India. S.D. is a recipient of Senior Research
Fellowship from University Grants Commission, and A.B. is a
recipient of National Bioscience Award for Career Development,
from the Department of Biotechnology, Govt. of India.
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