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Endogenous retroviruses and multiple sclerosis.

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EDITORIALS
Endogenous Retroviruses
and Multiple Sclerosis
Human endogenous retroviruses (HERVs) are DNA
sequences (retroelements) present throughout human
chromosomes that by some estimates comprise up to
7% percent of the genome.1 Given their characteristic
retroviral organization, with long terminal repeats
(LTRs) flanking gag, pol, and env genes, it has been
proposed that they are derived from ancestral infectious
agents long integrated into human DNA. All identified
HERVs—and there are hundreds—are defective; that
is, they do not encode infectious particles, are not
known to be transmissible, and frequently do not even
encode functional proteins. Nevertheless, many are
transcriptionally active. Additionally, some HERVs are
associated with particle formation, and there is a theoretical possibility that HERV genomes can be
transcomplemented, resulting in full-fledged virion formation. Their persistence in the primate and human
genome—some authorities place the introduction of
primate ERVs back millions of years2—argues for a
strong selective pressure against a generally pathogenic
phenotype.
HERVs have been categorized in several ways, and
one frequently used scheme divides HERVs according
to the transfer RNA (tRNA) that is potentially used to
prime the synthesis of a DNA copy of the (presumed)
ancestral RNA genome.1 For example, HERV-W contains a primer binding site that binds the tRNA for
tryptophan (single-letter amino acid code W);
HERV-K is potentially primed by lysine tRNA; and so
forth. Their persistence in the human genome has led
some investigators to search for functional roles for
HERVs. Perhaps the most compelling evidence for
their involvement in a normal cellular function is the
expression of HERV-W envelope (termed syncytin) in
normal placental syncytiotrophoblasts.3 Mi and colleagues3 demonstrated that high levels of syncytin in
placental cytotrophoblasts mediate fusion of the cytotrophoblasts, suggesting a role for this protein in normal human placental development. Moreover, syncytin
was not found in any other tissues, with the exception
of testis (from which it was originally cloned). To our
knowledge, there is no other evidence for positive selection for HERVs.
Similarly, there is no conclusive proof that any
HERVs play a role in human disease, although investigators have posited several possible pathogenetic
mechanisms. For example, HERVs could enhance the
transcription of cellular genes placed downstream of
the HERV long terminal repeats (LTRs). The LTRs
contain the promoter elements and associated regulatory sequences that interact with transcriptional factors;
these are themselves often regulated by various inflammatory cytokines and other cellular proteins.4 Alternatively, HERVs may encode superantigens that result in
enhanced inflammatory responses, or they could mimic
self-antigens and subsequently lead to the development
of autoimmune phenomena such as those associated
with systemic lupus erythematosus or multiple sclerosis
(MS).
Retroviruses have by no means escaped the long list
of potential pathogens associated with MS by different
investigative groups. For example, a decade ago, human T lymphotropic virus type 1 (HTLV-1) was implicated by polymerase chain reaction amplification
from patients with MS.5 Perron and colleagues first
proposed the importance of an MS-associated retrovirus that formed morphologically appropriate particles.6
The MS-associated retrovirus was eventually found to
be related to an endogenous retroelement, ERV-9,
which led to the discovery of the family of HERV-W
retroelements.7,8 The increased expression of HERV
RNA had been suggested to play a role in multiple
sclerosis9,10 as well as schizophrenia,11 without clear
causality.
The article by Johnston and colleagues in this issue
of the Annals of Neurology (pp. 434 – 442) presents
clear evidence for increased expression of certain
HERV sequences, specifically HERV-W and HERV-K,
in the brains of individuals with MS or human immunodeficiency virus (HIV)-1 infection. It further concludes that increased HERV expression is not associated with specific disease pathology. Using both an in
vitro model system and pathological analyses of autopsied brain, the authors conclude that the observed
change in HERV expression is likely to be the result,
and not the cause, of inflammatory diseases within the
brain, by showing an association between monocyte/
macrophage activation in vitro and induced expression
of certain HERV RNAs. MS and AIDS are two conditions associated with macrophage activation, tumor
necrosis factor-␣ (TNF-␣) expression, and transendothelial migration of monocytes and lymphocytes into
the central nervous system (CNS); these events could
trigger the expression of HERVs, as suggested by
Johnston and colleagues.12 Because the increased expression occurs in conditions with such varied cause
and pathology, it is unlikely that specific pathological
changes or disease entities are associated with the enhanced transcription of these retroelements. The authors appropriately indicate that this study does not
preclude a more generic role for HERVs in inflammatory CNS disease, but rather argue against a specific
cause-effect relationship. Additionally, the failure to detect significant differences in HERV expression between control brains and those from patients with Alz-
© 2001 Wiley-Liss, Inc.
429
heimer’s disease argues against a role for HERVs in
directly inducing neurodegeneration. Nonetheless, unforeseen effects of HERV transcriptional activation by
inflammatory factors in the CNS cannot be discounted, and further studies in other neurodegenerative diseases may demonstrate other consequences of
the presence of these retroelements.
These experiments extend previous reports of HERV
detection in cells of patients with MS by the direct
quantification of HERV transcripts in brain tissue, and
by demonstrating a possible mechanism for induction
of HERV-W overexpression. Macrophage activation,
which occurs in brain tissue in many inflammatory
CNS diseases such as multiple sclerosis and AIDS, is
linked directly to HERV transcriptional induction.
This conclusion is supported by this work as well as by
previous studies showing enhanced HERV expression
in vascular endothelial cells stimulated with TNF-␣
and other proinflammatory cytokines.4
Johnston and associates further contend that the
state of monocyte differentiation also affects HERV expression in cells of the macrophage lineage. While the
effect on HERV expression noted after induction with
phorbol esters is convincing, the relationship between
stage of differentiation and HERV expression is only
partially proven. The U937 cells, which are transformed and monocytoid in origin, are not ideal surrogates for differentiating monocytes/macrophages but
were used in these studies because of the inherent variability of HERV expression in primary monocytes
from different donors. Nonetheless, a comparison of
HERV expression patterns in undifferentiated monocytes with the pattern in fully differentiated monocytederived macrophages from the same donor would provide additional evidence of the importance of the
differentiation program in retroelement expression.
The significance of the presence of HERV transcripts in the human brain will likely remain contentious. HERVs are considered to be essentially nonfunctional components of the human genome, although
their mere presence suggests the potential for adaptive
or maladaptive influences on host cell functions under
conditions of induced expression.11 HERV gene expression may be regulated by mechanisms similar to
those affecting other retroviruses, such as HIV. HERVs
demonstrate at least partial sequence similarity to HIV,
with a characteristic LTR-gag-pol-env-LTR organization. As such, HERVs may be similarly subject to transcriptional regulation, suggesting a transactivation phenomenon resulting in increased HERV transcription
under inflammatory conditions. Consistent with this,
Johnston and colleagues found elevations in HERV
RNAs in brain tissues showing concomitant elevations
of TNF-␣, and in cultured macrophages stimulated
with phorbol esters and lipopolysachharide.
In summary, this interesting study provides strong
430
Annals of Neurology
Vol 50
No 4
October 2001
evidence that the HERVs found in MS are a byproduct of the inflammatory component of this disease, putting to rest thoughts that they could be the
exogenous pathogen that has been the “holy grail” of
studies on the pathogenesis of MS. At the same time,
the experiments raise the possibility that the increased
expression accompanying the inflammatory infiltrate
could end up by itself contributing to the pathology,
albeit in a nonspecific way.
Dennis L. Kolson, MD, PhD,
and Francisco González-Scarano, MD
Department of Neurology
University of Pennsylvania Medical Center
Philadelphia, PA
References
1. Bock M, Stoye JP. Endogenous retroviruses and the human
germline. Curr Opin Genet Dev 2000;10:651– 655.
2. Barbulescu M, Turner G, Seaman MI, et al. Many human endogenous retrovirus K (HERV-K) proviruses are unique to humans. Curr Biol 1999;9:861– 868.
3. Mi S, Lee X, Li X-p, et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 2000;403:785–789.
4. Katsumata K, Ikeda H, Sato M, et al. Cytokine regulation of
env gene expression of human endogenous retrovirus-R in human vascular endothelial cells. Clin Immunol 1999;93:75– 80.
5. Reddy EP, Sandberg-Wollheim M, Mettus RV, et al. Amplification and molecular cloning of HTLV-I sequences from DNA
of multiple sclerosis patients. Science 1989;243:529 –533.
6. Perron H, Gratacap B, Lalande B, et al. In vitro transmission
and antigenicity of a retrovirus isolated from a multiple sclerosis
patient. Res Virol 1992;143:337–350.
7. Blond JL, Beseme F, Duret L, et al. Molecular characterization
and placental expression of HERV-W, a new human endogenous retrovirus family. J Virol 1999;73:1175–1185.
8. Fujinami RS, Libbey JE. Endogenous retroviruses: are they the
cause of multiple sclerosis? Trends Microbiol 1999;7:263–264.
9. Christensen T, Dissing Sorensen P, Riemann H, et al. Molecular characterization of HERV-H variants associated with multiple sclerosis. Acta Neurol Scand 2000;101:229 –238.
10. Rasmussen HB, Lucotte G, Clausen J. Endogenous retroviruses
and multiple sclerosis. J Neurovirol 2000;6:S80 –S84.
11. Karlsson H, Bachmann S, Schroder J, et al. Retroviral RNA
identified in the cerebropsinal fluids and brains of individuals
with schizophrenia. Proc Natl Acad Sci U S A 2001;98:
4634 – 4639.
12. Johnston JB, Silva C, Holden J, et al. Monocyte activation and
differentiation augment human endogenous retrovirus expression:
implications for inflammatory brain diseases. Ann Neurol 2001;
50:434 – 442.
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