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Review Article
Viruses and the placenta: the essential virus first view
LUIS P. VILLARREAL
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Center for Virus Research, Department of Molecular Biology and Biochemistry, University of California
Irvine, Irvine, CA, USA
Villarreal LP. Viruses and the placenta: the essential virus first view. APMIS 2015.
A virus first perspective is presented as an alternative hypothesis to explain the role of various endogenized retroviruses
in the origin of the mammalian placenta. It is argued that virus–host persistence is a key determinant of host survival
and the various ERVs involved have directly affected virus–host persistence.
Key words: Virus evolution; host evolution; placenta; endogenous retroviruses.
Luis P. Villarreal Center for Virus Research, Department of Molecular Biology and Biochemistry, University of
California Irvine, Irvine, CA 92617 USA. e-mail: lpvillar@uci.edu
THE PROBLEM –WHY SHOULD ERVS
CONTRIBUTE TO THE COMPLEX
PLACENTAL NETWORK? CONFRONTING
THE ACCEPTED VIEWS
The emergence of mammalian vivipary and the pla-
centa presents many biological and behavioral
issues that challenge theories of evolution, see (1).
These biological and immunological dilemmas are
associated with the emergence of the ‘foreign’ mam-
malian placenta (expressing paternal genes). In
addition, the very first cell type to differentiate in
mammalian embryo is the trophectoderm which
will generate the placenta, thus major alterations to
programs of early developmental are also needed.
The placenta will mediate the blood (and immune)
exchange between mother and her non-self embryo
and contribute to very complex biological and
behavioral changes needed for live birth. All these
changes require complex and network based regula-
tory changes to the genetic programs that had
mostly been present in ancestral egg laying mam-
mals. This represents a major transition in the evo-
lution of complexity that has been difficult to
explain by traditional concepts. Over the years, it
has become increasingly evident that endogenized
retroviruses (ERVs) have been intimately and dee-
ply involved in the placenta of all mammalian lin-
eages (2). These historic retrovirus observations
include the presence of intercisternal A-type parti-
cles (IAPs) (3), presence in human oocytes (4), pres-
ence in early preimplanted embryo (5), antivial
activity of human sera (6), the presence of reverse
transcriptase (RT) inhibitors (7, 8), and the pres-
ence of ERV3 mRNA (9, 10). For a summary of
these early observations see (11). In 1997, I pro-
posed some general reasons why virus should be
involved in the origin of vivipary (12). ERVs asso-
ciated with mammalian reproductive biology are
lineage specific and their acquisition is associated
with the origin of each lineage (13, 14). But it was
the discovery of the involvement of ERV envelope
proteins (such as syncytins) in reproductive biology
that has really engaged the interest of many evolu-
tionary biologist in this virus–host relationship.
Overall, they have adopted a now well accepted
perspective that retroviruses have repeatedly pro-
vided env genes which have proved useful (were
exapated/domesticated) for the various functional
and structural requirements of a placenta (15–18).
And once the early env-mediated placenta emerged,
fitter (better) versions of placentas via newer ERVs
followed. This is the currently accepted perspective
on ERV involvement in the origin of the placenta
and it presents a ‘host come first’ perspective.
Here, the fortuitous virus is simply providing a
convenient and diverse source of useful env genes.
But, egg-laying animals (especially avians) are
highly successful and diverse, so why viruses might
mediate such a drastic change in reproductive host
Received 4 June 2015. Accepted 26 October 2015
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1
APMIS ©2015 APMIS. Published by John Wiley & Sons Ltd.
DOI 10.1111/apm.12485
A P M 12485
Dispatch: 11.11.15 CE: Kathiravan
Journal Code Manuscript No.
No. of pages: 11 PE: Nagappan
biology remains an open question. In this essay, I
present a virus first perspective that offers an alterna-
tive hypothesis for virus involvement in the origin of
the placenta.
A VIRUS FIRST PERSPECTIVE JUSTIFIED:
VIRUS PERSISTENCE AND DISTINCT
SOCIAL (NETWORK) FEATURES
It has been 10 years since I published my book
which was first to present the evolution of life
from a virus first perspective (19). If the main the-
sis of that book can be stated in simple terms it is
that we must first consider the virus–host relation-
ship with better understand evolution of the host.
From this perspective, we can then see that viruses
were involved in most all major transitions of host
biology in evolution. This will likely seem an over-
stated or even preposterous position to most read-
ers. How could genetic parasites (viruses) be
providing such fundamental capacity for host evo-
lution? And why would they do so? But we have
come to recently realize that viruses are omnipre-
sent so all life must survive in its virosphere habi-
tat. And such survival often involves virus
themselves since virus, their defective and various
other genetic parasites (mostly called transposons)
can and often do provide virus resistance systems.
These viral colonizers then can also be used to
provide new sources of host complexity (such as
the placenta). Thus, to understand the deep role
virus plays, we must always consider a virus first
perspective for the evolution of complexity in the
host. Essentially, the concept is that viruses are
fully competent agents and editors of all host sys-
tems of instruction (DNA, RNA, epigenetic, trans-
lational etc.) (20). Thus, they provide the host with
new sources of instruction systems (not errors). In
addition, they promote network formation by pro-
viding coherent societies (quasispecies populations)
of agents able to edit host code content (and add
new identity) in a diffuse, distributed manner,
which promotes the creation of and editing of host
regulatory networks. Thus, a viral role in the ori-
gin of the placental regulatory network can be
expected (21). Viruses possess all the advantages of
evolution relative to host: extreme genetic adapt-
ability, extreme diversity, extreme numbers,
extreme rates of genetic exchange, tolerance for
‘unfit’ variation, and the ability to reassemble from
cryptic or ‘dead’ parts. They can transition
between the chemical and living world. Thus, I am
asserting that most initial genetic and selective
events that transform host regulatory complexity
are usually ‘pushed’ by virus action in a general
direction of increasing complexity. In this way,
viruses present an omnipresent and ancient issue.
Hence, we must always consider how any virus
action on host will affect virus–host survival in
their respective virosphere or virus habitat (e.g.,
reproductive tissue). A most significant develop-
ment would be the emergence of a stable persistent
relationship between virus and host as this repre-
sents a virus–host symbiosis that now protects the
host form the same and often other lytic (disease
causing) viruses. Persistence is difficult to attain
not the indirect result of survivor of runaway (self-
ish) replicons. Persistence inherently requires self-
regulating and self-opposing functions. Thus, even
‘defective’ (and parasitic) components of viruses
(and transposons) can express virus-specific regula-
tory (opposing) molecules (including ncRNA),
clearly promote virus–host persistence, and
respond to oppose lytic virus infection. Thus, the
presence of incomplete viral elements in host gen-
omes are not simply the remnants of past viral
infection and disease (virus sweeps), but should be
considered as the savior of the host lineage by pro-
viding the capacity for self regulation and persis-
tence of viruses that can still threaten related
species. Virus persistence provides a large selective
advantage in the virosphere. It also presents a per-
spective that is essentially the converse of the cur-
rent view in evolutionary biology: viral persistence
is a big determinant of host survival with strong
effects on host group survival as well (via virus
communication) (22). It defines a relationship
between virus and host and between host them-
selves that does not adhere to the predator–prey
theory (23, 24). Nor does it adhere to the red-
queen hypothesis. Persistent virus is usually highly
prevalent, silent, often genetically stable, co-evol-
ving with the host and usually transmitted from
parent (old) to offspring (young) or in close coor-
dination to host reproductive biology. Establishing
persistence is difficult and can be thought of as
resulting from a successful hacking of host identity
networks to insert new code and promote survival
of a new more complex virus–host identity. Since
persistence is always regulated, it is a mostly silent
state in which reactivation is tightly linked to host
(reproductive) biology with big consequences to
host and virus fitness. This makes it much more
difficult to study. Asserting the core importance of
persistent virus to host survival thus presents a big
break from historic views in evolutionary biology
and adds a process of selection that stems from
the horizontal transmission of persistent virus. As
the virosphere provides no ‘virus-free’ habitat for
any life form, all living forms have adapted to
their own viral habitat.
2©2015 APMIS. Published by John Wiley & Sons Ltd
VILLARREAL
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APPLYING THE VIRUS FIRST PERSPECTIVE
TO PLACENTAL ORIGINS
Let us now conceptually reconsider the placenta
from this virus perspective. Accordingly, ‘exapted’
viral env genes were not initially a convenient
source of genetic errors for promoting a more effi-
cient placenta, but instead they were successful col-
onizers that allowed the host lineage to control
various persisting viruses prevalent in their repro-
ductive systems. The absence of these ERVs (envs)
would leave these host susceptible to these same
and/or other viruses (25). In this light, the presence
of an impervious eggshell would preclude the colo-
nization of the shell membrane by active and self
protective virus. But by creating a virus accessible
and rich tissue (trophectoderm; exposed after zona
pellucida loss) which is needed for host reproduc-
tion, it promotes virus-based network solutions
(e.g., genetic reprogramming, immune suppression,
transformation, membrane fusion) to biologically
difficult problems needed for vivipary to emerge
(12). In addition, the new virus–host symbiont has
acquired a very significant advantage compared the
uncolonized host that remain susceptible to the dis-
ease induced by related viruses. By modifying host
identity (and immunity), these ERVs have thus set
the stage needed to promote virus persistence as
well as a new host reproductive strategy. This
reproduction strategy must in turn promote the
reproductive success of the new virus–host combi-
nation. However, the ERV-host relationship is
often dynamic and can continue to be susceptible
to subsequent (competing, displacing) ERV colo-
nization as the persistent/acute virus habitat further
evolves [as an exemplar, see JSRV (26)]. Wild mice
show similar strain (mating) specific ERV-cancer
biology (27, 28). This virus first scenario can thus
provide an answer as to ‘why’ various distinct, but,
host lineage-specific viruses have been involved in
their placentas and promote more complex host
reproductive biology. These viruses thus resemble a
competent, but, diverse gang of highly effective net-
work hackers that seek to add new (viral) instruc-
tions. Because viruses can also disperse and interact
as populations [quasispecies: QS, see (29)], viruses
can modify distributed regulatory networks, not
simply a specific loci or individual host. Such net-
work editing need not occur by a serial set of indi-
vidual events involving master individual type virus
selection (30). They can instead involve quasis-
pecies-based and defective virus-based processes
that occur via population based virus colonization
(see the Koala-virus example below). Such diversity
makes these agents prone to multifunctional-, con-
ditional-, and context-dependent interactions.
Indeed, the QS-based feature of RNA viruses in
particular, allows us to think about the involvement
of a virus ‘consortia’ as natural editors of host
genetic content (31). Thus, the presence of such dis-
tributed virus-derived (often defective) information
is not the residual product of errors, but the pro-
duct of a QS-based colonization that directly
affected virus persistence, virosphere survival, host
competition, and has also modified host identity
systems. Host evolution is then free to adapt these
new viral network systems for host reproduction
and survival. Successful virus colonization of host
thus promotes new complex host group and indi-
vidual identity that strongly affects competition
with related, but, uncolonized host populations and
leads to a modified virosphere.
AN EXAMPLE OF ONGOING POPULATION-
BASED ENDOGINAZATION: KOALA
RETROVIRUS
Let us now outline some evidence that is most rele-
vant to this virus first scenario: that is, virosphere
survival via persisting new virus information. The
Koala’s of Australia provide a particularly recent,
relevant, and informative story, see (32). Koalas
have recently undergone an epidemic of retrovirus
(KoRV, a gamma retrovirus)-mediated leukemia.
Survivors, however, are undergoing endogenization
by an array of this same virus [which itself appears
to originated from an virus of rodents or bats (33)].
Survivors do not die from leukemia, but they can
generally still produce the virus, which is now held
in check by the endogenized (proviral) versions.
Thus, they have established persistent infections
with low disease. This endogenization is occurring
by a complex process involving geographically (and
tissue specific) distinct populations of both exoge-
neous and endogenous viruses involving an increas-
ingly large diversity of ERVs at low copy level (34).
Clearly, the endogenized KoRV must modify the
exogeneous KoRV-induced immune cell dis-regula-
tion (leukemia) that would otherwise occur. Indeed,
wild Koalas with endogenized KoRV no longer
make antibodies to KoRV (33). Thus, virus infor-
mation has become ‘one’ (symbiotic) with host and
must be involved in virus control. But not all Koala
populations have been equally affected by the epi-
demic. Populations isolated in some islands have
much less disease and no endogenization. However,
it would not be difficult to predict what might hap-
pen if the persistently infected mainland Koalas
now come in close contact with these isolated popu-
lations: survival of the persistently infected. This
new Koala KoRV virosphere requires that these
©2015 APMIS. Published by John Wiley & Sons Ltd 3
VIRAL ORIGIN OF THE PLACENTA
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ERVs must remain in Koala genome along with
their capacity to cause tumors in non-endogenized
populations. Thus, inducing lethal tumors (viral
harm) is not a breeding artifact but an important
phenotype that can be transmitted to compel unin-
fected Koalas to either die or become one (persis-
tent) with KoRV. This situation promotes
reproductive isolation via the survival of KoRV
endogenized Koalas.
GAMMA ERVS IN BATS, INTERACTION
WITH OTHER VIRUSES, AND
REPRODUCTIVE ISOLATION
Gamma retroviruses viruses (in contrast to len-
tiviruses) have been very successful in endogenizing
vertebrate species (as sources of ERVs). Gamma
retroviruses are mostly transmitted from old to
young, often via reproductive tissue. Indeed, the
reproductive tracts appear to generally provide a
‘virus-rich’ and also a ‘virus-mixed’ habitat. Thus,
we might also anticipate that the placenta will need
to provide general mixed virus resistance and that
such resistance will often be mediated by resident
or endogenized virus, as has been reported (35).
Gamma-retro virus endogenization has also
occurred in bats (36). Interestingly, ERVs seems to
have also been involved in (helped) the endogeniza-
tion of filoviruses (Ebola and Marburg) that has
also occurred in bats (37). Given the capacity of
bats to host many persisting RNA viruses that are
highly pathogenic to other species, their significant
genome colonization by the gamma retroviruses
and rolling circular DNA virus defectives (express-
ing stem-loop miRNAs) is particularly interesting
(38). Such persistence by potentially lethal virus is
not simply due to the fortuitous containment of an
infection, but must have resulted from the establish-
ment of a virus ‘addiction module’ in that the same
defective virus must resist similar virus. But if the
host were to lose this (defective) virus information,
it too would become susceptible to lethal infection.
This, I suggest, defines a general issue that applies
to all species and their viruses. It also can explain
the emergence of sexually incompatible populations
(due to incompatible persistent viruses). It is fur-
thermore likely that this issue also relates to sexual
incompatibilities seen via methylation (39). Virus
persistence (addiction) is not specific to ERVs. In
wild mouse colonies, for example, many viruses can
establish prevalent and highly stable persistent
infections, including MVM, MPV, Theilers virus,
LCMV, MHV. Although some of these viruses are
also capable of causing disease (even in wild
colonies), they are often held in check by
population-based ‘virus persistence’, for example
via maternal antibodies transmitted through the
placenta at birth (40). Generally, such persistently
infected wild colonies are healthy. Yet the introduc-
tion of such wild mice into uncolonized ‘virus-free’
breeding colonies will usually result in reproductive
collapse of the entire virus-free colony. Thus, the
history of persisting virus in a specific population
can have measurable and large survival conse-
quences. Along these lines, we can consider the
recent Ebola virus epidemic. Human male survivors
appear to persistently produce viruses in reproduc-
tive tissue (41). Clearly, such persistently infected
and sexually transmissible humans pose a major
risk to all extant human populations. In contrast to
rodents and bats, humans host a lot of persistent
DNA virus infections (polyomavirus, papillo-
mavirus, adenovirus, herpes virus). Many human-
specific viruses can also be found in the reproduc-
tive organs. Herpes 6/7 and HSV-2 are especially
present in such tissues (42) and able to cause fatal
encephalitis in unprotected newborns (via non-
immune mothers) (43). Interestingly, these HVs per-
sist via microRNAs that modify host apoptosis (44)
and can act cooperatively (45). HHV 6 can also
integrate into chromosomal (centromere) DNA and
allow genomic maternal to fetal transmission (46).
And the presence of such prevalent viruses in
human reproductive tissue can have major conse-
quences to other viruses, such as HIV-1. Indeed, in
the S. African epidemic, heterosexual transmission
of HIV-1 depends heavily on co-infection with
HSV-2 (47). A similar situation applies HIV-1 and
papillomavirus-induced cancers (48). Some viruses
can inhibit HIV (49). Interestingly, HERVK serum
immunity can also affect HIV (50). Thus, the repro-
ductive tract provides a virus-rich and mixed-virus
habitat.
VIRAL IDENTITY AND IMMUNE NETWORKS
VIA PARASITE DERIVED STEM-LOOP RNA
The importance of small non-coding RNAs for
DNA virus persistence has recently become clear
(51). But small non-coding RNA regions (with
stem-loops) are also the main identifying and regu-
latory elements for most if not all RNA virus.
Indeed, the definition of a gamma retrovirus
depends on such a stem-loop element. Also, within
retroviral LTRs and various other crucial control
elements, stem-loop RNA are essential for identifi-
cation and regulatory function. Thus, RNA–RNA
interactions via stem-loop regions promote the
establishment of RNA-based regulatory networks.
Other parasitic retro-agents (LINEs/SINES, alu’s)
4©2015 APMIS. Published by John Wiley & Sons Ltd
VILLARREAL
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can also be transcribed to produce non-coding
stem-loop RNAs. This suggests the possibility for
an extensive and mixed system of RNA-based regu-
lation all deriving from parasitic agents (52). From
the host perspective small non-coding RNAs are
mostly thought to control host–virus (retroposon)
interaction (53). Indeed, many human microRNA’s
target retroviruses and ERVs (54).
MULTIFUNCTIONAL NETWORK ISSUES FOR
THE PLACENTA SOLVED BY ERVS
Let us now further consider a virus first (virus-origin)
perspective for the origin of the placenta. Accord-
ingly, virus should: (i) be involved the origin of the
trophectoderm (first embryonic cell to differentiate),
(ii) promote embryo implantation, (iii) promote com-
plex placenta functions (including the cellular inter-
face and invasion that feeds the embryo), (iv)
regulate the mother’s (host) immune response, (v)
communicate to reprogram the mother’s (host) phys-
iology and behavior to support the embryo during
pregnancy and after birth. These may seem like
impossible and overly diverse tasks for viruses to
help solve. This is on top of the fact that prior egg-
based reproduction must have already been working
well. But let us recall the general competence of virus
to regulate all systems of host control, including all
genetic, epigenetic, transforming systems via a pro-
cess involving transmissible-, diffuse-, ERVs-, and
ncRNA-based regulation. Such new regulations can
be forcefully superimposed onto the host. Viruses are
good for this. In the next section (on Motherhood
behavior and virus), a related complex issue of virus–
host reproduction reprogramming in the context of
parasitoid wasps is also presented, but involving dis-
tinctly different DNA viruses. With respect to the
placenta, there is indeed evidence of viral (and antivi-
ral) involvement in all of the above issues. Retroviral
and retroposon RNA is highly expressed and regu-
lated in the early embryo. And although DNA
methylation is thought to restrict retrovirus and
retroposons, stem cells (and the placenta) are open
to ERVs as their DNAs are hypomethylated (55).
lncRNA, siRNA and RNAi are all involved in early
embryo regulation but are also either derived from
retroposons or thought to regulate ERVs and retro-
posons. The RNAi system in invertebrate animals
and plants is a core innate immune regulator of virus
infection. Yet, its antiviral function was mostly lost
in jawed vertebrates along with the emergence of the
interferon system and adaptive immunity. Interest-
ingly, it retains activity in the early embryo and is
needed for early development (56), but is not appar-
ent in most somatic tissue. This strongly suggests a
major alteration to antiviral systems occurred in
early mammalian embryos. Also, lncRNA appears
to be involved in early embryo programming, but
such RNAs are mostly derived from retrotrans-
posons (57). Other expressed functional repeat
RNAs are also derived from retrotransposon (58).
Indeed, ERVs themselves appear to be directly
involved in fetal imprinting (59). Subsequently,
embryo implantation involves reverse transcriptase
activity that is derived from retroposons (60). In
addition, the placenta clearly depends on the various
ERV env (syncytin) genes for both structural and
functional needs (61). And in at least ten lineages of
mammals have acquired their own version of envs
for placental function. But the regulatory regions for
these syncytins is complex and composed of mixtures
of LTRs and other regulatory regions derived from
other retroviruses (62). Indeed, the placental does
not seem to emerge from the acquisition of a lot of
new genes, but instead appears to result from a more
complex regulation of mostly previously existing
genes via a the emergence of a regulatory network
that was derived to a large degree from ERV-LTR
elements (63). These LTRs may be providing enhan-
cer-based gene regulation (64). In addition, LTR reg-
ulation of insulin (65), poly-A control (66), NOS3
expression (67) have all been reported in the pla-
centa. The acquisition of such regulatory complexity
in the placenta along with its coherence clearly pre-
sent a big problem. How can we explain the origin
and integration of this network? A selective process
involving serial individual fittest type selection
(exapted genes) does not account well for how net-
work coherence (cooperation) is attained. Indeed, I
think such step-wise selection is not possible given
the successive and long durations needed for differ-
ential offspring survival and also the clear similarity
of viral elements to be distributed in the network in
order for the placental to be formed and function.
However, if instead we invoke a process similar to
what is occurring in Koala ERV endogenization, we
see evidence for population (network)-based colo-
nization en mass. For this to occur via the placenta,
the placenta must have been initially involved in viral
and antiviral control, as has been reported (35).
Indeed, both network emergence and antiviral status
should associate with ERV acquisition. And other
human viruses, such as HIV, HSV, could also be
affected (68).
PLACENTAL VARIATION AND
CORRESPONDING ERVS
Biologically, the placenta varies greatly between
species (69), especially its invasiveness (70). The
©2015 APMIS. Published by John Wiley & Sons Ltd 5
VIRAL ORIGIN OF THE PLACENTA
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selective pressure and molecular basis for such vari-
ation has always been curious and difficult to
explain. However, if we consider the involvement of
distinct viral ecologies and colonization histories in
placental origins, we might better explain such pla-
cental variability. Endogenous viruses (often defec-
tive but some expressing env or gag) can clearly
provide restriction factors that limit exogenous
virus susceptibility (71, 72), especially env (73). Such
restrictions, however, are highly species, strain, and
virus specific. The sheep retrovirus (JSRV) seems to
provide the best model for how a virus is able to
both infect as exogenous disease causing virus yet
be essentially and required for reproduction as an
endogenized virus (74). Such a relationship can
establish a dynamic, ongoing change to host ERV
composition with degradation of older displaced
copies similar to that as seen in primates (75). This
JSRV model, I suggests, captures the essence of the
virus–host dynamic in reproductive tissue. Repro-
ductive transmission of virus becomes key. Indeed,
various other animals show reproductive virus
transmission and ERV changes, such as drosophila
(76). However, it is clear that many species are
unable to produce an exogenous virus from endoge-
nous copies, such as primates. Clearly, there are
distinct variability in species-specific virus–host
composition and ecology. In many situations, I
propose that it is likely that other viruses of the
reproductive tissue are also involved in the placen-
tal-ERV relationship. Thus, the ERVs expressed in
placental tissues may need to be evaluated in the
context of additional virus mixtures and could have
a more generalized antiviral affect.
ERV-DERIVED SYNCYTINS AND
GENERALIZED ANTIVIRAL ACTIVITIES
Recently, the presence of syncytin-like ERV env in
marsupial reproductive tissue has been reported
(77). Marsupials have simple short-lived placentas
in which embryos implant for periods of about 1
week, then the embryo is rejected from the interface
and must feed offof the pouch secretions. This sim-
ple placenta is much less invasive and long-lasting
then that of mammals and it also does not promote
the exchange of blood (and antibodies) between
mother and embryo. Yet even in this simplified pla-
centa it seems an ERV env gene were needed to
solve the interface problem posed by embryo
implantation. Why might a virus also provide a
good solution to this simplified biological situation?
Many ERVs that produce env genes in reproductive
tissue are dynamic and changing on an evolution-
ary time scale (75). If we adopt a virus first perspec-
tive to this situation, we could expect that an initial
and new ERV colonization resulted in a more
stable persistent relationship between virus and host
reproductive tissue, but that such a state will often
involve the emergence of a new antiviral state and
will occur via diffuse (Koala-like) network-like
mechanisms. The resulting virus–host combination
can still be subjected to further successful ERV col-
onizations that similarly further alter antiviral
states and regulatory networks. In this light, the
recent report regarding the expression patterns of
HERV-K in human reproductive tissue (early
embryos and placental cytotrophoblasts) is espe-
cially interesting (78). This ERV (env) does not
function as a syncytin, so env gene exaption is not
a possible explanation for its presence. Also, these
particular HERV Ks are relatively new and exoge-
nous additions to the human (but not chimpanzee)
genome, previously thought to provide no gene
function to humans due to polymorphisms. But
now it appears that this HERV K has provided
virus restriction factors (eng, gag) that are also
important for embryo function and it has also
induced a more general antiviral state via the
IFITM1-specific interferon response that more gen-
erally inhibits other virus replication. This general
response is operating thorough the HERVK-
encoded rec gene (a rev-like RNA transport pro-
tein) that interacts with stem-loop viral RNA
regions. In these specific embryos, however, about
1/3 of cellular mRNAs have 30UTRs that can bind
this rec and promote ribosome occupancy. Thus,
HERVK has promoted the emergence of a new reg-
ulatory translational network in these human cells
as well as a generalized antiviral response. Indeed,
it has been previously observed that HERVK can
also interact with other viruses. For example, HIV
infection activates many human-specific HERV-Ks
found at centromeres (79). In addition, HCMV has
been reported induces HERVK (80), as has EBV
(81). The relationship between ERV envs and host
is thus complex (82). But their ability to induce
general antiviral immunity as well as edit existing
host regulatory networks seems established.
MOTHERHOOD, BEHAVIOR, AND VIRUS?
In an early paper I compared the role of ERVs in
mammalian reproduction to that of polydnaviruses
in the reproduction of parasitoid wasp (12). In both
motherhood and wasp embryo parasitization of
caterpillars, the host (caterpillar or mother) must
be able to support an embryo that is foreign. Both
these situations have some surprisingly similar sets
of biological issues to overcome, including immune
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suppression of host, altered genetic program to sup-
port (feed) the embryo and altered development
and behavior of the host. And in both situations,
endogenized viruses provide solutions to these com-
plex problems. In the parasitoid wasp, the super-
coiled closed circular DNA’s that are packaged into
VLPs are now accepted to have been clearly virus
derived (83). This complex set of distributed viral
genomes have become endogenized, are mostly
defective and are expressed exclusively in female
wasp reproductive tissue. Relatively few viral ORFs
are expressed from these circular DNAs. Indeed,
most DNA segments have repeated sequences
within them. Interestingly, a differential microRNA
response is seen in response to parasitization (84).
What is particularly fascinating about the para-
sitoid wasp is that in some situations, the para-
sitized host caterpillar becomes immobile after the
wasp parasites exit its body. The caterpillar, how-
ever, is induced to protect these wasp larvae by
making a cocoon for them and guarding them
against other parasitoid wasp species, before the
caterpillar dies. The mechanism by which this dra-
matic behavior is induced is not understood. It
seems likely, however, that the polydnavirus is
involved. Given the paucity of polydnaviral ORFs,
I would guess that regulatory RNAs are also likely
to be involved. In mammals, mothers must also
undergo major behavioral changes. Indeed, some
increase in maternal brain size occurs during preg-
nancy. It has been proposed that a general link to
brain size is due to mother–offspring bonding (85).
It is also apparent that genomic imprinting essential
for maternal brain development (86). Many of these
changes are thought to be mediated by the pla-
centa, thus trophectoderm and the placenta are
likely sources of maternal behavioral control.
Unlike the fertilized parasitoid wasp egg, which is
surrounded by polydnaviral VLP layer, the sur-
rounding placenta of mammalian embryo provides
Fig. 1. The RNA gangen hypothesis: group identity and cooperativity of an RNA collective that requires opposite func-
tions for the genesis of life (social behavior of agents). Reprinted with permission from Villarreal, Luis P. 2015. ‘Force for
Ancient and Recent Life: Viral and Stem-Loop RNA Consortia Promote Life’. Annals of the New York Academy of
Sciences 1341 (1): 25–34.
COLOR
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much of the endogenous virus (ERVs) required for
reproduction. A question that arises is if these
human ERVs might also be involved in controlling
the behavioral changes of motherhood. Is the pla-
centa using ERVs in some way that alters the
mother’s physiology and behavior? As the mecha-
nism by which maternal brains are modified by the
placenta are not understood, we cannot answer this
question. Yet it is clear that the placenta does use
ERV products (env mediated budding) to communi-
cate with other maternal tissues. The human
cytotrophoblasts produce exosomes that have incor-
porated both syn-1 and syn2 (87). In addition, syn-
1 containing blood borne exosomes can regulate
the immune response (88). Also these placental
exosomes incorporate miRNA (89).
TRANSMISSIBLE SMALL RNAS, ERV
REGULATION AND MOTHERHOOD
BEHAVIOR: EVERYTHING FROM VIRUS
Given that RNAi (dicer) is active in preimplantation
embryos (56) and the ancestral role of miRNA in
silencing retroposons in preimplantation embryos
(90), ERV activity seems highly regulated by ncRNA
and specific to the placenta. Indeed, maternal plasma
has high levels miRNAs (91). And the placenta is a
major site of secretion of exosome-containing micro
RNAs (92, 93). Given the ability of miRNAs to con-
trol anxiety (94), a crucial maternal behavior, it thus
seems plausible these env (syncytin) expressing exo-
somes are involved in regulating maternal behavior.
Along these lines, the large human-specific C19MC
miRNA cluster is one of the sets of miRNAs
expressed in exosomes and this cluster is also
imprinted in placenta (95). But this primate-specific
C19MC cluster is also expressed in fetal brain and its
induced overexpression strongly associated with
pediatric brain tumors, see (96). Thus, there seems to
exist a clear pathway for the ERV mediated placen-
tal control via ncRNA’s of maternal brain growth
and behavior. The relationship of a mother to her
offspring is often considered in the context of
mother–offspring conflict. Clearly, a parasitiod lar-
vae is in a similar conflict with its caterpillar host.
But as I have outlined above, in both situations
endogenous viruses were involved in the origin (and
resolution) of these embryo–host relationships.
However, the survival advantage for the persisting
virus involved, is seldom considered. Viruses have
long been dismissed as simple selfish agents, not cen-
tral to evolution. And their persistence has been trea-
ted as a trivial matter. Here, I argue that the virus
perspective should instead be considered first. For
the virus–host relationship (e.g., persistence) sets the
stage for who will survive in the virosphere and what
may follow regarding virus–host selection. In sum-
mary, viruses are competent in all biological codes
and various forms of communication. And since
viruses can often function as diffuse populations,
they are capable ‘hackers’ of complex network sys-
tems not only able to reprogram a network but also
to provide novel solutions, often via mixed and
defective and counteracting viruses (via quasis-
pecies). In their capacity to promote persistence,
viruses also promote the infectious acquisition of
systems of identity and immunity. Because viruses
are transmissible, they affect the relationships (com-
munication) not just within individuals but also to
extended groups. This is the most powerful role.
Indeed, I have recently proposed that a quasispecies
consortia (Gangen) of transmissible stem-loop
RNA’s can better account for the origin of ribo-
zymes and the identity and communication networks
of RNA world organisms (97). See Fig. 1. From the
origin of life to the evolution of humans, viruses
seem to have been involved. Thus, the large scale
expansion ERV LTRs and other stem-loop RNA
elements (e.g., alu’s) in the recent evolution of the
human brain, might also indicate a viral role. So
powerful and ancient are viruses, that I would sum-
marize their role in life as ‘Ex Virus Omnia’ (from
virus everything).
REFERENCES
1. Loke YW. Life’s Vital Link: The Astonishing Role of
the Placenta. ?????: Oxford University Press, 2013:
276. 2
2. Churakov G, Kriegs JO, Baertsch R, Zemann A, Bro-
sius J, Schmitz J. Mosaic retroposon insertion pat-
terns in placental mammals. Genome Res
2009;19:868–75.
3. Seman G, Levy BM, Panigel M, Dmochowski L.
Type-C virus particles in placenta of the cottontop
marmoset (Saguinus oedipus). J Natl Cancer Inst
1975;54:251–2.
4. Larsson E, Nilsson BO, Sundstr€
om P, Wid"
ehn S.
Morphological and microbiological signs of endoge-
nous C-virus in human oocytes. Int J Cancer
1981;28:551–7.
5. Calarco PG. Intracisternal A particles in preimplanta-
tion embryos of feral mice (Mus musculus). Intervirol-
ogy 1979;11:321–5.
6. Maeda S, Yonezawa K, Yachi A. Serum antibody
reacting with placental syncytiotrophoblast in sera of
patients with autoimmune diseases–a possible relation
to type C RNA retrovirus. Clin Exp Immunol
1985;60:645–53.
7. Nelson JA, Levy JA, Leong JC. Human placentas
contain a specific inhibitor of RNA-directed DNA
polymerase. Proc Natl Acad Sci U S A 1981;78:1670–
4.
8©2015 APMIS. Published by John Wiley & Sons Ltd
VILLARREAL
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
8. Leong JC, Wood SO, Lyford AO, Levy JA. Purifica-
tion of a specific inhibitor of reverse transcriptase
from human placenta. Int J Cancer 1984;33:435–9.
9. Kato N, Pfeifer-Ohlsson S, Kato M, Larsson E, Ryd-
nert J, Ohlsson R, et al. Tissue-specific expression of
human provirus ERV3 mRNA in human placenta:
two of the three ERV3 mRNAs contain human cellu-
lar sequences. J Virol 1987;61:2182–91.
10. Larsson E, Venables P, Andersson AC, Fan W, Rigby
S, Botling J, et al. Tissue and differentiation specific
expression on the endogenous retrovirus ERV3
(HERV-R) in normal human tissues and during
induced monocytic differentiation in the U-937 cell
line. Leukemia 1997;11(Suppl 3):142–4.
11. Harris JR. Placental endogenous retrovirus (ERV):
structural, functional, and evolutionary significance.
BioEssays 1998;20:307–16.
12. Villarreal LP, Villareal LP. On viruses, sex, and moth-
erhood. J Virol 1997;71:859–65.
13. Lee A, Nolan A, Watson J, Tristem M. Identification
of an ancient endogenous retrovirus, predating the
divergence of the placental mammals. Philos Trans R
Soc Lond B Biol Sci 2013;368:20120503.
14. Murphy WJ, Pringle TH, Crider TA, Springer MS,
Miller W. Using genomic data to unravel the root of
the placental mammal phylogeny. Genome Res
2007;17:413–21.
15. Blond JL, Beseme F, Duret L, Bouton O, Bedin F,
Perron H, et al. Molecular characterization and pla-
cental expression of HERV-W, a new human endoge-
nous retrovirus family. J Virol 1999;73:1175–85.
16. Blond JL, Lavillette D, Cheynet V, Bouton O, Oriol
G, Chapel-Fernandes S, et al. An envelope glycopro-
tein of the human endogenous retrovirus HERV-W is
expressed in the human placenta and fuses cells
expressing the type D mammalian retrovirus receptor.
J Virol 2000;74:3321–9.
17. Dupressoir A, Lavialle C, Heidmann T. From ances-
tral infectious retroviruses to bona fide cellular genes:
role of the captured syncytins in placentation.
Placenta 2012;33:663–71.
18. Haig D. Retroviruses and the placenta. Curr Biol
2012;22:R609–13.
19. Villarreal LP. Viruses and the Evolution of Life [Inter-
net]. Washington, DC: ASM Press, 2005: xv, 395 p.
Available from: http://www.loc.gov/catdir/toc/
ecip0419/2004013977.html
20. Witzany G. Biocommunication and Natural Genome
Editing. New York: Springer, 2009.
21. Chuong EB, Rumi MAK, Soares MJ, Baker JC.
Endogenous retroviruses function as species-specific
enhancer elements in the placenta. Nat Genet [Inter-
net]. 2013 [cited 2013 Feb 13]; Available from: http://
www.nature.com/ng/journal/vaop/ncurrent/full/
ng.2553.html
22. Villarreal LP. Persistence pays: how viruses promote
host group survival. Curr Opin Microbiol
2009;12:467–72.
23. Villarreal LP, Defilippis VR, Gottlieb KA. Acute and
persistent viral life strategies and their relationship to
emerging diseases. Virology 2000;272:1–6.
24. Villarreal LP. Virus-host symbiosis mediated by per-
sistence. Symbiosis 2007;44:1–9.
25. Robinson HL, Astrin SM, Senior AM, Salazar FH.
Host Susceptibility to endogenous viruses: defective,
glycoprotein-expressing proviruses interfere with infec-
tions. J Virol 1981;40:745–51.
26. Black SG, Arnaud F, Palmarini M, Spencer TE.
Endogenous retroviruses in trophoblast differentiation
and placental development. Am J Reprod Immunol
????;64:255–64. 3
27. Gardner MB, Chiri A, Dougherty MF, Casagrande J,
Estes JD. Congenital transmission of murine leukemia
virus from wild mice prone to the development of
lymphoma and paralysis. J Natl Cancer Inst
1979;62:63–70.
28. Gardner MB, Rasheed S. Retroviruses in feral mice.
Int Rev Exp Pathol 1982;23:209–67.
29. Domingo E, Sheldon J, Perales C. Viral quasispecies
evolution. Microbiol Mol Biol Rev. 2012;76:???–???. 4
30. Villarreal LP, Witzany G. Rethnking quasispecies the-
ory: from fittest type to cooperative consportia. World
J Biol Chem 2013;23:71–82.
31. Witzany G. Natural genome-editing competences of
viruses. Acta Biotheor 2006;54:235–53.
32. Tarlinton RE. Koala retrovirus endogenisation in
action. In: Witzany G, editor. Viruses: Essential
Agents of Life [Internet]. The Netherlands: Springer,
2012[cited 2013 Feb 9]. p. 283–91. Available from:
http://link.springer.com/chapter/10.1007/978-94-007-
4899-6_14
33. Fiebig U, Keller M, M€
oller A, Timms P, Denner J.
Lack of antiviral antibody response in koalas infected
with koala retroviruses (KoRV). Virus Res
2015;16:30–4.
34. Ishida Y, Zhao K, Greenwood AD, Roca AL. Prolif-
eration of endogenous retroviruses in the early stages
of a host germ line invasion. Mol Biol Evol
2015;32:109–20.
35. Delorme-Axford E, Donker RB, Mouillet J-F, Chu T,
Bayer A, Ouyang Y, et al. Human placental tro-
phoblasts confer viral resistance to recipient cells. Proc
Natl Acad Sci U S A 2013;110:12048–53.
36. Cui J, Tachedjian M, Wang L, Tachedjian G, Wang
L-F, Zhang S. Discovery of retroviral homologs in
bats: implications for the origin of mammalian gam-
maretroviruses. J Virol 2012;86:4288–93.
37. Taylor DJ, Dittmar K, Ballinger MJ, Bruenn JA.
Evolutionary maintenance of filovirus-like genes in
bat genomes. BMC Evol Biol 2015;11:336.
38. Platt RN, Vandewege MW, Kern C, Schmidt CJ,
Hoffmann FG, Ray DA. Large numbers of novel
miRNAs originate from DNA transposons and are
coincident with a large species radiation in bats. Mol
Biol Evol 2014;???:msu112. 5
39. Schutt S, Florl AR, Shi W, Hemberger M, Orth A,
Otto S, et al. DNA methylation in placentas of inter-
species mouse hybrids. Genetics 2003;165:223–8.
40. Gustafsson E, Blomqvist G, Bellman A, Holmdahl R,
Mattsson A, Mattsson R. Maternal antibodies protect
immunoglobulin deficient neonatal mice from mouse
hepatitis virus (MHV)-associated wasting syndrome.
Am J Reprod Immunol 1996;36:33–9.
41. Rodriguez LL, Roo AD, Guimard Y, Trappier SG,
Sanchez A, Bressler D, et al. Persistence and genetic
stability of Ebola virus during the outbreak in Kikwit,
Democratic Republic of the Congo, 1995. J Infect Dis
1999;179(Suppl 1):S170–6.
42. Balachandra K, Chimabutra K, Supromajakr P, Wasi
C, Yamamoto T, Mukai T, et al. High rate of reacti-
©2015 APMIS. Published by John Wiley & Sons Ltd 9
VIRAL ORIGIN OF THE PLACENTA
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
vation of human herpesvirus 6 in children with dengue
hemorrhagic fever. J Infect Dis 1994;170:746–8.
43. Abel L, Plancoulaine S, Jouanguy E, Zhang S-Y,
Mahfoufi N, Nicolas N, et al. Age-dependent mende-
lian predisposition to herpes simplex virus type 1
encephalitis in childhood. J Pediatr 2010;157:623–9.
e1.
44. Gupta A, Gartner JJ, Sethupathy P, Hatzigeorgiou
AG, Fraser NW. Anti-apoptotic function of a micro-
RNA encoded by the HSV-1 latency-associated tran-
script. Nature 2006;442:82–5.
45. Feederle R, Haar J, Bernhardt K, Linnstaedt SD,
Bannert H, Lips H, et al. The members of an Epstein-
Barr virus microRNA cluster cooperate to transform
B lymphocytes. J Virol 2011;85:9801–10.
46. Cheema A, Katta J, Velez AP, Medveczky M, Med-
veczky PG, Quilitz R, et al. Encephalitis and inherited
HHV-6. Infect Dis Clin Pract 2012;20:419–21.
47. Tan DHS, Kaul R, Walsmley S. Left out but not for-
gotten: should closer attention be paid to coinfection
with herpes simplex virus type 1 and HIV? Can J
Infect Dis Med Microbiol 2009;20:e1–7.
48. Auvert B, Lissouba P, Cutler E, Zarca K, Puren A,
Taljaard D. Association of oncogenic and nononco-
genic human papillomavirus with HIV incidence. J
Acquir Immune Defic Syndr 1999 2010;53:111–6.
49. Kanak M, Alseiari M, Balasubramanian P, Addanki
K, Aggarwal M, Noorali S, et al. Triplex-forming
microRNAs form stable complexes with HIV-1 pro-
virus and inhibit its replication. Appl Immunohis-
tochem Mol Morphol 2010;18:532–45.
50. Jones RB, Garrison KE, Mujib S, Mihajlovic V,
Aidarus N, Hunter DV, et al. HERV-K–specific T
cells eliminate diverse HIV-1/2 and SIV primary iso-
lates. J Clin Invest [Internet]. 2012 Nov 12 [cited 2012
Nov 28]; Available from: http://www.jci.org/articles/
view/64560#sd
51. Seo GJ, Fink LHL, O’Hara B, Atwood WJ, Sullivan
CS. Evolutionarily conserved function of a viral
microRNA. J Virol 2008;82:9823–8.
52. Mattick JS, Taft RJ, Faulkner GJ. A global view of
genomic information–moving beyond the gene and the
master regulator. Trends Genet 2010;26:21–8.
53. Yeung ML, Benkirane M, Jeang KT. Small non-cod-
ing RNAs, mammalian cells, and viruses: regulatory
interactions? Retrovirology 2007;4:74.
54. Hakim ST, Alsayari M, McLean DC, Saleem S,
Addanki KC, Aggarwal M, et al. A large number of
the human microRNAs target lentiviruses, retro-
viruses, and endogenous retroviruses. Biochem Bio-
phys Res Commun 2008;369:357–62.
55. Gimenez J, Montgiraud C, Oriol G, Pichon J-P, Ruel
K, Tsatsaris V, et al. Comparative methylation of
ERVWE1/Syncytin-1 and other human endogenous
retrovirus LTRs in placenta tissues. DNA Res
2009;16:195–211.
56. Svoboda P, Flemr M. The role of miRNAs and
endogenous siRNAs in maternal-to-zygotic repro-
gramming and the establishment of pluripotency.
EMBO Rep 2010;11:590–7.
57. Kapusta A, Kronenberg Z, Lynch VJ, Zhuo X, Ram-
say L, Bourque G, et al. Transposable elements are
major contributors to the origin, diversification, and
regulation of vertebrate long noncoding RNAs. PLoS
Genet 2013;9:e1003470.
58. Matylla-Kulinska K, Tafer H, Weiss A, Schroeder R.
Functional repeat-derived RNAs often originate from
retrotransposon-propagated ncRNAs. Wiley Interdis-
cip Rev RNA 2014;5:591–600.
59. Sekita Y, Wagatsuma H, Nakamura K, Ono R, Kagami
M, Wakisaka N, et al. Role of retrotransposon-derived
imprinted gene, Rtl1, in the feto-maternal interface of
mouse placenta. Nat Genet 2008;40:243–8.
60. Liu JL, Yang ZM. Non-coding RNAs and embryo
implantation. Front Biosci Elite Ed ????;3:1092–9. 6
61. Mangeney M, Renard M, Schlecht-Louf G, Boual-
laga I, Heidmann O, Letzelter C, et al. Placental
syncytins: genetic disjunction between the fusogenic
and immunosuppressive activity of retroviral envel-
ope proteins. Proc Natl Acad Sci U S A
2007;104:20534–9.
62. P"
erot P, Bolze P-A, Mallet F. From viruses to genes:
syncytins. In: Witzany G, editor. Viruses: Essential
Agents of Life[Internet]. Netherlands: Springer, 2012
[cited 2012 Dec 18]. p. 325–61. Available from: http://
link.springer.com/chapter/10.1007/978-94-007-4899-
6_17
63. Emera D, Wagner GP. Transposable element recruit-
ments in the mammalian placenta: impacts and mech-
anisms. Brief Funct Genomics 2012;11:267–76.
64. Pavlicev M, Hiratsuka K, Swaggart KA, Dunn C,
Muglia L. Detecting endogenous retrovirus-driven tis-
sue-specific gene transcription. Genome Biol Evol
2015;7:1082–97.
65. Bi#
eche I, Laurent A, Laurendeau I, Duret L, Giovan-
grandi Y, Frendo J-L, et al. Placenta-specific INSL4
expression is mediated by a human endogenous retro-
virus element. Biol Reprod 2003;68:1422–9.
66. Goodchild NL, Wilkinson DA, Mager DL. A human
endogenous long terminal repeat provides a
polyadenylation signal to a novel, alternatively
spliced transcript in normal placenta. Gene 1992;121:
287–94.
67. Huh JW, Ha HS, Kim DS, Kim HS. Placenta-
Restricted Expression of LTR-Derived NOS3. Placenta
[Internet]. 2008; Available from: http://www.ncbi.nlm.
nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed
&dopt=Citation&list_uids=18474398
68. Patterson BK, Behbahani H, Kabat WJ, Sullivan Y,
O’Gorman MR, Landay A, et al. Leukemia inhibitory
factor inhibits HIV-1 replication and is upregulated in
placentae from nontransmitting women. J Clin Invest
2001;107:287–94.
69. Reiss D, Zhang Y, Mager DL. Widely variable
endogenous retroviral methylation levels in human
placenta. Nucleic Acids Res 2007;35:4743–54.
70. Elliot MG, Crespi BJ. Genetic recapitulation of human
pre-eclampsia risk during convergent evolution of
reduced placental invasiveness in eutherian mammals.
Philos Trans R Soc B Biol Sci 2015;370:20140069.
71. Ikeda H, Sato H, Odaka T. Mapping of the Fv-4
mouse gene controlling resistance to murine leukemia
viruses. Int J Cancer 1981;28:237–40.
72. GoffSP. Retrovirus restriction factors. Mol Cell
2004;16:849–59.
73. Malfavon-Borja R, Feschotte C. Fighting fire with
fire: endogenous retrovirus envelopes as restriction
factors. J Virol 2015;89:4047–50.
74. Arnaud F, Caporale M, Varela M, Biek R, Chessa B,
Alberti A, et al. A paradigm for virus-host coevolution:
10 ©2015 APMIS. Published by John Wiley & Sons Ltd
VILLARREAL
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
sequential counter-adaptations between endogenous
and exogenous retroviruses. PLoS Pathog 2007;3:
1716–29.
75. Esnault C, Cornelis G, Heidmann O, Heidmann T.
Differential evolutionary fate of an ancestral primate
endogenous retrovirus envelope gene, the EnvV Syn-
cytin, captured for a function in placentation. PLoS
Genet 2013;9:e1003400.
76. Pelisson A, Sarot E, Payen-Groschene G, Bucheton
A. A novel repeat-associated small interfering RNA-
mediated silencing pathway downregulates comple-
mentary sense gypsy transcripts in somatic cells of the
Drosophila ovary. J Virol 2007;81:1951–60.
77. Cornelis G, Vernochet C, Carradec Q, Souquere S,
Mulot B, Catzeflis F, et al. Retroviral envelope gene
captures and syncytin exaptation for placentation in
marsupials. Proc Natl Acad Sci U S A 2015;112:
E487–96.
78. K€
ammerer U, Germeyer A, Stengel S, Kapp M, Den-
ner J. Human endogenous retrovirus K (HERV-K) is
expressed in villous and extravillous cytotrophoblast
cells of the human placenta. J Reprod Immunol
2011;91:1–8.
79. Contreras-Galindo R, Kaplan MH, He S, Contreras-
Galindo AC, Gonzalez-Hernandez MJ, Kappes F,
et al. HIV infection reveals wide-spread expansion of
novel centromeric human endogenous retroviruses.
Genome Res [Internet]. 2013 May 8 [cited 2013 May
16]; Available from: http://genome.cshlp.org/content/
early/2013/05/08/gr.144303.112
80. Bergallo M, Galliano I, Montanari P, Gambarino S,
Mareschi K, Ferro F, et al. CMV induces HERV-K
and HERV-W expression in kidney transplant recipi-
ents. J Clin Virol 2015;68:28–31.
81. Sutkowski N, Conrad B, Thorley-Lawson DA, Huber
BT. Epstein-Barr virus transactivates the human
endogenous retrovirus HERV-K18 that encodes a
superantigen. Immunity 2001;15:579–89.
82. Grow EJ, Flynn RA, Chavez SL, Bayless NL,
Wossidlo M, Wesche DJ, et al. Intrinsic retroviral
reactivation in human preimplantation embryos and
pluripotent cells. Nature [Internet]. 2015 Apr 20 [cited
2015 May 18];advance online publication. Available
from: http://www.nature.com/nature/journal/vaop/
ncurrent/full/nature14308.html
83. Bezier A, Annaheim M, Herbiniere J, Wetterwald C,
Gyapay G, Bernard-Samain S, et al. Polydnaviruses
of braconid wasps derive from an ancestral nudivirus.
Science 2009;323:926–30.
84. Gundersen-Rindal DE, Pedroni MJ. Larval stage
Lymantria dispar microRNAs differentially expressed
in response to parasitization by Glyptapanteles flavi-
coxis parasitoid. Arch Virol ????;155:783–7.
7
85. Weisbecker V, Goswami A. Brain size, life history,
and metabolism at the marsupial/placental dichotomy.
Proc Natl Acad Sci U S A 2010;107:16216–21.
86. Keverne EB. Importance of the matriline for geno-
mic imprinting, brain development and behaviour.
Philos Trans R Soc B Biol Sci [Internet]. 2013 Jan 5
[cited 2015 May 14];368(1609). Available from:
http://www.ncbi.nlm.nih.gov/pmc/articles/
PMC3539356/
87. Vargas A, Zhou S,
"
Ethier-Chiasson M, Flipo D,
Lafond J, Gilbert C, et al. Syncytin proteins incorpo-
rated in placenta exosomes are important for cell
uptake and show variation in abundance in serum
exosomes from patients with preeclampsia. FASEB J
2014;28:3703–19.
88. Tolosa JM, Schjenken JE, Clifton VL, Vargas A,
Barbeau B, Lowry P, et al. The endogenous retro-
viral envelope protein syncytin-1 inhibits LPS/
PHA-stimulated cytokine responses in human blood
and is sorted into placental exosomes. Placenta
2012;33:933–41.
89. Ouyang Y, Mouillet J-F, Coyne CB, Sadovsky Y.
Review: Placenta-specific microRNAs in exosomes –
good things come in nano-packages. Placenta [Inter-
net]. [cited 2014 Jan 24]; Available from: http://www.
sciencedirect.com/science/article/pii/
S0143400413007959
90. Svoboda P, Stein P, Anger M, Bernstein E, Hannon
GJ, Schultz RM. RNAi and expression of retrotrans-
posons MuERV-L and IAP in preimplantation mouse
embryos. Dev Biol 2004;269:276–85.
91. Miura K, Miura S, Yamasaki K, Higashijima A,
Kinoshita A, Yoshiura K, et al. Identification of preg-
nancy-associated MicroRNAs in maternal plasma.
Clin Chem 2010;56:1767–71.
92. Chim SSC, Shing TKF, Hung ECW, Leung T, Lau T,
Chiu RWK, et al. Detection and characterization of
placental microRNAs in maternal plasma. Clin Chem
2008;54:482–90.
93. Luo S-S, Ishibashi O, Ishikawa G, Ishikawa T,
Katayama A, Mishima T, et al. Human villous tro-
phoblasts express and secrete placenta-specific micro-
RNAs into maternal circulation via exosomes. Biol
Reprod 2009;81:717–29.
94. Mui~
nos-Gimeno M, Espinosa-Parrilla Y, Guidi M,
Kagerbauer B, Sipil€
a T, Maron E, et al. Human
microRNAs miR-22, miR-138-2, miR-148a, and miR-
488 are associated with panic disorder and regulate
several anxiety candidate genes and related pathways.
Biol Psychiatry 2011;69:526–33.
95. Noguer-Dance M, Abu-Amero S, Al-Khtib M,
Lef#
evre A, Coullin P, Moore GE, et al. The primate-
specific microRNA gene cluster (C19MC) is imprinted
in the placenta. Hum Mol Genet 2010;19:3566–82.
96. Morales Prieto DM. Markert UR. MicroRNAs in
pregnancy. J Reprod Immunol 2011;88:106–11.
97. Villarreal LP. Force for ancient and recent life: viral
and stem-loop RNA consortia promote life. Ann N Y
Acad Sci 2015;1341:25–34.
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