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Viruses and the placenta: the essential virus first view

February 2016
Apmis 124(1-2):20-30

Authors:

University of California, Irvine

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.

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Review Article

Viruses and the placenta: the essential virus ﬁrst view

LUIS P. VILLARREAL

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

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.

VILLARREAL

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

VIRAL ORIGIN OF THE PLACENTA

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)

VILLARREAL

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

VIRAL ORIGIN OF THE PLACENTA

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

VILLARREAL

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

VIRAL ORIGIN OF THE PLACENTA

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).

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VIRAL ORIGIN OF THE PLACENTA

From Molecular Recognition to the “Vehicles” of Evolutionary Complexity: An Informational Approach

Article

Full-text available

Nov 2021
INT J MOL SCI

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.

Os Vírus são "singulares" e desafiam os paradigmas da Ciência

Article

Full-text available

Feb 2022

Luis Calafate

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.

A great ape perspective on the origins and evolution of human viruses

Chapter

Full-text available

Jan 2021
ADV VIRUS RES

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.

Non-Random Genome Editing and Natural Cellular Engineering in Cognition-Based Evolution

Article

Full-text available

May 2021

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.

Social Networking of Quasi-Species Consortia drive Virolution via Persistence

Article

Full-text available

Apr 2021

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.

To the End of Dogmatism in Molecular Biology

Article

Full-text available

Apr 2021

Guenther Witzany

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.

Do the Biological Roles of Endogenous and Lysogenous Viruses Represent Faustian Bargains?

Chapter

Jan 2022

Christon Hurst

DEFINING THE ECOLOGY OF VIRUSES

Chapter

Jul 2021

Christon Hurst

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.

THE RELATIONSHIP BETWEEN HUMANS, THEIR VIRUSES AND PRIONS

Chapter

Jul 2021

Christon Hurst

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.

Viruses, Underestimated Drivers of Ecology and Evolution of Life

Chapter

May 2021

Antje Lauer

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.

Viruses and the Evolution of Life

Book

Full-text available

Jan 2005

Luis Villarreal

Virus-host symbiosis mediated by persistence

Conference Paper

Full-text available

Jan 2007
SYMBIOSIS

Luis Villarreal

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.

Review article: Virus-host symbiosis mediated by persistence

Article

Full-text available

Jan 2007
SYMBIOSIS

Luis Villarreal

Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells

Article

Full-text available

Apr 2015
NATURE

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.

Detecting Endogenous Retrovirus-Driven Tissue-Specific Gene Transcription

Article

Full-text available

Mar 2015

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.

Encephalitis and Inherited HHV-6

Article

Full-text available

Nov 2012
Infect Dis Clin Pract

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.

Biocommunication and natural genome editing

Article

Jan 2010

Guenther Witzany

Viruses: Essential Agents of Life

Chapter

Sep 2012

Rachael Tarlinton

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

CMV induces HERV-K and HERV-W expression in kidney transplant recipients

Article

Apr 2015
J CLIN VIROL

Fighting Fire with Fire: Endogenous Retrovirus Envelopes as Restriction Factors

Article

Feb 2015

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.