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Abstract

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.
Review Article
Viruses and the placenta: the essential virus first view
LUIS P. VILLARREAL
1
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 virushost persistence is a key determinant of host survival
and the various ERVs involved have directly aected virushost 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 dierentiate 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 dicult 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 virushost 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 (1518).
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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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 oers 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 virushost 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 diuse, 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 aect virushost 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 virushost symbiosis that now protects the
host form the same and often other lytic (disease
causing) viruses. Persistence is dicult 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 virushost 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
eects 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 predatorprey
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 ospring (young) or in close coor-
dination to host reproductive biology. Establishing
persistence is dicult 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 virushost 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
dicult 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 e-
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
dicult problems needed for vivipary to emerge
(12). In addition, the new virushost 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 virushost 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 eective 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
aected 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 aects 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 aected by the epi-
demic. Populations isolated in some islands have
much less disease and no endogenization. However,
it would not be dicult 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 aect 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, RNARNA
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
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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 hostvirus (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 dierentiate),
(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-, diuse-, 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 dierent 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 dier-
ential ospring 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
aected (68).
PLACENTAL VARIATION AND
CORRESPONDING ERVS
Biologically, the placenta varies greatly between
species (69), especially its invasiveness (70). The
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selective pressure and molecular basis for such vari-
ation has always been curious and dicult 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
virushost 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 virushost
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 aect.
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 oof 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 diuse (Koala-like) network-like
mechanisms. The resulting virushost 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 dierential 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 motherospring 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): 2534.
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
ospring is often considered in the context of
motherospring 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 embryohost 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 virushost relationship (e.g., persistence) sets the
stage for who will survive in the virosphere and what
may follow regarding virushost selection. In sum-
mary, viruses are competent in all biological codes
and various forms of communication. And since
viruses can often function as diuse 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 aect 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).
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©2015 APMIS. Published by John Wiley & Sons Ltd 11
VIRAL ORIGIN OF THE PLACENTA
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... Seemingly, our species has counted with around 4 million mobile insertion events [10]. Ancestral viral proteins can be found in human placental adhesion and development [84,85], in splicing machinery and in nuclear pores [11,66], in master gene regulators [86], and all across the mammalian and human proteomes [87]. ...
... Would eukaryotes constitute the more virus 'friendly' or labile line capable of fully integrating the viral codemaking resources into the later complexity explosion? Ex virus omnia, according to [84]. ...
Article
Full-text available
Countless informational proposals and models have explored the singular characteristics of biological systems: from the initial choice of information terms in the early days of molecular biology to the current bioinformatic avalanche in this “omic” era. However, this was conducted, most often, within partial, specialized scopes or just metaphorically. In this paper, we attempt a consistent informational discourse, initially based on the molecular recognition paradigm, which addresses the main stages of biological organization in a new way. It considers the interconnection between signaling systems and information flows, between informational architectures and biomolecular codes, between controlled cell cycles and multicellular complexity. It also addresses, in a new way, a central issue: how new evolutionary paths are opened by the cumulated action of multiple variation engines or mutational ‘vehicles’ evolved for the genomic exploration of DNA sequence space. Rather than discussing the possible replacement, extension, or maintenance of traditional neo-Darwinian tenets, a genuine informational approach to evolutionary phenomena is advocated, in which systemic variation in the informational architectures may induce differential survival (self-construction, self-maintenance, and reproduction) of biological agents within their open ended environment.
... A certa altura, o antecessor dos atuais mamíferos foi infetado por um retrovírus que conseguiu, eventualmente, alterar a estrutura da membrana interior do ovo, transformando-a numa placenta. De facto, sem essa infeção ancestral, não poderíamos ter usufruído do desenvolvimento intrauterino (Villarreal, 2016). ...
Article
Full-text available
A história do progresso do conhecimento científico dos vírus demonstra que a tendência dos investigadores para se prenderem a paradigmas e teorias específicas sobre as causas das doenças, não os deixa ver as ameaças de patógenos conhecidos e desconhecidos (Honigsbaum, 2021). É o caso, por exemplo, da “teoria dos germes” da doença, apresentada pelo bacteriologista alemão Robert Koch e o seu colega francês Louis Pasteur, na década de 1880. O paradigma bacteriológico da gripe humana, ao ser defendido por Richard Pfeiffer em 1892, atrasou durante décadas a compreensão da sua etiologia viral. Infelizmente, raro era o homem de ciência que ousava desafiar a autoridade de Koch e dos seus discípulos. Neste artigo pretendemos contribuir para a elaboração de uma imagem científica dos vírus, confrontando-a, sempre que necessário, com a ontologia da vida quotidiana. Para Dennett (2021), a imagem científica é algo que se tem de aprender na escola, e a maioria das pessoas adquire um conhecimento superficial da mesma. Não obstante, na nossa relação com os vírus, temos que aprender quais as “coisas” a retirar da nossa ontologia da vida quotidiana e quais as novas categorias a introduzir para criar uma ontologia da imagem científica dos vírus, fundamentando a nossa compreensão destas entidades singulares que desafiam os paradigmas científicos. É neste contexto que a abordagem do processo de produção do conhecimento científico tem sido apontada como de fundamental importância para compreender a Ciência, e a Virologia, como atividade humana historicamente contextualizada.
... For example, some viruses can cause massive mortality in eukaryote populations, e.g., algae infecting viruses (Brussaard, 2004). Others have been key to the evolution of the placenta in all mammalian lineages, e.g., endogenized retroviruses (Villarreal, 2016). Clearly, understanding the viruses that infect us can greatly enhance our insight into human (evolutionary) history. ...
Chapter
Full-text available
Over the last two decades, the viromes of our closest relatives, the African great apes (AGA), have been intensively studied. Comparative approaches have unveiled diverse evolutionary patterns, highlighting both stable host-virus associations over extended evolutionary timescales and much more recent viral emergence events. In this chapter, we summarize these findings and outline how they have shed a new light on the origins and evolution of many human-infecting viruses. We also show how this knowledge can be used to better understand the evolution of human health in relation to viral infections.
... All types of eukaryotic viruses can be integrated into a recipient heritable genome [76]. The domestication of their endogenized sequences has stimulated new genes [77]. Some viruses are resisted, but others are recruited for physiological development, such as for the formation of the numerous syncytiotrophoblastic tissues and the placenta [78]. ...
Article
Full-text available
Neo-Darwinism presumes that biological variation is a product of random genetic replication errors and natural selection. Cognition-Based Evolution (CBE) asserts a comprehensive alternative approach to phenotypic variation and the generation of biological novelty. In CBE, evolutionary variation is the product of natural cellular engineering that permits purposive genetic adjustments as cellular problem-solving. CBE upholds that the cornerstone of biology is the intelligent measuring cell. Since all biological information that is available to cells is ambiguous, multicellularity arises from the cellular requirement to maximize the validity of available environmental information. This is best accomplished through collective measurement purposed towards maintaining and optimizing individual cellular states of homeorhesis as dynamic flux that sustains cellular equipoise. The collective action of the multicellular measurement and assessment of information and its collaborative communication is natural cellular engineering. Its yield is linked cellular ecologies and mutualized niche constructions that comprise biofilms and holobionts. In this context, biological variation is the product of collective differential assessment of ambiguous environmental cues by networking intelligent cells. Such concerted action is enabled by non-random natural genomic editing in response to epigenetic impacts and environmental stresses. Random genetic activity can be either constrained or deployed as a ‘harnessing of stochasticity’. Therefore, genes are cellular tools. Selection filters cellular solutions to environmental stresses to assure continuous cellular-organismal-environmental complementarity. Since all multicellular eukaryotes are holobionts as vast assemblages of participants of each of the three cellular domains (Prokaryota, Archaea, Eukaryota) and the virome, multicellular variation is necessarily a product of co-engineering among them.
... Current knowledge about the evolutionary origin of placenta organ in mammals clearly indicates natural genome editing by persistent retroviruses [100]. Another intrugiung example is human brain evolution. ...
Article
Full-text available
The emergence of cooperative quasi-species consortia (QS-C) thinking from the more accepted quasispecies equations of Manfred Eigen, provides a conceptual foundation from which concerted action of RNA agents can now be understood. As group membership becomes a basic criteria for the emergence of living systems, we also start to understand why the history and context of social RNA networks become crucial for survival and function. History and context of social RNA networks also lead to the emergence of a natural genetic code. Indeed, this QS-C thinking can also provide us with a transition point between the chemical world of RNA replicators and the living world of RNA agents that actively differentiate self from non-self and generate group identity with membership roles. Importantly the social force of a consortia to solve complex, multilevel problems also depend on using opposing and minority functions. The consortial action of social networks of RNA stem-loops subsequently lead to the evolution of cellular organisms representing a tree of life.
... Also the evolution of the leading proponent of this process, the eukaryotic nucleus must seemingly have descended from a large double-stranded DNA virus which was able to build membrane structures and coordinate genetic integration of the various participants of the eukaryotic cell (Takemura 2020). Also the placenta organ of mammals is not the result of a series of mutation processes, but dates back to a massive persistent viral infection of egg laying mammals, as it transferred retroviral syncytin genes that could protect the foreign embryo from the immune system of the mother by forming a certain layer of fused cells (trophectoderm) until the immune system of the growing embryo is strong enough to protect itself (Villarreal 2016). Also, the synaptic arc protein, which is a crucial player in storing neuronal based memory, stems from persistent retroviral infection (Pastuzyn et al. 2018). ...
Article
Full-text available
Denis Nobel looks at four important misinterpretations of molecular biology concerning evolutionary processes and demonstrates that the new synthesis today looks rather outdated. The modern synthesis is nearly 80 years old. The proponents who worked out the modern synthesis had no access to the current knowledge on cell biology, genetics, epigenetics, RNA biology and virology. Therefore this contribution adds several aspects which Nobel’s article does not explicitly mention, providing some examples for a better understanding of evolutionary novelty.
Chapter
This chapter begins with an introduction which defines and briefly explains what a virus is, what viral ecology is, and the reasons for studying viral ecology. The interactions between a virus and its host are then described along with an understanding of the ecological niches which viruses have evolved to occupy. Some viruses have an endogenous or lysogenous relationship with their host, and those relationships can result in the virus forging such a strong genomic presence within the cells of its host that the virus never needs to move from one host individual to another. Most viruses do, however, seem to require transferrence between hosting individuals. The chapter explains that routes of viral transferrence can be grouped into three categories and the approach which a virus family uses will represent a choice that has been developed through evolution. Those three routes are direct contact between hosting individuals, transmission that depends upon vectors which by definition are living carriers or transporters, and transmission which relies upon vehicles which by definition are inanimate carriers or transporters. The chapter also includes information that can help readers to understand why some viruses tend to be fatal to their hosts, while other viruses tend to be more benign, and how those genetic tendencies result in equilibria between the populations of viruses and their hosts.
Chapter
This chapter provides summaries of information regarding 33 viral families that are associated with human infections. This chapter also provides information on the prions associated with human populations. Being successful as a virus requires attainment of two goals. The first goal is reproduction within a host and the second goal is transmission between hosts. Viral reproduction requires achievements in three strategic areas. First among these areas is developing a successful course of infection. Many viruses use a productive course of infection, which means that the infection results in generation of progeny viruses. There are other viruses whose success has come from choosing a nonproductive strategy. Endogenous viruses, for which the course of infection yields either few or absolutely no progeny viral particles, represent a nonproductive approach to success. The second strategic area requires accomplishing tasks that relate to viral reproductive decisions made at the cellular metabolic level, at tissue and organ levels, and at the host population level. The third strategic area is evasion of the hosts’ defensive mechanisms. Some viruses have evolved to achieve transmission during direct contact between hosts. Other viruses need to rely upon successfully being transported to their next host. The two options for achieving transportation between hosts are either for the virus to be carried by a living being, which is termed a vector, or for the virus to be carried by a vehicle, which is by definition non-living. Vehicular transportation options include carriage by the movement of air, liquids, or solid materials.
Chapter
Viruses are the most understudied microbial agents on our planet; their polyphyletic origin is still shrouded in mysteries. At least some RNA viruses appear to have evolved from self-replicating molecules in the so-called RNA-world that researchers believe to have existed before DNA evolved billions of years ago. Many theories of viral origin and evolution are debated and, even though the fossil record of viruses is basically non-existent in the traditional sense, modern phylogenetic sequencing and electron microscopy have revealed astonishing secrets of viral diversity regarding genome, shape, and size and elucidated many sophisticated mechanisms behind their ability to thrive and replicate as obligate parasites, enslaving their host’s replication machinery for their own purposes. Furthermore, evidence exists that many proviruses have evolved with their host, some being part of the so-called junk DNA that we find in prokaryotes and eukaryotes alike, whereas others shaped the evolution of multicellular species becoming even necessary for the survival of the host. With the detection of giant viruses with large genomes including genes coding for replication, one might consider a fourth domain of life for these agents. Ignored and despised, these representatives of the microbial world have been significantly involved in shaping the evolution and ecology of all living species on Earth, in the past, currently, and will continue so in the future. Therefore, viruses, as well as viroids, deserve to be considered as being part of the foundation stone of Earth’s biosphere.
Conference Paper
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In the last several years, numerous reports have suggested that viruses of various types might have contributed to the evolution of important and basic host characteristics. This would represent a symbiotic viral involvement in host evolution. Here, I outline many of these suggestions. However, in order for viruses to succeed as symbionts, they must attain a stable or persisting relationship with their host. This review focuses on the relationship between persisting viruses and their host. In particular, mechanisms of persistence that involve addiction (toxin/antitoxin) strategies are presented with respect to viral defense. The potential role of persisting viruses in cyanobacterial and prokaryotic evolution is also presented. Popular models of symbiosis are then evaluated from the perspective of potential viral involvement. Human evolution in relationship to endogenous retroviruses is also mentioned, but this topic presented more thoroughly in a companion manuscript (F. Ryan). Finally, an example is presented using symbiotic dinoflagellates in which evaluating the possible role of persisting viruses is suggested.
Article
Full-text available
In the last several years, numerous reports have suggested that viruses of various types might have contributed to the evolution of important and basic host characteristics. This would represent a symbiotic viral involvement in host evolution. Here, I outline many of these suggestions. However, in order for viruses to succeed as symbionts, they must attain a stable or persisting relationship with their host. This review focuses on the relationship between persisting viruses and their host. In particular, mechanisms of persistence that involve addiction (toxin/antitoxin) strategies are presented with respect to viral defense. The potential role of persisting viruses in cyanobacterial and prokaryotic evolution is also presented. Popular models of symbiosis are then evaluated from the perspective of potential viral involvement. Human evolution in relationship to endogenous retroviruses is also mentioned, but this topic presented more thoroughly in a companion manuscript (F. Ryan). Finally, an example is presented using symbiotic dinoflagellates in which evaluating the possible role of persisting viruses is suggested.
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Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections, and comprise nearly 8% of the human genome. The most recently acquired human ERV is HERVK(HML-2), which repeatedly infected the primate lineage both before and after the divergence of the human and chimpanzee common ancestor. Unlike most other human ERVs, HERVK retained multiple copies of intact open reading frames encoding retroviral proteins. However, HERVK is transcriptionally silenced by the host, with the exception of in certain pathological contexts such as germ-cell tumours, melanoma or human immunodeficiency virus (HIV) infection. Here we demonstrate that DNA hypomethylation at long terminal repeat elements representing the most recent genomic integrations, together with transactivation by OCT4 (also known as POU5F1), synergistically facilitate HERVK expression. Consequently, HERVK is transcribed during normal human embryogenesis, beginning with embryonic genome activation at the eight-cell stage, continuing through the emergence of epiblast cells in preimplantation blastocysts, and ceasing during human embryonic stem cell derivation from blastocyst outgrowths. Remarkably, we detected HERVK viral-like particles and Gag proteins in human blastocysts, indicating that early human development proceeds in the presence of retroviral products. We further show that overexpression of one such product, the HERVK accessory protein Rec, in a pluripotent cell line is sufficient to increase IFITM1 levels on the cell surface and inhibit viral infection, suggesting at least one mechanism through which HERVK can induce viral restriction pathways in early embryonic cells. Moreover, Rec directly binds a subset of cellular RNAs and modulates their ribosome occupancy, indicating that complex interactions between retroviral proteins and host factors can fine-tune pathways of early human development.
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Transposable elements (TEs) comprise approximately half of the human genome, and several independent lines of investigation have demonstrated their role in rewiring gene expression during development, evolution, and oncogenesis. The identification of their regulatory effects has largely been idiosyncratic, by linking activity with isolated genes. Their distribution throughout the genome raises critical questions - do these elements contribute to broad tissue-and lineage-specific regulation? If so, in what manner, as enhancers, promoters, RNAs? Here, we devise a novel approach to systematically dissect the genome-wide consequences of TE insertion on gene expression, and test the hypothesis that classes of endogenous retrovirus long terminal repeats (LTRs) exert tissue-specific regulation of adjacent genes. Using correlation of expression patterns across 18 tissue types, we reveal the tissue-specific uncoupling of gene expression due to 62 different LTR classes. These patterns are specific to the retroviral insertion, as the same genes in species without the LTRs do not exhibit the same effect. While the LTRs can be transcribed themselves, the most highly transcribed TEs do not have the largest effects on adjacent regulation of coding genes, suggesting they function predominantly as enhancers. Moreover, the tissue-specific patterns of gene expression that are detected by our method arise from a limited number of genes, rather than as a general consequence of LTR integration. These findings identify basic principles of co-opting LTRs for genome evolution, and support the utility of our method for the analysis of TE, or other specific gene sets, in relation to the rest of the genome. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
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Invasive pulmonary aspergillosis (IPA) is rare in patients without underlying immune defects, such as prolonged neutropenia. There have been few reports of IPA complicating influenza infection during the last 60 years. We present 2 more cases of IPA after influenza and review the previous English-language reports of this entity. The cases presented here represent the third and fourth reported cases of IPA associated with 2009 H1N1 influenza infection. This may represent an increased propensity of 2009 H1N1 to facilitate IPA when compared with other strains of influenza.
Chapter
Koala retrovirus (KoRV) is a unique example of a retroviral group ­currently undergoing the process of endogenisation. While endogenous retroviruses (ERVs) are ubiquitous elements in vertebrate genomes there is currently little understanding of the process by which they enter, modify and are modified by the organisms whose genomes they colonise. KoRV displays elements of both an endogenous and an infectious exogenous virus. It is variably present in different koala populations and has probably arisen from a recent host species jump from rodents. This review outlines the initial discovery of KoRV, it’s cross species infection potential and the exciting opportunities this virus provides to elucidate missing information on this fundamental process in mammalian evolution
Article
A considerable portion of vertebrate genomes are made up of endogenous retroviruses (ERVs). While aberrant or uncontrolled ERV expression has been perceived as a potential cause of disease, there is mounting evidence that some ERVs have become integral components of normal host development and physiology. Here we revisit the longstanding concept that some of the gene products encoded by ERVs and other endogenous viral elements may offer to the host protection against viral infection. Notably proteins produced from envelope (env) genes have been shown to act as restriction factors against related exogenous retroviruses in chicken, sheep, mice, and cats. Based on the proposed mode of restriction and the domain architecture of known antiretroviral env, we argue that many more env-derived restriction factors await discovery in vertebrate genomes, including the human genome. Copyright © 2015, American Society for Microbiology. All Rights Reserved.