subject of XMRV and related MLV's.
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http://www.ncbi.nlm.nih.gov/pubmed/21978843
Trends Microbiol. 2011 Oct 4. [Epub ahead of print]
Xenotropic murine leukaemia virus-related virus (XMRV) does not cause
chronic fatigue
Mark J. Robinson, Otto Erlwein and Myra O. McClure
Section of Infectious Diseases, Jefferiss Research Trust Laboratories,
Imperial College London, St Mary=92s Campus, London, W2 1PG, UK
The xenotropic murine leukaemia virus-related virus (XMRV), a
gammaretrovirus, was discovered in prostate cancer tumours by Virochip
technology in 2006. It was subsequently detected in chronic fatigue
patients in 2009. The association between XMRV and chronic fatigue has
proved to be controversial. No study has confirmed these findings and
many have refuted them. Here, we present the evidence for our
contention that XMRV is not a human pathogen.
Human retroviruses and disease
Both before and after the discovery of the first human retrovirus in
1980, there have been many claims of an association of retroviruses
with diseases as diverse as cancers, schizophrenia and thyroiditis
(for review, see [1]; Box 1). The fact is that two human T-cell
leukaemia viruses (HTLV-1 and HTLV-2) and two immunodeficiency viruses
(HIV-1 and HIV-2) are the only known human retroviruses. No other
claim has withstood the test of time and thorough independent
confirmation.
One reason for this is that endogenous retroviruses have constituted
something of an occupational hazard to virologists looking for new
disease associations. First, they make up approximately 8% of the
human genome [2] and 10% of the mouse genome [3], so their sequences
can be amplified erroneously from human tissue and be misinterpreted
as an exogenous virus infection. Second, it is well known that human
cell lines commonly used in laboratories are frequently contaminated
with endogenous murine leukaemia viruses (MLVs), as reviewed in [4].
This stems from the fact that many of these cell lines have been
established from xenografts passaged through nude mice carrying
xenotropic MLVs and are infected during passage. Third, monoclonal
antibodies commonly used in biological research are produced from
mouse hybridomas secreting MLVs [5=967]. Thus, it is against this
background that any new allegation of a retrovirus association with a
disease must be judged and validated.
The discovery of xenotropic murine leukaemia virus-related virus (XMRV)
The XMRV story starts in 2006 when this novel gammaretrovirus was
discovered by means of DNA microarray technology. Robert Silverman had
worked for some years on the hereditary prostate cancer 1 gene that
encodes RNaseL, an enzyme that plays a key role in the
interferon-induced antiviral response [8]. Individuals with defective
RNaseL are, as a result, more prone to viral infection. His elegant
hypothesis was that patients with prostate cancer, who had an
inherited mutation in the RNaseL gene, would be more likely to harbour
a chronic virus infection. Using Virochip technology in which highly
conserved sequences derived from all known virus families are
displayed on microarrays, Silverman, di Risi and others demonstrated
that cDNA derived from the aforementioned tumours specifically
hybridised to sequences derived from xenotropic MLVs. The virus,
called XMRV, was found in the stroma surrounding the tumours of 40% of
prostate cancer patients homozygous for the RNaseL mutation [9].
Later, XMRV was found in the tumour epithelium of 6.2% of 233 prostate
cancers, independent of the RNaseL variant [10], increasing its
apparent importance in the pathogenesis of this disease. Together,
these papers marked the first identification of a gammaretrovirus in
any human population.
A potential linkage of XMRV to chronic fatigue syndrome (CFS)
RNase L dysfunction had in the past been reported in CFS patients and,
in a reasonable extrapolation from the prostate cancer studies,
Lombardi et al. from the Whittemore Peterson Institute (WPI) reported
in Science that 68 of 101 CFS patients (67%) and eight of 208 (3.7%)
healthy controls were infected with XMRV [11]. We were puzzled by some
of the supporting data. For example, it is usual to find in any viral
infection that infected and uninfected cells exist in equilibrium as
two discrete populations. In flow cytometric analysis, this is
represented by a bimodal peak. Flow cytometric analysis of peripheral
blood mononuclear cells (PBMCs) taken from CFS patients was shown in
the paper as a single peak, indicating that almost every cell was
infected with XMRV. The second aspect that surprised us was that XMRV
gag and env sequences could be amplified from patient PBMCs in some
cases following single round PCR (not nested PCR, which is usually
necessary in order to detect retroviral infection in human specimens).
This suggests that the proviral load in these patients was very high
and, indeed, this is borne out by an electron micrograph in which many
virions are seen to be budding from an infected cell. With so much
virus around, then why did only nine of 18 patients have a serological
response to infection? And, with so many people looking for a
candidate virus for this syndrome over the years, why was it not
discovered earlier? Third, and perhaps surprisingly for a
replication-competent retrovirus, the sequences found in CFS patients
were almost identical to those found in prostate cancer patients with
XMRV infection. Finally, there is no indication from the paper that
the study was conducted in a randomised blinded fashion.
Despite these reservations, we did not set out to confirm or disprove
this study. This particular disease had not been of specific interest
to us, but we had developed PCR methods to investigate the
epidemiology of XMRV infection in prostate cancer patients from
diverse regions worldwide [12,13]. On request, therefore, we agreed to
apply the PCR we had developed to the investigation of a cohort of UK
CFS patients, for the reasons that: (i) all virologists dream of
having a new human pathogen to work on; (ii) if the virus were
associated with a major disease, it would revolutionise the diagnosis
and management of the disease in question; and (iii) a department,
such as our own, which incorporates a Clinical Pathology Accredited
(CPA) Molecular Diagnostics Unit and a Clinical Trials Centre, as well
as the National Centre for Human Retroviral Disease, would find itself
playing a central role in investigating this new virus, both in vitro
and in vivo.
Thus, for the benefit of those who attacked scientists for not finding
this virus, it should be made clear that confirmation of Lombardi et
al.=92s findings would have been a much more desirable option than not
finding it.
Failure to confirm the CFS=96XMRV association
We designed two sets of PCR primers, one which would specifically
amplify XMRV, and a second set taken from a highly conserved region of
the MLV genome, which would amplify most, if not all, MLVs. The reason
for the latter was twofold. We had worked in a department containing
MLVs and MLV vectors for many years (although not in the laboratory in
which we worked with XMRV), so the possibility of contamination was
real. The generic primers would allow us to detect this. Second, at
this stage, XMRV had only been identified in US patients and we did
not know how diverse any UK isolate might be from the prototype virus.
These primers would give us the best chance of detecting any MLV in
the first instance, and we would distinguish XMRV from other MLVs by
sequence analysis at a later date. Despite highly sensitive assays
that could detect one provirus copy, we failed to find either [14].
Later, serological analyses and repetition of the PCR using the same
primers used in the Science paper [11] also proved negative [15].
Subsequent papers from the WPI [16] indicated that PCR was not the
most sensitive method of XMRV detection, that it was more reliable to
isolate virus. Given the sensitivity of the PCR, this does not make
sense. Nevertheless, we attempted to isolate virus from a patient who
had been advised that he carried XMRV, and we failed to do so, despite
over 25 years experience in our laboratory of propagating retroviruses
in culture.
With the exception of the study from the WPI [11], no group has
published any evidence for XMRV in CFS [7,14,15,17=9625]. It is worth
noting that two of these negative studies [7,25] applied the same
methodology and the same patient selection criteria [16] as described
in the original study and, indeed, tested a subset of patients that
had been reported as being positive by the WPI. The first of these
studies [14,17=9619] published subsequent to the WPI report are compared
in some detail with the original paper [11] in Table 1.
A second paper claiming to find MLVs in CFS did not confirm the XMRV story
Endogenous MLVs have been traditionally classified into xenotropic
viruses that grow in a variety of cell types, including human cells,
but not in mouse cells, and polytropic viruses that will replicate in
both mouse and human cells. They are distinguished by their envelope
sequence and the form of the xenotropic and polytropic retrovirus 1
(XPR1) receptor they use to enter cells [26].
A study by Lo et al. linked the second class of endogenous viruses to
CFS when they found three groups of polytropic (p) MLV sequences in up
to 86.5% (32 of 37) CFS patients and another in healthy controls by
nested PCR [27]. Again, we were concerned about some technical aspects
of this paper [28], not least that the samples were =91coded=92, but not
blinded or randomised, which could account for similar pMLV sequences
in 6.8% of the healthy controls. Surprisingly, using the same gag
primers, Lombardi et al. [11] had exclusively found XMRV, whereas Lo
et al. only detected pMLV sequences [27]. In light of the prevalence
published for each infection (67% for XMRV and 86.5% for pMLV,
respectively), one might have expected some crossdetection. A full
account of our misgivings has been published on line [28] and
responded to [29].
The key issue about the Lo et al. paper is that it did not claim to
find XMRV, but sequences characteristic of a different class of
endogenous MLV. It, therefore, cannot be quoted as confirmatory
evidence for the findings described by Lombardi et al. [11].
What is the explanation for MLVs being found in human tissue?
The history of virology is littered with examples of =91new human
viruses=92 turning out to be laboratory contaminants. It is extremely
easy to find oneself in this situation and makes for fascinating
reading [1,30,31] (Box 1). How does it happen? The fact that cell
lines and monoclonal antibodies can harbour MLV sequences and
infectious virus has already been mentioned. Several reports have
highlighted the fact that commercial reagents occasionally contain
traces of murine DNA carrying endogenous murine retroviruses [6,7,32].
Importantly, the sequences generated by these reagents are almost
identical to the ones amplified by Lo et al. [27], and a number of
papers have now suggested that detection of MLV sequences is due to
murine DNA contamination [13,32=9636]. The indisputable proof of whether
a murine retrovirus constitutes a human infection lies in the
definition of the integration sites of the virus in the host cell. If,
following cloning and sequencing, they prove to be human, then the
infection is human. This evidence has not been forthcoming for
integration sites derived from CFS patients apparently infected with
XMRV. When a BLAST search was performed on the 14 integration sites of
XMRV in human prostate cancer tissue, two were found to be identical
to the published integration sites of experimentally infected DU145
cells [35]. This considerably weakens the argument in favour of XMRV
being a human pathogen and is suggestive of laboratory contamination.
Further direct evidence for contamination was revealed when the
published 14 integration sites were analysed for single nucleotide
polymorphisms (SNPs) [37]. SNPs identified in alleged human
integration sites were compared to those from cell lines artificially
infected with XMRV. Two SNPs in two human integration sites matched
SNPs found in DU145 and 22Rv1 cells. Together these data demonstrate
that, on analysing the integration sites, contamination occured for at
least three out of a total of nine prostate cancer patients.
It is now apparent that many prostate tumour cell lines are infected
with murine xenotropic gammaretroviruses which are
replication-competent. A recent publication described the ease with
which LNCaP and DU145 cells became infected with XMRV from 22Rv1 cells
(which secrete XMRV, see below), despite the two cell lines not being
handled simultaneously [38]. Shin et al. [25] reported that a DNA
extraction robot that had previously handled XMRVinfected tissue
culture cells subsequently contaminated DNA extracted from patient
samples and led to false positive findings of XMRV infection.
Unbelievable as it may seem, contamination can also happen during
liquid nitrogen storage. Tedder et al. [39] demonstrated leakage of
hepatitis B virus (HBV) from one sample, which contaminated the
cryopreservation tank and its contents with HBV. This led to
subsequent HBV infections in transplantation patients.
XMRV provenance
It was always a source of concern that the discovery of XMRV in
prostate cancer patients and the prostate cancer cell line 22Rv1 that
sheds XMRV originated from the same place (Cleveland). Paprotka et al.
[31] has been able to follow the trail of the 22Rv1 cell line by
investigating material remaining from the original experiments to show
that, although early passages of the human prostate cells were
XMRV-negative, tissue from later passages were not (Figure 1). It
seems that XMRV emerged in the mid 1990s through a recombination event
between two endogenous murine proviruses, pre-XMRV1 and pre-XMRV2,
which occurred following in vivo passage of the CWR22 prostate cell
xenograft through nude mice. The recombinant virus (XMRV) then spread
throughout the tumour cell lines that were derived from the passaged
xenograft. One half of XMRV (including the XMRV-specific 24-bp
deletion in the leader gag region) is present in a commonly-handled
mouse fibroblast cell line, NIH/3T3 [40]. It is telling that no
full-length XMRV has been found in any mouse strain to date.
After passage of a human prostate xenograft through nude mice, the
resulting human prostate cancer cell line, 22Rv1, contained between 10
and 20 proviral copies of XMRV [41] and was used in many laboratories
without knowing that they were releasing XMRV virions, possibly
contaminating the laboratories.
Knox et al. [7] determined the sequence between the primers used by
Lombardi et al. of long-term passaged XMRV in cell culture and found
changes over time [7]. However, because all published XMRV sequences
are more than 99% similar and the probability of the same XMRV
sequence being generated by another independent recombination event is
remote (1.3 ! 10=9612) [31], then XMRV from the 22Rv1 cell line is the
genetic ancestor of all the other XMRV isolates from prostate cancer
or CFS patients [34]. Because XMRV was generated in the mid 1990s it
is, therefore, impossible that it caused CFS in patients diagnosed in
the 1980s [42].
Human infection with gammaretroviruses is unlikely
Gammaretroviruses can cross the species barrier. For example, a
southeast Asian rodent virus is known to have jumped species to infect
gibbon apes and koala bears [43,44], therefore murine virus infection
of higher primates is not impossible. As proof of cross-species
transmission of XMRV, much has been made of the experiment of Onlamoon
et al. [45] who inoculated macaques with the virus and established in
them a persistent infection. However, the macaques received an
enormously high (certainly not physiological) dose of intravenous
virus, yet failed to produce antigen-specific cellular responses, a
robust and durable antibody response or evidence of pathology.
Although humans have lived for aeons in close proximity with cats and
mice, which frequently harbour gammaretroviruses, there are sound
reasons why gammaretroviruses fail to establish infections in humans.
Foremost is that we have innate immune mechanisms to reduce the
chances of it happening. One such mechanism is represented by the
APOBEC superfamily of RNA editing proteins. Another one is tetherin, a
host protein that prevents virus budding from the cell membrane at the
end of the replication cycle. Replication of XMRV in PBMCs is
inhibited by both of these mechanisms [46=9649]. Moreover, it is well
established that human complement can lyse MLVs [50,51] and Knox et
al. [7] have demonstrated that XMRV is inactivated by human serum
(including those of CFS patients!), all of which makes it extremely
difficult, although not impossible, for the virus to establish a
productive infection in the human population. Recently, the Blood XMRV
Scientific Research Working Group (SRWG), working with coded replicate
blood samples from 15 subjects found by Lombardi et al. [11] and Lo et
al. [27] to be XMRV/MLV-positive (14 with CFS), and from 15 healthy
donors previously found to be virus-negative, failed to confirm any
XRMV/MLV infection by nucleic amplification testing, serology, or
virus culture in patients with CFS [52]. Inability to replicate sample
results supports contamination as an explanation of the original
findings. Indeed, crucial figures from Lombardi et al. [11] were
derived using data obtained from contaminated samples, leaving the
validity of the Lombardi study in serious doubt and, in turn, led some
of the authors to instigate a partial retraction [53].
Concluding remarks
XMRV as a natural human infection associated with two major human
conditions, prostate cancer and chronic fatigue syndrome, initially
appeared to be a most exciting finding. Indeed, had these links been
substantiated, it would have dramatically changed the management and
treatment of both conditions. However, XMRV has clearly been shown to
have arisen as a result of a recombination event in mice and has no
natural reservoir in humans.
References
1 Voisset, C. et al. (2008) Human RNA =91rumor=92 viruses: the search for
novel human retroviruses in chronic disease. Microbiol. Mol. Biol.
Rev. 72, 157=96196
2 Li, W. et al. (2001) Evolutionary analysis of the human genome.
Nature 409, 847=96849
3 Stocking, C. and Kozak, C.A. (2008) Murine endogenous retroviruses.
Cell Mol. Life Sci. 65, 3383=963398
4 Takeuchi, Y. et al. (2008) Identification of gammaretroviruses
constitutively released from cell lines used for human
immunodeficiency virus research. J. Virol. 82, 12585
5 Weiss, R.A. (1982) Retroviruses produced by hybridomas. New Eng. J.
Med. 307, 1587
6 Sato, E. et al. (2010) An endogenous murine leukemia viral genome
contaminant in a commercial RT-PCR kit is amplified using standard
primers for XMRV. Retrovirology 7, 110
7 Knox, K. et al. (2011) No evidence of murine-like gammaretroviruses
in CFS patients previously identified as XMRV-infected. Science 333,
94
8 Silverman, R.H. (2007) A scientific journey through the 2-5A/RNase L
system. Cytokine Growth Factor Rev. 18, 381=96388
9 Urisman, A. et al. (2006) Identification of a novel Gammaretrovirus
in prostate tumors of patients homozygous for R462Q RNASEL variant.
PLoS Pathog. 2, e25
10 Schlaberg, R. et al. (2009) XMRV is present in malignant prostatic
epithelium and is associated with prostate cancer, especially
highgrade tumors. Proc. Natl. Acad. Sci. U.S.A. 106, 16351=9616356
11 Lombardi, V.C. et al. (2009) Detection of an infectious retrovirus,
XMRV, in blood cells of patients with chronic fatigue syndrome.
Science 326, 585=96589
12 Robinson, M.J. et al. (2011) No evidence of XMRV or MuLV sequences
in prostate cancer, diffuse large B cell lymphoma, or the UK blood
donor population. Adv. Virol. DOI: 10.1155/2011/782353
13 Robinson, M.J. et al. (2010) Mouse DNA contamination in human
tissue tested for XMRV. Retrovirology 7, 108
14 Erlwein, O. et al. (2010) Failure to detect the novel retrovirus
XMRV in chronic fatigue syndrome. PLoS ONE 5, e8519
15 Erlwein, O. et al. (2011) Investigation into the presence of and
serological response to XMRV in CFS patients. PLoS ONE 6, e17592
16 Mikovits, J.A. et al. (2010) Detection of an infectious retrovirus,
XMRV, in blood cells of patients with chronic fatigue syndrome.
Virulence 1, 386=96390
17 Groom, H.C. et al. (2010) Absence of xenotropic murine leukaemia
virus-related virus in UK patients with chronic fatigue syndrome.
Retrovirology 7, 10
18 van Kuppeveld, F.J. et al. (2010) Prevalence of xenotropic murine
leukaemia virus-related virus in patients with chronic fatigue
syndrome in the Netherlands: retrospective analysis of samples from an
established cohort. BMJ 340, c1018
19 Switzer, W.M. et al. (2010) Absence of evidence of xenotropic
murine leukaemia virus-related virus infection in persons with chronic
fatigue syndrome and healthy controls in the United States.
Retrovirology 7, 57
20 Hong, P. et al. (2010) Failure to detect Xenotropic murine
leukaemia virus-related virus in Chinese patients with chronic fatigue
syndrome. Virol. J. 7, 224
21 Henrich, T.J. et al. (2010) Xenotropic murine leukaemia
virus-related virus prevalence in patients with chronic fatigue
syndrome or chronic immunomodulatory conditions. J. Infect. Dis. 202,
1478=961481
22 Hohn, O. et al. (2010) No evidence for XMRV in German CFS and MS
patients with fatigue despite the ability of the virus to infect human
blood cells in vitro. PLoS ONE 5, e15632
23 Satterfield, B.C. et al. (2011) Serologic and PCR testing of
persons with chronic fatigue syndrome in the United States shows no
association with xenotropic or polytropic murine leukemia
virus-related viruses. Retrovirology 8, 12
24 Schutzer, S.E. et al. (2011) Analysis of cerebrospinal fluid from
chronic fatigue syndrome patients for multiple human ubiquitous
viruses and xenotropic murine leukemia-related virus. Ann. Neurol. 69,
735=96738
25 Shin, C.H. et al. (2011) Absence of XRMV and other MLV-related
viruses in patients with Chronic Fatigue Syndrome. J. Virol. 85,
7195=967202
26 Kozak, C.A. and Ruscetti, S. (1992) Retroviruses in Rodents, In The
Retroviridae (Vol. 1) (Levy, J.A., ed.), In pp. 405=96481, Plenum Press
27 Lo, S.C. et al. (2010) Detection of MLV-related virus gene
sequences in blood of patients with chronic fatigue syndrome and
healthy blood donors. Proc. Natl. Acad. Sci. U.S.A. 107, 19132
28 Erlwein, O. et al. (2010) Chronic fatigue syndrome: xenotropic
murine leukemia virus-related virus, murine leukemia virus, both, or
neither? Proc. Natl. Acad. Sci. U.S.A. 107, e161
29 Lo, S. et al. (2010) Reply to Erlwein et al. and Martin: on
detection of murine leukemia virus-related virus gene sequences in
blood of patients with chronic fatigue syndrome and healthy blood
donors. Proc. Natl. Acad. Sci. U.S.A. 107, e163
30 Weiss, R.A. (2010) A cautionary tale of virus and disease. BMC Biol. 8, =
124
31 Paprotka, T. et al. (2011) Recombinant origin of the retrovirus
XMRV. Science 333, 97
32 Tuke, P.W. et al. (2011) PCR master mixes harbour murine DNA
sequences. Caveat emptor! PLoS ONE 6, e19953
33 Oakes, B. et al. (2010) Contamination of human DNA samples with
mouse DNA can lead to false detection of XMRV-like sequences.
Retrovirology 7, 109
34 Hue=B4, S. et al. (2010) Disease-associated XMRV sequences are
consistent with laboratory contamination. Retrovirology 7, 111
35 Garson, J.A. et al. (2011) Analysis of XMRV integration sites from
human prostate cancer tissues suggests PCR contamination rather than
genuine human infection. Retrovirology 8, 13
36 Yang, J. et al. (2011) Xenotropic murine leukemia virus-related
virus (XMRV) in prostate cancer cells likely represents a laboratory
artefact. Oncotarget 2, 358=96362
37 Rusmevichientong, A. et al. (2011) Analysis of single nucleotide
polymorphisms in XMRV patient-derived integration sites reveals
contamination from cell lines acutely infected by XMRV. J. Virol.
doi:10.1128/JVI.05624-11.
38 Sfanos, K.S. et al. (2011) Identification of replication competent
murine gammaretrovirus in commonly used prostate cancer cell lines.
PLoS ONE 6, e20874
39 Tedder, R.S. et al. (1995) Hepatitis B transmission from
contaminated cryopreservation tank. Lancet 346, 137=96140
40 Mendoza, R. et al. (2011) The left half of XMRV is present in an
endogenous retrovirus of NIH/3T3 Swiss mouse cells. J. Virol. 85,
9247=969248
41 Knouf, E.C. et al. (2009) Multiple integrated copies and high-level
production of the human retrovirus XMRV (xenotropic murine leukemia
virus-related virus) from 22Rv1 prostate carcinoma cells. J. Virol.
83, 7353
42 Mikovits, J.A. and Ruscetti, F.W. (2010) Response to comments on
=91Detection of an infectious retrovirus, XMRV, in blood cells of
patients with chronic fatigue syndrome=92. Science 328, 825
43 Kurth, R. and Bannert, N., eds (2010) Retroviruses: Molecular
Biology, Genomics and Pathogenesis, Caister Academic Press
44 Voevodin, A. and Marx, P.A. (2009) Simian Virology, Wiley-Blackwell
45 Onlamoon, N. et al. (2011) Infection, viral dissemination, and
antibody responses of rhesus macaques exposed to the human
gammaretrovirus XMRV. J. Virol. 85, 4547=964557
46 Stieler, K. and Fisher, N. (2010) Apobec 3G efficiently reduces
infectivity of the human exogenous gammaretrovirus XMRV. PLoS ONE 5,
e11738
47 Paprotka, T. et al. (2010) Inhibition of xenotropic murine leukemia
virus-related virus by APOBEC3 proteins and antiviral drugs. J. Virol.
84, 5713=965729
48 Groom, H.C. et al. (2010) Susceptibility of xenotropic murine
leukemia virus-related virus (XMRV) to retroviral restriction factors.
Proc. Natl. Acad. Sci. U.S.A. 107, 5166
49 Bogerd, H.P. et al. (2011) Human APOBEC3 proteins can inhibit
xenotropic murine leukemia virus-related virus infectivity. Virology
410, 234=96239
50 Welsh, R.M. et al. (1975) Human serum lyses RNA tumour viruses.
Nature 257, 612=96614
51 Cooper, N.R. et al. (1976) Complement-dependent lysis of RNA tumor
viruses. J. Immunol. 116, 1730
52 Simmons, G. et al. (2011) Failure to Confirm XMRV/MLVs in the Blood
of Patients with Chronic Fatigue Syndrome: A Multi-Laboratory Study.
Science doi:10.1126/science.1213841.
53 Silverman, R.H. et al. (2011) Partial Retraction. Science
doi:10.1126/science.1212182.
54 Griffiths, D.J. et al. (1999) Detection of human retrovirus 5 in
patients with arthritis and systemic lupus erythematosus. Arthritis
Rheum. 42, 448=96454
55 Griffiths, D.J. et al. (2002) Novel endogenous retrovirus in
rabbits previously reported as human retrovirus 5. J. Virol. 76, 7094
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