How did XMRV enter the human population?

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http://www.frontiersin.org/virology/10.3389/fmicb.2010.00147/abstract




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Of mice and men:
on the origin of XMRV


Antoinette Cornelia Van der kuyl,
Marion Cornelissen and Ben Berkhout


Journal Name: Frontiers in Microbiology
ISSN: 1664-302X
Article type: Perspective Article
Received on: 20 Sep 2010
Accepted on: 26 Dec 2010
Provisional PDF published on: 26 Dec 2010


Frontiers website link: www.frontiersin.org

Citation: Van der kuyl AC, Cornelissen M and Berkhout B
(2010) Of mice and men: on the origin of XMRV. Front.
Microbio. 1:147. - doi:10.3389/fmicb.2010.00147

http://www.frontiersin.org/virology/10.3389/fmicb.2010.00147/abstract

s=1161&name=virology&ART_DOI=10.3389/fmicb.2010.00147

(If clicking on the link doesn't work, try copying and pasting it
into your browser.)




Perspective


Of mice and men:
on the origin of XMRV



Running title:

How did XMRV enter the
human population?


Antoinette C. van der Kuyl, Marion Cornelissen
and Ben Berkhout


Laboratory of Experimental Virology, Department of Medical
Microbiology, Center for Infection
and Immunity Amsterdam (CINIMA), Academic Medical Center,
University of Amsterdam,
Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands






Abstract


The novel human retrovirus XMRV (xenotropic murine leukemia
virus-related virus) is arguably the most controversial virus of
this moment.

After its original discovery in prostate cancer tissue from North
American patients, it was subsequently detected in individuals
with chronic fatigue syndrome (CFS) from the same continent.

However, most other research groups, mainly from Europe,
reported negative results.

The positive results could possibly be attributed to
contamination with mouse products in a number of cases, as
XMRV is nearly identical in nucleotide sequence to endogenous
retroviruses in the mouse genome.

But the detection of integrated XMRV proviruses in prostate
cancer tissue proves it to be a genuine virus that replicates in
human cells, leaving the question: how did XMRV enter the
human population?

We will discuss two possible routes: either via direct virus
transmission from mouse to human, as repeatedly seen for
e.g. hantaviruses, or via the use of mouse-related products by
humans, including vaccines.
We hypothesize that mouse cells or human cell lines used for
vaccine production could have been contaminated with a
replicating variant of the XMRV precursors encoded by the
mouse genome.





Introduction


The xenotropic murine leukemia virus-related virus (XMRV) is
undoubtedly the most controversial human virus since its first
detection in human samples in 2006 [1].

XMRV infection still lacks a firm disease association, although
the virus was originally isolated from prostate cancer tissue
and subsequently detected in the blood of American patients
with chronic fatigue syndrome (CFS) [2], and in the respiratory
tract of patients with or without a respiratory tract infection
[3].

However, irregular XMRV detection [2-7] suggests that it is not
likely to be a major causal factor. First, we do not know
whether the biological reservoir has been investigated thus
far, as most studies focused exclusively on blood or prostate
tissue (summarized in Table 1).

Second, some pathogenic retroviruses do not cause much of a
viraemia, and experimental infection of macaques suggests
that this is also the case for XMRV [8].

In these monkeys, virus inoculation resulted in a low transient
plasma viraemia, followed by a wide dissemination of
replicating virus into various organs including spleen, lymph
nodes and gastrointestinal tract.

Third, sequence variation may exist, but such variant virus
strains could be missed by the PCR primers used.



Whether or not the virus causes disease in humans (reviewed
extensively by Silverman et al. [9], see also comments by
Coffin and Stoye [10], by Kearney and Maldarelli [11], by
Kaiser [12], and the cautionary note by Weiss [13]), and how
and when XMRV entered the human population - as the first
gammaretrovirus to do so - remains unclear.

To add to the ongoing discussion, we would like to propose an
alternative possible source for XMRV, human vaccines or other
biological products that were produced in murine cells.



How did XMRV enter the human population? One of the most
striking aspects of XMRV biology is the high sequence
similarity to mouse chromosal sequences that encode
endogenous retroviruses.

Initially, this raised the speculation that contamination with
mouse DNA could explain the presence of XMRV in human
samples.

However, the absence of other mouse-derived sequences,
combined with the ease of infection of human cells with XMRV
in vitro [14], and the detection of integrated proviruses in
prostate cancer tissues [15,16] indicated that laboratory
contamination with mouse products is not a likely explanation
for the origin of XMRV, at least for some of these studies.

If contamination does not provide an explanation, where does
the virus come from and how did it end up in humans?



Direct transmission of viruses from wild rodents to humans is
not uncommon, e.g. rodent hantaviruses and arenaviruses
spread through excrement via aerosols and are able to infect
nonrodent species, including humans [17-19].

Transmission of xenotropic murine leukemia viruses (XMLV’s)
to humans is possible as human cells do express the XPR1
protein that is able to function as receptor for xenotropic and
polytropic murine retroviruses.

The human XPR1 receptor protein shows a preference for
xenotropic retroviruses, but is also able to mediate infection of
polytropic murine leukemia retroviruses (P-MLV’s) [20].

Classical laboratory mice strains are hybrids between Mus
musculus musculus, M. m. domesticus and M. m. castaneus,
with around two-thirds of the genome coming from M. m.
domesticus [21].
X-MLV’s cannot (re-)infect most of the laboratory mouse
strains due to polymorphisms in the XPR1 protein that disable
xenotropic virus entry [22].

Interestingly, the XPR1 genotype that prohibits X-MLV entry
was not found in wild-caught M. m. domesticus, suggesting
that it is a rare allele [23]. Indeed, extensive screening
identified 7 strains of laboratory mice strains containing a
permissive allele, of which at least three were susceptible to
XMLV and XMRV in cell culture [23].

In addition, the F/St mouse strain also produced infectious
XMLV together with a lifelong viraemia [23]. Many feral mice
species, e.g. M. dunni and M. spretus, are also susceptible to
infection with X-MLV’s [20,22,24].

Evidence on M. m. castaneus is conflicting, with some
reporting a non-functional and others a susceptible XPR1
phenotype [22,25]. The ability of XPR1 to function as a
receptor for xenotropic viruses was found to depend on the
identity of two amino acid residues [22].





The origin of XMRV?

Every mouse genome contains multiple copies of endogenous
MLV and has thus the capacity to express viral RNA and
possibly viral particles.

Endogenous MLV transcription has been described for many
tissues and several mouse strains. It remains unclear if and
when virus particles are generated and whether these particles
are actually excreted.

Zoonotic transmission of these viruses could have occurred in
the many million years that mice and men have shared the
same environment.

But current XMRV sequences isolated from human samples do
closely mimic mouse genomic sequences, thus suggesting a
low number of replication cycles since zoonotic transmission,
which is thus likely to have occurred recently.

The mutation rate of MLV’s is not different from other
retroviruses [26] (although its replication rate may be low),
implying that if the transmission had taken place a long time
ago, more nucleotide substitutions should have become fixed.

Phylogenetic sequence analysis, however, revealed very short
branches for XMRV and the mouse xMERV sequences on
chromosomes 7 and 9, indicating that very few mutations have
occurred since transmission [1,3,4].

In addition to the loci on chromosomes 7 and 9, a BLAST
search using the NCBI sequence database
(http://blast.ncbi.nlm.nih.gov/Blast.cgi) retrieves loci on
mouse chromosomes 4, 11 and 12 with a much higher
(98-100%) sequence identity to XMRV-gag nucleotide
sequences (e.g. GenBank accession numbers AC124739,
AY349138, and AL627314).

Blasting whole genome XMRV sequences recovers very similar
sequences with large stretches of sequence identity on mouse
chromosomes 4, 5, 13 and Y, especially for the 3’ end of the
XMRV genome.

These results suggest that the genome of human XMRV is
present, albeit in two parts, in the mouse genome with
effectively no nucleotide changes. Even in slowly evolving
retroviruses like foamy viruses, 100% sequence identity is only
seen in animals with close contact or humans that have been
bitten by an infected primate, suggestive of direct
transmission, while intraspecies variation is generally around
85-95% for the pol gene [27-29].


A recently described locus [23] on chromosome 1 of M.
musculus (GenBank accession number AC115959) contains a
provirus that is 92% homologous to XMRV from the 22Rv1 cell
line (GenBank accession number FN692043) over its complete
genome length. This provirus, Bxv1, is mainly found in
Japanese M. molossinus (a natural hybrid of M. castaneus and
M. musculus) and is highly expressed in some laboratory
mouse strains [23].

However, the Bxv1 provirus is less likely to be the source of
XMRV, as its similarity to XMRV is much lower than that of
other murine loci.





XMRV is a novel recombinant retrovirus

XMRV is actually a recombinant virus, resembling
polytropic-endogenous sequences for the 5’ half up to
approximately the middle of the pol gene and
xenotropic-endogenous sequences for the 3’ half of the
genome, which includes the env gene (see: [30]).

This recombination event is likely to have occurred in the
mouse before transmission to humans. At least one
recombinant provirus, Bxv1, is already found in the M.
musculus genome [23]. This locus is heterogeneous in
subspecies of M. musculus, suggesting that it represents a
recent integration.

Recombination rates are high for all retroviruses because they
package two copies of the RNA genome in virions, which drives
subsequent mixing of sequences during the reverse
transcription process.

Recombination also enables the generation of
replication-competent viruses from defective endogenous
proviruses. Recombination can also extend the viral host range
(cell type and/or host species).

A virus carrying a xenotropic env-gene is more infectious for
human cells as the human XPR1 protein has a preference for
xenotropic murine envelope proteins over polytropic ones.

The replication-competent endogenous cat retrovirus RD-114 is
an example of a recombinant virus expressed from endogenous
sequences. It combines FcEV gag-pol genes (FcEV is an
endogenous retrovirus of cats) and a BaEV env-gene (BaEV is
an endogenous retrovirus of African monkeys) [31].

RD-114 is expressed by all species of the genus Felis, but not
in other felines, and probably originates from a cross-species
transmission of BaEV, followed by a recombination event and
subsequent germ-line integration.





Are mouse-derived biological products the source
of XMRV?

Detection rates of XMRV in populations are extremely variable,
with 0-67% positivity in patients and 0-3.7% in healthy
controls [2-7], suggesting that virus prevalence and thus
exposure could vary significantly with geographic location.

Although the virus could possibly be transmitted from feral
mice to humans in a natural setting, followed by a rapid
dissemination in the human population, the high XMRV
sequence similarity on two continents would suggest an
alternative transmission route.

Likely sources of XMRV are mouse-derived products. Some
mouse genomes encode complete copies of X-MLV’s with at
least 92% similarity to XMRV; segments with even higher
homology are present on other locations, and could result in
novel recombinant viruses.

So, X-MLV’s that closely resemble XMRV could then be
produced from these loci and virions could be excreted from
mouse tissue or cell cultures.




Are X-MLV’s produced in mice?

MLV’s, including xenotropic sequences, are actively transcribed
in mouse brain [32], and mice can produce virus particles of
different MLV classes [33]. In vivo recombination between
endogenous and exogenous polytropic MLV’s has also been
reported, resulting in viable viral offspring capable of infecting
a variety of species [34].

The Bxv1 locus in M. musculus molossinus is an example of an
endogenous xenotropic/polytropic recombinant MLV that is
expressed and gives rise to a life-long viraemia in laboratory
mice of the F/St strain [23].


Although there was no evidence of X-MLV transmission to
human embryonic stem cells expressing XPR1 after
cocultivation with murine cells expressing X-MLV particles in a
single report [35], this does not imply that transmission may
not have occurred on another occasion.

The prostate carcinoma cell line 22Rv1 is a popular research
tool because it contains approximately 10 integrated copies of
the XMRV provirus and it produces infectious virus [36].

The origin of the 22Rv1 cell line may represent a recent
transmission case as a carcinoma was grafted in nude mice to
establish this permanent cell line [37]. The complete 22Rv1
provirus has 99% sequence similarity with other XMRV isolates
[38].

Possibly, the 22Rv1 carcinoma cells were infected with XMRV
by mouse cells surrounding the tumour graft [36].




Vaccines, viruses and contamination


One of the most widely distributed biological products that
frequently involved mice or mouse tissue, at least up to recent
years, are vaccines, especially vaccines against viruses.

Some, for instance vaccines against rabies virus [39], yellow
fever (YF) virus [40], and Japanese encephalitis (JE) virus [41],
consisted of viruses that were cultured on mouse brains.

Such vaccines were in use from 1931 (YF vaccine) until now
(Japanese encephalitis vaccine, licensed in Japan since 1954).

For rabies virus, early vaccines were mainly of goat or sheep
nerve tissue origin. In addition, suckling mouse brain-derived
rabies virus vaccines were used in South America and France
[39].

No mouse-derived rabies vaccine was ever licensed in the USA
[42]. Live-attenuated YF vaccines were originally also grown
on mouse brain, but an YF vaccine grown on chicken eggs
(named 17D) became available in 1937, and was since the
vaccine of choice in the America’s.

In 1962, contamination of the 17D vaccine with oncogenic
avian leukosis virus was detected both in England and in the
USA, but fortunately no excess of cancer incidence among
vaccinees was reported [40]. In France, the mouse-brain
derived YF vaccine was discontinued as late as 1982.


Although being the most effective means to prevent infectious
diseases and to safe lives, serious contamination problems
involving vaccines have occurred [43].

Contamination with unrelated viruses such as the presence of
hepatitis B virus (HBV) in yellow fever vaccine preparations
stemming from the use of human serum for stabilization, and
simian virus 40 (SV40) and foamy viruses through the use of
monkey cell cultures [43].

Some vaccine viruses are inactivated before use, hopefully
also inactivating any contaminating virus particles, but the
contaminating virus may be more stable than the vaccine
virus.

For instance, SV40 is highly resistant to inactivation [44].

Endogenous retroviruses constitute a distinct class of
contaminating viruses, as these viruses are encoded by all
cells of a certain species, and therefore cannot be avoided
even through rigorous screening [45].

Contamination with endogenous avian leukosis viruses is a
major problem for vaccine viruses grown in chicken embryos or
chicken embryonic fibroblasts [46]. Infectious cat endogenous
RD-114 virus has been found in several veterinary vaccines
produced in cat cell cultures [47,48].





XMRV and monoclonal antibodies.

Apart from vaccines, other mouse-derived biologicals could
have been a source of XMRV in the human population.

Monoclonal antibodies present a modern treatment for many
cancers and other diseases including cardiovascular disease,
psoriasis and auto-immune disorders (for a review see: [49]).

The first monoclonal antibody, OKT3 (to be used against
transplant rejection), was approved by the FDA in 1986.

The market for monoclonal antibody therapy has been
expanding rapidly after the year 2000. Initially, murine
antibodies produced by the hybridoma technique were used
[50], but these have been largely abandoned because of
(sometimes severe) allergic reactions.

The murine antibodies were often replaced by humanised
antibodies mainly produced in transgenic mice. Monoclonal
antibodies generated in mice could possibly be polluted by
XMRV and related viruses.

Platinum Taq polymerase from Invitrogen Corporation,
prepared using mouse monoclonal antibodies, is known to be
frequently contaminated with mouse DNA, which can generate
falsepositive PCR amplifications in combination with X-MLV or
XMRV primers [51].

It is less likely that monoclonal antibodies from mice are a
major source of XMRV in the human population as they are in
use only recently, but they could provide a future supply of
mouse-derived viruses.

Although monoclonals are treated with detergents before use
in patients, virus inactivation may not be complete, especially
as protein function should be conserved. And if retroviral
particles containing RNA genomes are copurified with the
antibody proteins, the absence of mouse DNA may give a false
impression of safety.





XMRV contamination of cell lines?

It is possible that XMRV particles were present in virus stocks
cultured in mice or mouse cells for vaccine production, and
that the virus was transferred to the human population by
vaccination.

The sequence homogeneity of all XMRV isolates known today
suggests that only a single or very few transmissions have
occurred, which is consistent with the proposed vaccination
route.

Nowadays, vaccine batches are carefully checked with
sensitive PCR assays for the presence of contaminating
retroviruses, but this screening was not performed in the early
years of vaccination ([52] see also [48]).

Apart from vaccines, other biological products have been
generated using mice or mouse cells. Alternatively, laboratory
contamination with a mouse-derived virus of cell lines used for
e.g. vaccine production could have occurred [53-55]. The virus
could then unintentionally have been transmitted to the
human population.

Nowadays, many vaccine strains are grown in human diploid
cell lines [56], which are susceptible to MLV infection. A recent
report detected other MLV-related sequences in CFS patients
and healthy controls from North America [57], suggesting that
more MLV strains may have been transmitted to the human
population, possibly in a similar fashion.

However, solid evidence that these polytropic MLV sequences
represent replicating virus is currently lacking.




Where was XMRV transmitted?

XMRV was found in samples from CFS patients in North
America, but not in Europe. The virus was detected in prostate
cancer tissue from patients on both continents. There is a
single report with negative results from China [58], and a
single report with one positive sample from Mexico [59] but
none from other areas of the world, leaving many questions
about the true distribution of XMRV in humans.

Prevalence of XMRV from North American studies varies
between 3.7-67% in four studies with two other studies
reporting negative results (one in CFS patients and healthy
controls [6], and one in HIV-infected patients receiving
antiretroviral therapy and untreated men at risk for HIV
infection [60]).

In Europe, XMRV was detected in two studies from Germany
[3], and in one from The Netherlands [61], but not in the
United Kingdom [5,62], France [63], Denmark [64], and two
other studies from The Netherlands [7,65], although the
nature of the samples analysed differed between studies.
Table 1 summarizes the results from these studies.




XMRV sequences from Germany and North America exhibit very
little nucleotide divergence, suggesting that they descended
from a common ancestor relatively recently.

A close inspection of the phylogenetic trees obtained with
XMRV-gag sequences [3,4] suggests that XMRV sequences
from the USA are closer to the common ancestor than German
XMRV sequences, although the trees are not optimal due to
the high sequence conservation.

Being closer to the most recent common ancestor (MRCA) is
suggestive of an older virus. Possibly, XMRV was transmitted
from mice to men in the USA, and soon after this event
introduced into Germany.

Germany had close connections with the USA after World War
II, with large numbers of military personnel (and their
families) stationed in Germany from 1945 till present times.

In 2006, there were still 57.080 American army employees
distributed over more than 200 locations in Germany, mainly in
the south and west of the country
(www.defense.gov/pubs/BSR_2007_Baseline.pdf).

US military personnel are highly vaccinated, e.g. virtually all
recruits were vaccinated with YF vaccine in 1941- 1942 after
the outbreak of World War II [40].

A massive outbreak of jaundice, with at least 26,000 cases in
the Western region of the USA, was due to the use of human
serum contaminated with HBV in the vaccine (see [40]).

Recently, massive smallpox vaccination of the US army
personnel has been carried out [66]. XMRV infected Americans
could subsequently have introduced the virus into Germany.




Spread of XMRV

The combined results suggest (1) that XMRV was recently
transmitted from mice to humans, either from a single source,
or at least from a single (sub) species of mice, and (2) that all
XMRV-positive individuals known today were infected with this
newly-emerged virus only recently, as a very high sequence
identity is normally only seen after a direct retrovirus
transmission.

Whatever the mechanism of XMRV cross-species transmission
from mouse in humans, the possible spread from human to
human forms a major health threat.

Sexual transmission was initially proposed [67], but XMRV was
not detected in seminal plasma from HIV- infected men [65].

The detection of XMRV fragments in the respiratory tract [3]
suggests that the virus may be transmitted by saliva, although
RNA concentrations were low. Transmission through saliva,
mainly by biting, has been reported for most retrovirus genera,
including ecotropic MLV’s [68].

Another major threat is transmission through blood products
as infectious virus has been cultured from blood cells [2].


Up till now, all patients with detectable XMRV have been
adults, the majority of them middle-aged or older (mean ± 55
years).

A study in 142 children with a diversity of pathologies,
including respiratory diseases in France revealed no XMRV
infections in that age group [63], although the incidence of
XMRV in France is not known.

Another study in autistic children from the USA and Italy was
also negative for XMRV [69].

XMRV can likely be acquired at any age, and then probably
establishes a chronic, latent infection like other retroviruses.
Therefore the age of XMRV-infected individuals does not
provide an unambiguous clue about when XMRV entered the
human population.




Conclusion


In conclusion, the most likely mode of XMRV transmission
points to mouse-derived biological products, but it cannot
formally be excluded that the virus was once transferred from
feral mice to humans.

The latter scenario is less likely as it would imply that a very
rapid spread in the human population must have occurred to
explain its presence on two continents. In this scenario, the
extreme sequence similarity among XMRV genomes, both
between and within individuals, would argue that the virus
replicates at very low levels.

Among the biological products, vaccines that were produced in
mice or mouse cells are possible candidates that warrant
further inspection. If XMRV was introduced in the human
population through the use of biologicals, a background level
of the virus in the human population, possibly varying with
geography or age group, would be expected.

Such a low level presence would then also explain the
(absence of) detection of the virus in different studies, as
well as its controversial association with disease.



We hope that this hypothesis will spur further discussion and
help to resolve the many remaining XMRV questions.




Acknowledgement

We thank Hans Zaaijer for insightful discussions and
proofreading of the manuscript.




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