Viruses and Endogenous Retroviruses as Roots for Neuroinflammation and Neurodegenerative Diseases

Abstract

Many neurodegenerative diseases are associated with chronic inflammation in the brain and periphery giving rise to a continuous imbalance of immune processes. Next to inflammation markers, activation of transposable elements, including long intrespersed nuclear elements (LINE) elements and endogenous retroviruses (ERVs), has been identified during neurodegenerative disease progression and even correlated with the clinical severity of the disease. ERVs are remnants of viral infections in the human genome acquired during evolution. Upon activation, they produce transcripts and the phylogenetically youngest ones are still able to produce viral-like particles. In addition, ERVs can bind transcription factors and modulate immune response. Being between own and foreign, ERVs are reviewed in the context of viral infections of the central nervous system, in aging and neurodegenerative diseases. Moreover, this review tests the hypothesis that viral infection may be a trigger at the onset of neuroinflammation and that ERVs sustain the inflammatory imbalance by summarizing existing data of neurodegenerative diseases associated with viruses and/or ERVs.

Full text

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REVIEW
published: 12 March 2021
doi: 10.3389/fnins.2021.648629
Edited by:
Elena Zenaro,
University of Verona, Italy
Reviewed by:
Douglas F. Nixon,
Cornell University, United States
Hervé Perron,
Geneuro Innovation, France
*Correspondence:
Christine Römer
christine.roemer@mdc-berlin.de
Specialty section:
This article was submitted to
Neurodegeneration,
a section of the journal
Frontiers in Neuroscience
Received: 01 January 2021
Accepted: 05 February 2021
Published: 12 March 2021
Citation:
Römer C (2021) Viruses and
Endogenous Retroviruses as Roots
for Neuroinflammation
and Neurodegenerative Diseases.
Front. Neurosci. 15:648629.
doi: 10.3389/fnins.2021.648629
Viruses and Endogenous
Retroviruses as Roots for
Neuroinflammation and
Neurodegenerative Diseases
Christine Römer*
Max Delbrück Center for Molecular Medicine in the Helmholtz Association, The Berlin Institute for Medical Systems Biology,
Berlin, Germany
Many neurodegenerative diseases are associated with chronic inflammation in the brain
and periphery giving rise to a continuous imbalance of immune processes. Next to
inflammation markers, activation of transposable elements, including long intrespersed
nuclear elements (LINE) elements and endogenous retroviruses (ERVs), has been
identified during neurodegenerative disease progression and even correlated with the
clinical severity of the disease. ERVs are remnants of viral infections in the human
genome acquired during evolution. Upon activation, they produce transcripts and the
phylogenetically youngest ones are still able to produce viral-like particles. In addition,
ERVs can bind transcription factors and modulate immune response. Being between
own and foreign, ERVs are reviewed in the context of viral infections of the central
nervous system, in aging and neurodegenerative diseases. Moreover, this review tests
the hypothesis that viral infection may be a trigger at the onset of neuroinflammation
and that ERVs sustain the inflammatory imbalance by summarizing existing data of
neurodegenerative diseases associated with viruses and/or ERVs.
Keywords: HERV, LINE, virus, neurodegeneration, neuroinflammation
INTRODUCTION
Viruses have long been linked with diseases of the nervous system. Several viruses, including human
α-herpesvirus types 1, 2, and 3 (HHV-1 and HHV-2, known as herpes simplex viruses, and HHV-
3, known as varizella zoster virus), human cytomegalovirus (CMV), human immunodeficiency
virus (HIV), Epstein–Barr virus (EBV), Ebola virus, and rabies virus are capable of reaching
the central nervous system (CNS) (Dando et al., 2014). Often, particular viral nucleic acids or
proteins are found in the brain, cerebrospinal fluid (CSF), or peripheral blood of patients with a
certain neurological disease. For example, HHV-3 and HHV-6 are present in the CSF (Mancuso
et al., 2007;Alvarez-Lafuente et al., 2008), coronaviruses in the CNS of multiple sclerosis (MS)
patients (Burks et al., 1980), and HIV and human T-cell leukemia virus-1 (HTLV-1) in the brains
of amyotrophic lateral sclerosis (ALS) patients (Verma and Berger, 2006). HHV-6A DNA and
transcripts, in turn, are increased in the brains of Alzheimer’s disease (AD) patients and closely
correlate with neuronal loss (Readhead et al., 2018). Tracing neuropathologies to viral infections
can, however, be challenging. This holds particularly true when the virus becomes “slower” or
“latent” following acute infection (Sigurdsson, 1954;Murphy and Yunis, 1976;Steiner et al., 2007;
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Kennedy and Cohrs, 2010;Shu et al., 2015;Rodriguez et al.,
2020). The tremendous research from the beginning of the HIV
pandemic has greatly enhanced evidence and understanding
of this slow action of viruses in the CNS (Garcia et al.,
1999). Important to consider also is the long-term risk from
accumulated infections during a lifetime that might lead to a
cumulative and individual risk of developing neuropathology,
such as stroke and dementia (Almeida and Lautenschlager, 2005;
Ruprecht et al., 2006;Tai et al., 2009;Sico et al., 2015).
More recent research has shown that viruses, such as HIV,
EBV, CMV, influenza, herpesviruses, and HTLV-1 can activate
viral sequences originating from retroviral infections in the
distant past of human evolution that have been incorporated
into the human genome (Nellaker et al., 2006;Toufaily et al.,
2011;Young et al., 2012;Leboyer et al., 2013;Li et al., 2014;
Kury et al., 2018). While their ability to express viral products is
mostly lost, some of these endogenous retroviruses (ERVs) have
evolved to play important roles in physiological processes, such
as placentation, early human embryogenesis, neurodevelopment,
and immune response regulation (Kammerer et al., 2011;
Wang et al., 2014, 2020;Chuong et al., 2016;Romer et al.,
2017;Xue et al., 2020). Activation of ERVs, such as by
exogenous viruses or environmental factors, can contribute
to a multitude of neurodevelopmental, neurodegenerative, and
neuroinflammatory disorders (Balestrieri et al., 2019;Gruchot
et al., 2019, 2020;Tam et al., 2019;Evans and Erwin, 2020;
Groger et al., 2021), including HIV-associated neurodegenerative
disorder (HAND), AD, MS, ALS, schizophrenia, stroke, and
neuropathogenesis of severe acute respiratory syndrome
coronavirus-2 (SARS-CoV-2) as well as to accelerated
neurological decline in aging.
This review highlights the interplay between endogenous
viruses and retroelements, on the one hand, and exogenous
viruses, on the other hand, and aims at revealing
underlying mechanisms in aging, and neurodegenerative
and neuroinflammatory diseases summarizing recent
advances in this field.
VIRAL INFECTION OF THE CENTRAL
NERVOUS SYSTEM
The central nervous system (CNS) is not a common target organ
for viruses. It is neither easily accessible nor as advantageous
in terms of contagiousness and successful viral transmission to
new hosts as the respiratory or gastrointestinal tract. Shielded
by the meninges, CSF, and blood brain barrier (BBB), the CNS
is immunologically unique and privileged (Louveau et al., 2015).
Although the CNS itself is armed with an array of immunological
mechanisms, including support from the periphery, it may be
considered as a sanctuary where viral replication occurs despite a
complete viral suppression in the peripheral blood. This has been
shown, for example, for the HIV (Walker et al., 2008). In addition
to viruses with neurotropism, only minor mutations may be
sufficient to create viruses that can access the CNS via various
routes (Wiley, 2020). Permeability of the BBB may be increased
by high viremia accompanied by elevated cytokine levels and also
by direct interaction with tight junction proteins (Toborek et al.,
2005;Chai et al., 2014). Viruses can infect endothelial cells of the
BBB, allowing viral replicates to be released into the CNS (Verma
et al., 2009;Fletcher et al., 2012), while infection of leukocytes
or monocytes by, for example, HIV and SARS-CoV-2, that pass
BBB physiologically, provides a “trojan-horse” mechanism to
enter the CNS (Larochelle et al., 2011;Takeshita and Ransohoff,
2012;Bostanciklioglu, 2020). Attention is currently drawn to
the CNS invasion through retrograde neuronal transport of
infected peripheral nerve afferents, as SARS-CoV-2 and other
coronaviruses are associated with CNS entry via the olfactory
pathway, a mechanism that has been also described for other viral
families such as influenza A virus, rabies virus, and herpesviruses
(van Riel et al., 2015), and other peripheral nerves, for example,
the sciatic nerve and vagus nerve (Ren and Racaniello, 1992;
Ohka et al., 1998;Guadarrama-Ortiz et al., 2020;Liu et al., 2020).
Figure 1 depicts the mechanisms of viral entry into the CNS.
Once in the CNS, acute infections present with encephalitis,
myelitis, or viral meningitis. Generally, virus-triggered immune
reaction is limited in time and ends with the virus being
combated; however, certain neurotropic viruses can continue
to elicit progressive damage on brain structure, function, and
cognition long after the clearance of virus from the peripheral
blood. In addition to this type of chronic infections, viruses
can enter a latent (dormant) phase, interrupted by occasional
full awakening of the virus. Sometimes, the same virus can
contribute to both. This is the case for the HIV (Rodriguez
et al., 2020), measles morbillivirus (Murphy and Yunis, 1976),
HHV-1 (Shu et al., 2015), and HHV-3, to name a few (Steiner
et al., 2007;Kennedy and Cohrs, 2010). The high worldwide
seroprevalence of some of these viruses, such as that of HHV-
1 and HHV-2 being around 90% (Wald and Corey, 2007),
indicates that facilitating factors must exist that ultimately decide
upon disease development. In consideration are comorbidities
such as traumas to latently infected neurons (Zhang et al.,
2013), immune-depriving conditions such as AIDS (Rodriguez
et al., 2020), leukemia (Koskenvuo et al., 2008;Lancman et al.,
2020), or stroke-induced immunodepression (Deroux et al., 2012;
Hetze et al., 2013;Romer et al., 2015;Bertrand et al., 2019),
and cumulative infectious burden (Sico et al., 2015), and also
environmental factors (Liu et al., 2013;Brutting et al., 2018;
Mueller et al., 2018;Del Re and Giorgi, 2020). The role of aging
as a facilitating factor and the interplay with ERVs are discussed
in detail below.
ENDOGENOUS RETROVIRUSES AND
RETROELEMENTS
Exogenous retroviruses from which ERVs originate, like other
retroviruses, contain single-stranded (ss) anti-sense RNA and
RNA reverse polymerase to generate double-stranded DNA
(dsDNA). With the help of the retroviral integrase, this DNA
copy may become endogenized into the host genome, essentially
when infecting gametes (germ cells) with chromosomal insertion
sites that will allow the birth of viable offspring over generations.
Over the evolution, this type of infections and endogenizations
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FIGURE 1 | Entry routes of exogenous viruses into the central nervous system (CNS). Virus can enter the CNS via (A) Peripheral nerve terminals (in this example of
the olfactory nerve) and retrograde axonal transport. (B) Infection of and damage to endothelial cells of the blood brain barrier (BBB). (C) Infection of circulating
immune cells that travel across the BBB. (D) Modulation of tight junction molecules of the BBB, increasing BBB permeability. A specific entry route can be typical for
a specific virus, however, often more than one route is used. Entry route may vary during the course of infection (e.g., BBB damage in conditions of high viremia) and
new CNS entry mechanisms can follow when the viral genome sustains mutational changes. A neurotrophic virus often infects specific cell types within the CNS.
Reaching the CNS enables the virus to circumvent the peripheral immune response. To evade also the CNS immune response, viruses may enter a dormant state
forming a viral episome or integrating into the host cell DNA.
of retroviruses have occurred multiple times (Kozak, 1985).
Gradually, ERVs become non-infectious, lose the ability to exit
the host cell, and adopt the nature of transposable elements. ERV
sequences become transpositionally inactive, mutated, degraded,
and epigenetically silenced as part of the host control in
protection of genome stability. ERV sequences take up about 8%
of the modern human genome (Gannet, 2019). ERV families that
have been less prone to be degraded by the host, such as human
ERV H (HERV-H) and HERV-K, have shaped the evolution and
complexity of innate and adaptive immune pathways (Villarreal,
2011;Chuong et al., 2016, 2017). Regulation mechanisms to
control the HERV activity, mainly via epigenetics (for example,
cytosine methylation) form the basis for proper host–HERV
interaction in controlling vital processes (Lavie et al., 2005;Turelli
et al., 2014). The Krüppel-associated box domain (KRAB)-
associated protein-1 (KAP1)-mediated silencing continues to be
the key mechanism of ERV control in adult brain (Fasching
et al., 2015). KAP1 deletion during brain development is lethal,
and heterozygous deletion of KAP1 causes behavioral changes
resembling those observed in human psychiatric conditions
associated with HERV upregulation (Jakobsson et al., 2008).
Long interspersed nuclear elements (LINEs) are a group of
non-LTR (long terminal repeat) retroelements that compose
up to 21% of the human genome (Gannet, 2019). LINE-1
elements are a major source of structural polymorphisms in
humans (Hancks and Kazazian, 2012). Higher LINE-1 activity is
characteristic to brain areas of adult neurogenesis, in particular
to the hippocampal dentate gyrus (Baillie et al., 2011;Kurnosov
et al., 2015;Bachiller et al., 2017) and to human neural
progenitor cells (Coufal et al., 2009). LINE-1 insertions often
locate at neuronal genes, and LINE-1 activity can initiate
neuronal differentiation (Muotri et al., 2005). Hippocampal
LINE-1 activity and genomic mosaicism are involved in cognitive
processes such as memory formation (Bachiller et al., 2017).
Alu family is the most common member of the short
interspersed nuclear elements (SINEs) and accounts for about
13% of the human genome (Gannet, 2019). Alu elements
are actively transposing. However, they do not encode a
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functional reverse transcriptase protein and therefore rely on the
machinery of other retroelements, especially LINEs (Wei et al.,
2001;Dewannieux et al., 2003). Alu elements are involved in
neurogenesis, brain connectome development, and in shaping
cognition networks (Mehler and Mattick, 2007;Baillie et al., 2011;
Bedrosian et al., 2016).
HERVs, LINEs, and Alus regulate gene expression networks
at multiple levels, providing a rich pool for RNA diversification
(Lev-Maor et al., 2003;Laperriere et al., 2007;Fujii, 2010;Gim
et al., 2014;Goke and Ng, 2016), functioning as promoters
and enhancers (Norris et al., 1995;Shen et al., 2011;Lee,
2012;Wu et al., 2013;Romer et al., 2017), and coordinating
3D genomic arrangements via topologically associated domains
(Dixon et al., 2012;Zhang et al., 2019). These elements contribute
significantly to defining neurobiological processes, including
neuronal mosaicism and shaping brain development (Coufal
et al., 2009;Baillie et al., 2011;Richardson et al., 2014;Bodea
et al., 2018). Alteration of these networks are associated with
neurodevelopmental, neurodegenerative, neuroinflammatory,
and autoimmune diseases. HERVs, LINE, and Alu elements are
subject to a multitude of environmental factors and xenobiotics,
which can activate normally well-controlled HERV expression,
such as hypoxia (Brutting et al., 2018), drugs (aspirin, caffeine,
and valproic acid) (Diem et al., 2012;Liu et al., 2013), and
hormones (Norris et al., 1995;Mueller et al., 2018). Also,
LINE-1 retroelement activity is sensitive to a multitude of
factors including social isolation stress, heavy metals, and anti-
inflammatory and psychoactive drugs (Del Re and Giorgi, 2020).
Together, (H)ERVs, LINE, and Alu elements regulate early
human embryogenesis, neurodevelopment, neural diversity, and
plasticity. All three are subject to a number of environmental
factors, affecting a healthy brain.
INTERPLAY BETWEEN ENDOGENOUS
AND EXOGENOUS VIRUSES
Inherent ERVs and exogenous viruses, being distant relatives,
share common mechanisms but can also be opponents. When
viruses first try to enter a cell, HERV, coming from inside
the host genome, can provide protection by blocking the
cellular receptors relevant for the exogenous retrovirus entry
(Spencer et al., 2003). ERVs can protect against exogenous
retroviral infections by receptor interference if both viruses
share the specificity of the env glycoprotein (Weiss et al.,
1985). Substantial similarity between HERV and exogenous
retrovirus, such as that between HERV-K (HML-2) gag and
HIV gag, could lead to fusion of viral proteins and production
of defective viral particles (Monde et al., 2012). In addition,
HERV antisense transcripts can interact with complementary
exogenous retrovirus transcripts to block viral replication and
generate dsRNA to be recognized as a pathogen-associated
molecular pattern (PAMP) by the host immune system (Tang
et al., 2012;Shekarian et al., 2017). Sensing PAMPs, such
as viral proteins and nucleic acids, and danger-associated
molecular patterns (DAMPs) derived from damaged cells, are
part of the innate immune response. Cytoplasmic sensors
for viral DNA include cyclic GMP-AMP synthase (cGAS),
Z-DNA-binding protein 1 (ZBP1), and TLR9 (Rigby et al.,
2014;Hayashi et al., 2015;Xia et al., 2016;Sandstrom et al.,
2017;Jiao et al., 2020). Viral RNA are sensed by TLR8 (Heil
et al., 2004), TLR3, melanoma-differentiated-associated gene 5
(MDA5), ZBP-1 (Gurtler and Bowie, 2013;Jiao et al., 2020),
and retinoic acid inducible gene I (RIG-I) (Gurtler and Bowie,
2013). Innate immune response to viral infections leads to
pro-inflammatory cytokine, chemokine, and type I interferon
(IFN) release to stimulate adaptive immune response, the
T lymphocyte-mediated cellular and B lymphocyte-mediated
humoral immunity.
Activated innate and adaptive immune system cells both
can stimulate ERV transcription (Bannert and Kurth, 2004).
Generally, immune reactions are limited in time and cleared by
the immune system. However, HERVs are continuously present
and, under certain conditions, also continuously active. Aiming
at clearing up the infection triggered by HERVs, TLR stimulation
can, via IFN release, actually activate HERVs further (Bannert
and Kurth, 2004). Dispersed at relevant immune genes, activated
HERVs and in particular the polymorphic HERV-K (HML-2)
loci, form another layer of immune response regulation (Nexo
et al., 2011). Certain HERV insertions function as IFN-inducible
enhancers, and type I IFN is one of the main innate immune
response products to viral infection (Chuong et al., 2016).
Neuroinflammation will awaken and activate HERVs in the
human brain (Johnston et al., 2001;Manghera et al., 2015, 2016).
In this feedback loop, HERV activity is upregulated by anti-viral
immune response through inflammatory mediators and also by
epigenetic dysregulation (Manghera and Douville, 2013;Hurst
and Magiorkinis, 2015, 2017), leading to chronic stimulation of
the immune system (Hurst and Magiorkinis, 2015, 2017;Grandi
and Tramontano, 2017;Mameli et al., 2017;Ramasamy et al.,
2017). Continuous ERV activation is associated with sustained
neuroinflammation and predisposes to neurodegenerative and
autoimmune diseases (Nexo et al., 2011).
Activation of ERV transcription can directly be achieved by
several exogenous viruses, such as HIV, EBV, CMV, influenza, and
herpesviruses, some of which can even induce a self-sustained
HERV activation (Nellaker et al., 2006;Young et al., 2012;
Leboyer et al., 2013;Li et al., 2014;Kury et al., 2018). Among
exogenous retroviruses, HTLV-1 Tax can increase HERV-H,
HERV-K, HERV-W, and HERV-E expression in T lymphocytes
(Toufaily et al., 2011). HIV transactivator of transcription (Tat)
protein can stimulate expression of HERV-K and HERV-W
in astrocytes and peripheral blood cells and that of HERV-W
also indirectly via TLR4 and proinflammatory cytokine (TNF-
α, NF-κB) production (Uleri et al., 2014). Using mimicry,
HIV rev, which mediates nuclear export of HIV messenger
RNA (mRNA), also mediates the nuclear export of HERV-K
mRNA, thereby promoting HERV-K translation (O’Carroll et al.,
2020). Exogenous viruses can further facilitate expression of
endogenous superantigens, linked in particular with the CNS-
affecting autoimmune diseases (Acha-Orbea, 1992). This occurs,
for example, between rabies virus and HERV-W (Lafon et al.,
1992;Perron et al., 2001;Lafon et al., 2002) and between EBV
and HERV-K18 (Sutkowski et al., 2001). In turn, ERVs may assist
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their exogenous counterparts to escape immune surveillance,
repair defects in exogenous retroviruses (Schwartzberg et al.,
1985), and facilitate chronic viral replication (Rasmussen, 1997).
Also, transcriptionally active ERVs provide a rich pool for
recombinational events with exogenous retroviruses. When a
host cell is infected by two different viruses, heterologous trans-
activation can take place where transcription of one virus is
initiated by factors produced by the other virus. When ERVs
provide envelope glycoproteins to exogenous retroviruses, these
could establish a new host cell repertoire and circumvent
immune system response (Lusso et al., 1990). A certain degree
of epitope similarity between ERV and exogenous retrovirus
can lead to a weaker immune response against this virus
(Miyazawa and Fujisawa, 1994).
Similar interplay between endogenous retroviruses and
exogenous viruses exists in the periphery and may pave way
to chronic inflammation. In fact, viruses and endogenous
retroviruses have been linked with autoimmune disease
pathology, such as systemic lupus erythematosus (Ogasawara
et al., 2000;Moon et al., 2004), rheumatoid arthritis (Herve
et al., 2002), and diabetes (Levet et al., 2017, 2019). Continued
upregulation of HERV-H and HERV-K after the clearance of
hepatitis C virus from the peripheral blood of chronic hepatitis C
patients was recently associated with higher risks for cancer and
autoimmunity in these patients (Tovo et al., 2020).
Peripheral inflammation can reach the brain via transversal
of circumventricular organs, peripheral nerves, or through pro-
inflammatory cytokine influx upon direct cytokine–endothelial
interactions, resulting in reduced BBB integrity (Toborek et al.,
2005;Chai et al., 2014). Moreover, peripheral inflammation
processes can trigger major neurological events such as stroke
via platelet aggregation, hypercoagulation, impaired endothelial
function, and thrombosis (Elkind et al., 2020;Oxley et al., 2020).
Figure 2 draws common mechanisms in the interplay of
exogenous and endogenous retroviruses leading to sustained
neuroinflammation and subsequent CNS damage.
VIRAL AND ENDOGENOUS RETROVIRAL
ASSOCIATED PATHOLOGIES
Table 1 summarizes exogenous viral and endogenous retroviral
disorders discussed in the following sections.
HIV-Associated Neurodegenerative
Disorder
HIV infection causes acquired immunodeficiency syndrome
(AIDS) affecting multiple systems in the body. One of
the complications of HIV infection is the HIV-associated
neurodegenerative disorder (HAND) (Navia et al., 1986), which
can develop into HIV-associated dementia (Nookala et al., 2017),
the most common cause of dementia in young adults (Janssen
et al., 1992) with higher prevalence among women (Duarte
et al., 2020). HIV is transported to the brain with infected
T-lymphocytes and monocytes (Wiley et al., 1986;Takahashi
et al., 1996). These long-lived cells are referred to as sources
of HIV chronic infection (Nookala et al., 2017). In the brain,
HIV infects primarily the immunocompetent cells, perivascular
macrophages, and microglia where it replicates (Watkins et al.,
1990;Albright et al., 2000). HIV persists in the CNS, causing
motor, cognitive, and behavioral deficits, which can be further
aggravated by opportunistic infections by CMV, EBV, HHV-3,
and HHV-6 (Almeida and Lautenschlager, 2005).
Neurodegeneration characteristic to HAND emanates from
chronic inflammation, sustained by activated monocytes,
macrophages and astrocytes, and neurotoxic HIV viral proteins
(Ghafouri et al., 2006;Kraft-Terry et al., 2010). These include
HIV Tat, HIV viral protein R (Vpr), and HIV env glycoprotein
gp160 cleaved product gp120. HIV viral proteins induce
neuropathology by aberrant calcium signaling, mitochondrial
damage, oxidative stress, excitotoxicity, and inflammation
(Nookala et al., 2017), collectively leading to neuronal death
(Masliah et al., 1992).
Further augmentation of neurodegeneration and
neuroinflammation in HAND comes from HIV and infection-
induced cytokines’ (IL-6, IL-1β, TNF-α, and IFN-γ) ability to
dynamically activate HERVs, such as HERV-W (Uleri et al.,
2014) and HERV-K (Bhardwaj et al., 2014;O’Carroll et al.,
2020). In particular, HIV induces HERV-K transcription and can
trigger adaptive immune response against the HERV-K capsid
protein (de Mulder et al., 2017). A distinct temporal pattern
between HIV and HERV-K activation has been observed in the
brains of HIV-infected individuals, demonstrating increased
HERV-K activation ahead of spikes in HIV replication in the
peripheral blood (Contreras-Galindo et al., 2007) and ahead
of clinical symptoms of neurocognitive impairment (Douville
and Nath, 2017). HIV-associated motor neuron disease affecting
upper and lower motor neurons is likewise escorted by increased
HERV-K expression at the onset of neurological symptoms
(Bowen et al., 2016). HIV can directly facilitate HERV-K
expression, transcript transportation to cytoplasm, and viral
particle production (O’Carroll et al., 2020) and regulate anti-
viral gene expression through activating (H)ERV promoters
(Srinivasachar Badarinarayan et al., 2020). Increased HERV-K
env expression in cortical neurons of HIV-infected individuals
has been linked with restricting HIV replication in these cells
(Bhat et al., 2014). In the long term, however, neuronal HERV-K
expression leads to neurite retraction and neuronal death
(Dembny et al., 2020), in line with HAND. The antiretroviral
therapy against HIV is effective also against HERV-K (Bowen
et al., 2016). Overall, the neuropathology induced by HIV and
HERV-K might have a certain overlap and is difficult to separate.
It might be beneficial to monitor the level of HERV-K within
the course of HAND.
Of note, incidence of HIV-associated dementia has reduced
threefold after the combination antiretroviral therapy became
available (Lawrence and Major, 2002). New medical concerns
involve premature aging-related neurocognitive disorders
(Robertson et al., 2007). HIV-associated dementia bares certain
similarities with that of Alzheimer disease (AD) (Clifford et al.,
2009). The neurons of HIV-associated dementia patients contain
diffuse Aβplaques, similar to the early stages of AD (Ortega
and Ances, 2014), which could indicate a slower progression of
HIV-associated dementia (Fulop et al., 2019).
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FIGURE 2 | Model of the role of exogenous virus and endogenous retrovirus (ERV) in initiating neuropathologies, illustrating the entry of viruses into the body
(“house”) and the presence of ERVs, the physiological immune response on the first level and continuous imbalance on the second, thus leading to damage of the
CNS (“roof”). Infections with exogenous viruses often activate the transcription of endogenous retroviruses which are already present in the mammalian genome.
This results from disruption of the host-control over ERVs, bordering between own and foreign. Separately and together, activated exogenous viruses and ERVs
produce PAMPs, such as viral nucleic acids, viral-like particles, fused transcripts between exogenous virus, and ERV, which are sensed by PAMP sensors (TLR,
cGAS, ZBP-1, MDA5, and RIG-I). Collectively, PAMP activation alarms the immune system by initiating innate immune response involving mainly IFN signaling which
will trigger the adaptive (humoral and cellular) immunity. Viral infections are generally limited in time as they are combated by the immune system. However, the
activation of ERVs and neurotrophic viruses which remain silent yet present within the body, can lead to sustained neuroinflammation via antibodies against ERVs,
superantigen formation, demyelination, and neuronal death. In parallel, IFN-mediated innate immune response can further activate ERVs which contain IFN response
elements (such as HERV-K), thereby creating an IFN loop. Next to the danger of chronic neuroinflammation, this additionally carries mutational burden for the host,
collectively leading to the CNS damage. The probability and scope of the CNS damage is further determined by facilitating factors, including comorbidities and
environmental triggers as well as age. Abbreviations: cGAS, cyclic GMP-AMP synthase; CNS, central nervous system; ERV, endogenous retrovirus; IFN, interferon;
MDA5, melanoma differentiated associated gene 5; PAMP, pathogen-associated molecular pattern; RIG-I, retinoic acid inducible gene I; TLR, toll-like receptor;
ZBP-1, Z-DNA binding protein 1.
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TABLE 1 | Overview of disorders affecting the central nervous system (CNS) associated with an onset mediated by exogenous viruses and/or endogenous retroviruses.
Disorder Clinical CNS
symptoms
Associated
peripheral
pathology
CNS targets Associated
exogenous
viruses
Associated
endogenous
retroviruses
Mechanisms
HIV-associated
neurodegenerative
disorder (HAND)
Cognitive, motor,
and behavioral
deficits similar to
AD
AIDS Microglia,
astrocytes, and
perivascular
macrophages,
neurons (motor
and cortical)
HIV-1
(aggravation by
CMV, EBV,
HHV-3, and
HHV-6)
HERV-K
(HERV-E, HERV-T, two
ERV9 subgroups)
•Neurotoxic viral products (Tat, Vpr,
HIV-1 gp120)
•Cytokine-induced HERV expression
(IL-6, IL-1β, TNF-α, IFN-γ)
•Viral induction of antibody against
HERV-K capsid protein
•Sustained inflammation
•Increased pTau, neopterin,
neurofilament light and diffuse Aβ
plaques
Alzheimer’s
disease (AD)
Cognitive deficits
(memory loss,
learning difficulty,
impaired logical
thinking, confusion,
speech problems,
shortened attention
span)
Systemic immune
activation, and
chronic peripheral
inflammation
Microglia,
hippocampal
pyramidal neurons
lymphocytes,
neuronal, and
endothelial cells
parahippocampal,
inferior frontal and
superior temporal
gyrus
HHV-1,
HHV-6A,
HHV-6B,
HHV-7, EBV,
and CMV
HERV-K, HERV-H,
HERV-W, HERV-L,
solitary long-terminal
repeats (LTRs)
•Extension of inflammation to CNS
(immune cells entry to brain via
transversal of circumventricular
organs, vagus nerve stimulation or
pro-inflammatory cytokine influx)
•Viral RNA sensor MAVS
•Gliosis
•Viral activation of HERVs
•Higher rate of DNA damage and
higher expression of
pluripotency-related genes
•HERV fusion products (ARC viral-like
capsid protein overexpression)
•HERV-induced TLR8 activation
•Progressive neuronal death
(PARP1-driven, caspase-independent
apoptosis)
•Dense Aβplaques, Tau neurofibrillary
tangles
Multiple sclerosis
(MS)
Progressive
physical and
cognitive
disabilities
neurobehavioural
deficits, such as
weakness, gait
unsteadiness, and
altered executive
functions
Hints for chronic
inflammation,
association with
peripheral
neuropathy
B cells, microglia,
astrocytes, and
macrophages that
orchestrate
damage to
oligodendrocytes
HHV-1, HHV-2,
HHV-3, HHV-6,
EBV, CMV, JCV
HERV-W (HERV-K,
HERV-H)
•Viral activation of HERV-W
transcription
•HERV-W env protein and syncytin
expression
•HERV-W env is a powerful
superantigen
•Syncytin induces neuroinflammation
via oxidative stress
•Stimulate anti-viral response
associated with MS pathology by
binding TLR4 and CD14
•Pro-inflammatory (anti-viral) response
involving TLR4, CD14, IL-1beta
•Increase in cellular protein oxidation,
inhibition of oligodendrocyte
maturation, myelin damage and
antagonization of remyelination
Amyotrophic lateral
sclerosis (ALS)
Fasciculation,
cramps, muscle
atrophy, and
marked limb
weakness
HERV-W env and
gag are present in
muscle biopsies
from ALS patients,
linked with
macrophage
activation and
neurogenic atrophy
of muscular tissue
HERV activity in
prefrontal, sensory,
motor, occipital
cortex
Weak
connection
with HIV-1, and
HTLV-1
HERV-K •HERV-K transcription in ALS is
stimulated by the TDP-43
•HERV-K transcription can be also
initiated by HIV-Tat protein HERV-K
env in cortical and spinal neurons
•neuronal HERV-K activation is
associated with the nuclear
translocation of interferon regulatory
factor 1 (IRF1)
•Sustained neuroinflammation with
progressive loss of cortical and spinal
motor neurons
Schizophrenia
spectrum disorders
Psychosis,
hallucinations,
delusions, apathy
and disorganized
thinking
Subclinical
inflammation
Neurons of
prefrontal cortex
and (developing)
hippocampus
HHV-2,
perinatal
influenza
infection
HERV-W, LINE-1
(HERV-K, HERV-H)
•Impairment of synaptic genes
•Upregulation of immune response
genes
•Lasting inflammatory dysregulation of
the nervous system
(Continued)
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TABLE 1 | Continued
Disorder Clinical CNS
symptoms
Associated
peripheral
pathology
CNS targets Associated
exogenous
viruses
Associated
endogenous
retroviruses
Mechanisms
Neuropathogenesis
of SARS-CoV-2
Dizziness,
headache,
encephalitis,
seizures,
intracerebral
hemorrhage, and
stroke,
neuromuscular and
autoimmune
syndromes
Acute respiratory
disease
Viral infection of
neurons and glial
cells
SARS-CoV-2 none •Interacts with stress response, vesicle
trafficking, lipid metabolism pathways,
production of reactive oxygen species,
RNA processing, RNA regulation,
ubiquitin ligases and mitochondrial
activity
•Impaired lysosomal function
combined with inhibition of
ubiquitin-proteasome system
•Protein misfolding and formation of
protein aggregates
•Expected neuroinflammation and
neurodegeneration
Aβ, amyloid β; AD, Alzheimer’s disease; AIDS, acquired immunodeficiency syndrome; ALS, amyotrophic lateral sclerosis; CD14, cluster of differentiation 14; CMV,
cytomegalovirus; EBV, Epstein-Barr virus; gp120, glycoprotein 120; HAND, HIV-associated neurodegenerative disorder; HERV, human endogenous retrovirus; HHV-1,
human alphaherpesvirus-1/herpes simplex virus-1; HHV-2, human alphaherpesvirus-2/herpes simplex virus-2; HHV-3, human alphaherpesvirus-3/varicella zoster virus;
HHV-6, human alphaherpesvirus-6; HHV-7,human alphaherpesvirus-7; HIV-1, human immunodeficiency virus-1; HTLV-1, human T-cell leukemia virus-1; IFN-γ, interferon
γ; IL, interleukin; IRF1, interferon regulatory factor 1; JCV, John Cunningham virus; LINE-1, long interspersed repetitive element 1; LTR, long-terminal repeat; MAVS,
mitochondrial antiviral-signaling protein; MS, multiple sclerosis; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; Tat transactivator of transcription; TDP-43,
trans-activation responsive TAR; DNA-binding protein 43; TLR, toll-like receptor; TNF-α, tumor necrosis factor α; Vpr, viral protein R.
Alzheimer’s Disease
Alzheimer’s disease (AD) is a progressive neurodegenerative
disorder characterized by gradual cognitive decline. AD can start
even decades before the appearance of clinical symptoms (Taylor
et al., 2016;Fulop et al., 2018). AD is associated with systemic
immune activation and chronic peripheral inflammation
(Culibrk and Hahn, 2020). Neuropathologically, AD is
characterized by presence of Aβplaques, Tau neurofibrillary
tangles, progressive neuronal death, neuroinflammation, and
gliosis in the brain.
Growing evidence points to the role of pathogens, such as
HHV-1, HHV-6A, HHV-7 (Lovheim et al., 2015;Readhead et al.,
2018), EBV, and CMV (Carbone et al., 2014) in developing
sporadic AD. As the worldwide seroprevalence of HHV-1
is around 90% (Wald and Corey, 2007), facilitating factors
essentially contribute to the probability of HHV-1 triggering
AD (Looker et al., 2015). HHV-1, HHV-6A, and HHV-6B viral
glycoproteins can bind β-amyloid oligomers and accelerate Aβ
plaque deposition (Eimer et al., 2018).
HERV-H, HERV-K, HERV-L, and HERV-W are
transcriptionally active in the brains of AD patients (Johnston
et al., 2001;Sun et al., 2018;Dembny et al., 2020). This activation
could be directly mediated by HHV-1, HHV-3, and HHV-6
(Ruprecht et al., 2006;Brudek et al., 2007;Tai et al., 2009), or by
heterochromatin relaxation and loss of epigenetic host control
over HERVs (Sun et al., 2018), increasing DNA damage and
expression of pluripotency-related genes (Frost et al., 2014).
Upregulation of ERV-K family member in a streptozotocin
murine model of sporadic AD was linked with upregulation
of immune response genes and downregulation of genes
involved in histone modifications and transmembrane transport
and associated with cognitive impairments in contextual fear
memory and spatial learning (Sankowski et al., 2019). HERV-K
(HML-2) transcripts containing a motif 50-GUUGUGU-30
contribute to neuronal death and microglial accumulation
associated with AD via TLR8 activation (Dembny et al., 2020).
ERVs can be transmitted between neurons in the brains of AD
patients, packed into an ARC viral-like capsid protein, which
is overexpressed in AD patients and is associated with Aβ
production (Wu et al., 2011).
Multiple Sclerosis
Multiple sclerosis (MS) is a neurodegenerative and
neuroinflammatory CNS disease characterized by multifocal
demyelinating lesions in the brain and spinal cord leading to
progressive physical and cognitive disabilities. Development
of MS has been associated with viral infections and activation
of HERVs (Alvarez-Lafuente et al., 2008;Kriesel et al., 2017;
Morandi et al., 2017;Gruchot et al., 2020).
Among viruses, higher transcription levels of HHV-3 and
HHV-6 have been found in the CSF of individuals suffering from
MS (Mancuso et al., 2007;Alvarez-Lafuente et al., 2008). Also,
coronaviruses have been detected in the CNS of MS patients
(Burks et al., 1980). EBV has been even suggested as a trigger
for MS that activates HERV-W, which then sustains the disease
(Mameli et al., 2012).
HERV-W is also the main HERV associated with MS
pathology. Further, the expression level of HERV-W in the brain
of MS patients correlates positively with the severity of disability
and disease progression (Sotgiu et al., 2010). HERV-W and its
env transcript and protein are upregulated in the brains (Perron
et al., 1997;Antony et al., 2004) as well as in the peripheral blood
and serum of MS patients (Garson et al., 1998;Perron et al.,
2012a). HERV-W can be activated in MS by EBV (Mameli et al.,
2012) and HHV-1 (Ruprecht et al., 2006;Marrodan et al., 2019).
HHV-1-triggered HERV-W transcription occurs in immune cells
central to the MS pathology, such as B cells, microglia, astrocytes,
and macrophages (Ruprecht et al., 2006;Marrodan et al., 2019).
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HERV-W env protein activates dendritic cells and boosts T helper
lymphocyte type-1 (Th1) immune response, acting as a PAMP.
It stimulates pro-inflammatory anti-viral response by binding
TLR4 and CD14 (Rolland et al., 2006;Saresella et al., 2009).
Upon binding the TLR4 on oligodendroglial precursor cells,
HERV-W env stimulates release of pro-inflammatory cytokines,
inducible nitric oxide synthase, and formation of nitrotyrosine
groups leading to reduction of myelin expression in MS lesions
(Kremer et al., 2013). In addition to the above, HERV-W env
is a powerful superantigen linked with demyelination in MS
(Perron et al., 2001;Rolland et al., 2005), perhaps associated with
molecular mimicry with myelin oligodendrocyte glycoprotein
(MOG) (do Olival et al., 2013;de Luca et al., 2019). Accordingly,
treatment with HERV-W env antibody can effectively rescue
myelin expression (Kremer et al., 2015).
Mechanistically, HERV-W env protein has been shown
to induce microglial polarization and closely associate with
myelinated axons in MS lesions ultimately leading to structural
damage of these axons (Kremer et al., 2019). HERV-W env,
encoded from a full-length provirus at locus 7q21.2, gives rise
to a syncytin glycoprotein (Blond et al., 2000;Mi et al., 2000),
the expression of which, similar to HERV-W env, is increased
by threefold in the brain tissue of MS patients compared
with the controls (Antony et al., 2004;van Horssen et al.,
2016). HERV-W env and syncytin expression is confined to
immunologically active cells, including cells resembling activated
glia and phagocytic macrophages at acute and chronic MS
demyelinating lesions (Antony et al., 2004;van Horssen et al.,
2016). Syncytin activation leads to a myriad of MS-associated
pathology, such as pro-inflammatory profile in astrocytes,
interleukin-1β(IL-1β) production, cellular protein oxidation,
inhibition of oligodendrocyte maturation, myelin damage, and
antagonization of remyelination up to neurobehavioral deficits
(Antony et al., 2004).
The central role of HERV-W env in MS neurodegeneration
has led to the development of a specific monoclonal antibody,
Temelimab (GNbAC1) (Curtin et al., 2012), an agent
currently being tested in clinical phase II (ClinicalTrials.gov
identifier: NCT02782858).
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative
disease, characterized by progressive loss of cortical and spinal
motor neurons. While majority of ALS cases are sporadic,
mutations in certain genes, such as trans-activation responsive
(TAR) DNA-binding protein 43 (TDP-43), have been associated
with ALS development (Yousefian-Jazi et al., 2020).
That ALS might be linked with viral infections, comes from
finding HIV and HTLV-1 presence in the brains of ALS patients
(Verma and Berger, 2006). Further, antiretroviral therapy of
HIV-infected individuals with ALS-like syndrome reverses the
symptoms related to ALS (Moulignier et al., 2001). The CSF of
ALS patients negative of HIV, contains viral reverse transcriptase
at levels seen in HIV-infected individuals (MacGowan et al.,
2007;McCormick et al., 2008). This has led to investigation
of HERVs and revealed the central role of HERV-K among
the HERVs in ALS pathogenesis. HERV-K pol, gag, and env
are all transcriptionally active in the prefrontal, sensory, motor,
and occipital cortex of ALS patients (Douville et al., 2011;Li
et al., 2015) and HERV-K env additionally in spinal neurons
of sporadic ALS patients. Higher serum IgG and IgM reactivity
toward HERV-K gag is also characteristic to ALS patients (Li
et al., 2015). HERV-K in ALS can be activated by several
mechanisms and occur from distinct cytogenic loci (at 7q36.1)
(Douville et al., 2011). These mechanisms include neuronal injury
and neuroinflammation through interferon-stimulated response
elements in the viral promoter (Gonzalez-Hernandez et al.,
2014;Manghera et al., 2016). Once activated, neuronal HERV-
K upregulation contributes to sustained neuroinflammation
through promoting nuclear translocation of IFN regulatory
factor 1 (IRF1) and NF-κB isoforms p50 and p65 (Manghera et al.,
2016). Also, TDP-43 activates HERV-K upon binding its DNA (Li
et al., 2015). HERV-K and TDP-43 expression in ALS are strongly
correlated (Douville et al., 2011). HERV-K env expression leads to
neurite retraction, beading, and neurodegeneration (Chen et al.,
2014;Li et al., 2015).
Schizophrenia Spectrum Disorders
Schizophrenia is a neuropsychiatric and neurodevelopmental
disorder characterized by episodes of psychosis, hallucinations,
and delusions. Disease typically starts in young adulthood and is
strongly affected by genetic background and environmental
factors (Owen et al., 2016). The neurobiology behind
schizophrenia is poorly understood.
The likelihood of developing schizophrenia is increased by
infections (most significantly evidenced with studies on HHV-
2) (Arias et al., 2012), subclinical inflammation (Frydecka et al.,
2018), and variation within brain-associated and immune genes
(Schizophrenia Working Group of the Psychiatric Genomics,
2014). Altered immune response and lasting inflammatory
dysregulation of the nervous system are associated with chronic
stress exposure (Pearce et al., 2019;Nettis et al., 2020).
Upregulated immune response genes induce hyperactivation of
LINE-1, which is common in schizophrenia patients (Bundo
et al., 2014). Increased retrotransposition of LINE-1 is found in
the neurons of prefrontal cortex, affecting intragenic regions and
synaptic genes (Bundo et al., 2014).
In addition to LINE-1, expression of several HERV families,
such as HERV-K, HERV-W, and HERV-H, has been shown to
be dysregulated in the brains, cerebrospinal fluid, and blood
of schizophrenia patients (Perron et al., 2012b;Li et al., 2019;
Mak et al., 2019). This could involve activation of distinct
HERV loci. For example, activated HERV-W env transcripts in
schizophrenia have been shown to differ from these activated in
bipolar disorder or MS. Combined with HERV-W copy number
differences between schizophrenia patients and healthy controls,
this might point to perinatal HERV-W activation (for instance by
infections such as influenza), potentially leading to inflammation
and subsequent neurotoxicity (Limosin et al., 2003;Perron et al.,
2008, 2012b). HERV-W env protein expression in developing
hippocampus was recently shown to alter the N-methyl-d-
aspartate receptor (NMDAR)-mediated synaptic organization
and plasticity. This was associated with defective glutamate
synapse maturation, behavioral impairments, and psychosis
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(Johansson et al., 2020). Apart from HERV-W, lower DNA
methylation levels at HERV-K sequences in peripheral blood
have been shown to be specific to early stages of schizophrenia
(Mak et al., 2019).
Neuropathogenesis of SARS-CoV-2
Highly pathogenic severe acute respiratory syndrome
coronavirus-2 (SARS-CoV-2) is a single-stranded RNA virus
from the coronavirus’s family (Su et al., 2016).
SARS-CoV-2 enters host via its immunogenic spike
glycoprotein binding to ACE2 receptor on endothelial and
smooth muscle cells (Lan et al., 2020;Kaneko et al., 2021).
Resultant coronavirus disease 2019 (COVID-19) mainly presents
as an acute respiratory disease; however, also neurological
symptoms have been reported, including dizziness, headache,
encephalitis, seizures, intracerebral hemorrhage, and stroke
(Benger et al., 2020;Guadarrama-Ortiz et al., 2020;Huang
et al., 2020;Lu et al., 2020;Moriguchi et al., 2020). In addition,
neuromuscular and autoimmune complications are associated
with COVID-19. These include most frequently Guillain Barré
syndrome but also Miller Fisher syndrome, polyneuritis cranialis,
acute myelitis, oculomotor paralysis, and Bell’s palsy have been
reported (Guadarrama-Ortiz et al., 2020;Katyal et al., 2020).
SARS-CoV-2 uses the olfactory nerves and possibly the vagus
nerve to access the brain (Guadarrama-Ortiz et al., 2020;Liu
et al., 2020) where ACE2 receptor is expressed on neurons
and glial cells (Zou et al., 2020). The neuromuscular invasion
of SARS-CoV-2 likely involves retrograde axonal transfer
of the virus in trans-synaptic pathway and cytokine storm
(Katyal et al., 2020).
SARS-CoV-2 viral proteins interact with human proteins that
regulate cellular longevity and aging, and are involved in stress
response, vesicle trafficking, lipid metabolism, production of
reactive oxygen species, RNA regulation, ubiquitin ligases, and
mitochondrial activity (Gordon et al., 2020). Impaired lysosomal
function combined with inhibition of ubiquitin–proteasome
system can cause protein misfolding and protein aggregation in
affected cells, including neurons, a common mechanism of many
neurodegenerative diseases (Lippi et al., 2020).
Up to one third of COVID-19 patients develop neurological
symptoms beyond the acute stage of the disease, mainly
manifesting with chronic fatigue syndrome and myalgic
encephalomyelitis (Nath and Smith, 2021). That several
coronaviruses (CoV-OC-43, CoV-229E, and HCoV) are found
in the brains of MS patients or have been associated with
MS pathology (Burks et al., 1980;Murray et al., 1992) could
indicate MS-like demyelinating neuropathology as a possible
long-term complication of COVID-19. Further, it remains to be
investigated how SARS-CoV-2 affects the expression of HERVs,
LINE-1, and Alu elements and interacts with other viruses and
environmental factors.
AGING
Aging is a progressive deterioration of physiological functions
at the cellular, organ, and organism levels eventually leading
to senescence. Aging disrupts the balance between the nervous
and the immune system and increases risk for various
neurodegenerative and neuroinflammatory diseases (Streit et al.,
2004;Godbout et al., 2005;Valdes-Ferre et al., 2020).
Aging increases genomic instability (Lombard et al., 2005)
by gradual loss of global DNA methylation and region-specific
DNA hypermethylation (Jung and Pfeifer, 2015). Increased age-
related activation of certain retrotransposon families is found in
mice (ERVs) (Odaka, 1975) and Drosophila (LINE-like R2, LTR
element gypsy transcripts, and env glycoprotein) (Li et al., 2013).
In humans, aging causes profound de-repression of HERV-K,
Alu, and LINE-1 elements (Bollati et al., 2009;Cardelli, 2018)
with increasing chromatin openness at Alu, SVA, and LINE-
1 elements in senescent cells (De Cecco et al., 2013). This
affects most significantly evolutionarily younger elements (De
Cecco et al., 2013). Transcription levels of HERV-H, HERV-
K, and HERV-W change in distinct patterns during human
life. HERV-H is highly transcribed in childhood, while HERV-
K and also HERV-W transcription increases on reaching higher
age (Balestrieri et al., 2015;Autio et al., 2020). ERV activation
in aging Drosophila causes shorter lifespan, neurodegeneration,
and memory deficits (Li et al., 2013). Similar effects of ERV
activation on hippocampal memory and cognitive impairment
are observed in mice (Sankowski et al., 2019). Particularly, in
combination with chronic inflammation, the effect of HERV
activation in aging brain can be detrimental and contribute to
neuronal decline (Johnston et al., 2001;Sankowski et al., 2019). In
addition to HERVs, LINE-1 hypomethylation has been described
in the peripheral blood of elderly individuals (Mahmood et al.,
2020). Some of the age-related epigenetic changes, such as
those related to Alu methylation, seem to be regulated by
longevity-associated genetic factors, including genes involved
in nucleotide biosynthesis, metabolism, and signal transduction
(Gentilini et al., 2013).
Aging can determine the outcome of interplay between
endogenous and exogenous viruses. Interaction of the
endogenous murine leukemia virus with the generally
non-pathogenic murine togavirus lactate dehydrogenase-
elevating virus leads to a fatal and progressive neurological
disease in up to 100% of aged mice. This suggests convergence
of age-related, genetic, immunological, and viral factors in
the development of a neurological disease resembling ALS in
humans (Contag and Plagemann, 1989).
CONCLUDING REMARKS
This review brings together studies that have described a role
for exogenous viruses and (H)ERVs in CNS pathologies and
thereby highlights the interplay between the inherent and the
foreign. A contribution of exogenous and endogenous viruses,
separately and together, is increasingly evident in common
forms of dementia in young (HAND) and elderly population
(AD), MS, ALS, and also schizophrenia. In other neurological
complications of viral origin, such as SARS-CoV-2, it remains
to be seen if and how HERV, LINE-1, and Alu expression
may be involved. Viral CNS infections can be early triggers
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Römer Viruses and (H)ERVs in Neuroinflammation
of neuroinflammation; however, if viruses are successfully
combated or entered in a latent state, a central role might
be attributed to endogenous retroviruses. ERV activation
during infections seems to be a common (physiological)
mechanism that the host may not be able to control at
some point. ERVs can become continuously activated and
sustain the inflammatory imbalance. The crosstalk with IFN
seems to play an important role here. Facilitating factors
that are associated with continuous ERV activation such
as aging, stress, and other comorbidities as well as re-
awakening of a latent virus, cumulative or opportunistic
infections, as seen in immune-deprived conditions, contribute
to the progressive neurodegeneration or delayed CNS
pathologies. We are only beginning to understand how
exogenous viruses in connection with HERVs and other
retroelements affect normal aging and development of
neurodegenerative diseases and other neuropathologies. The
central role of HERV-W in MS pathology has led to its
targeting in clinical trials. It remains to be seen, whether other
HERVs could provide key targets in other neurodegenerative
diseases, such as HERV-K in ALS, to which there is
currently no cure.
AUTHOR CONTRIBUTIONS
CR designed the manuscript idea, performed literature search,
and wrote the manuscript.
FUNDING
This publication was funded by the publication fund of the
Max Delbrück Center for Molecular Medicine in the Helmholtz
Association, Berlin, Germany.
ACKNOWLEDGMENTS
CR would like to thank Dr. Lutz Römer for critical reading
of the manuscript.
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