Monday, October 12, 2009

A new virus for old diseases?

Perspective

A New Virus for Old Diseases?

Journal: Science  [Online October 8, 2009]

Authors: John M. Coffin [1] and Jonathan P. Stoye [2]

Affiliations:
[1] Department of Molecular Microbiology, Tufts University, Boston,
MA 02111, USA. E-mail: john.coffin@tufts.edu
[2] National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.

NLM Citation: PMID: 19815721


A retrovirus associated with cancer is linked to chronic
fatigue syndrome.

There is little consensus in the medical community on
whether chronic fatigue syndrome is a distinct disease. As its
name implies, the condition is characterized by debilitating
fatigue persisting for many years, and it affects as much as
1% of the world's population. Although chronic inflammation
is often found in these patients, no infectious or toxic agent
has been clearly implicated in this disease, which is
diagnosed largely by excluding other conditions that cause
similar symptoms (1). In this week's Science Express,
Lombardi et al. (2) describe the detection of xenotropic
murine leukemia virus-related virus (XMRV) in about twothirds
of patients diagnosed with chronic fatigue syndrome.


Both laboratory and epidemiological studies are now needed
to determine whether this virus has a causative role, not only
in this disease, but perhaps in others as well.


Chronic fatigue syndrome is not the first human disease to
which XMRV has been linked. The virus first was described
about 3 years ago in a few prostate cancer patients (3), and
recently detected in nearly a quarter of all prostate cancer
biopsies (4). It has been isolated from both prostate cancer
and chronic fatigue syndrome patients, and is similar to a
group of endogenous murine leukemia viruses (MLVs) found
in the genomes of inbred and related wild mice. Although a
half century of studies on MLVs and other
gammaretroviruses have led to important discoveries on
which much of our current understanding of cancer rests,
there has been no clear evidence demonstrating human
infection with gammaretroviruses, or associating these agents
with any human disease.

Endogenous viruses, such as xenotropic MLV, arise when
retroviruses infect germline cells. The integrated viral DNA,
or provirus, is passed on to offspring as part of the host
genome (see the figure). Endogenous proviruses form a large
part of the genetic complement of modern mammals-about
8% of the human genome, for example. Xenotropic
proviruses first entered the mouse germ line about a million
years ago, but cannot infect cells of the mice that carry them
because of a mutation in the cellular receptor for the virus
presumed to have arisen after viral entry into the germ line.
The propensity of xenotropic MLVs to infect rapidly dividing
human cells has made it a common contaminant in cultured
cells, particularly in certain human tumor cell lines (5).

There is more than 90% DNA sequence identity between
XMRV and xenotropic MLV, and their biological properties
are virtually indistinguishable (6-9), leaving little doubt that
the former is derived from the latter by one or more crossspecies
transmission events. There are several lines of
evidence that transmission happened in the outside world and
was not a laboratory contaminant. One is that XMRVs from
disparate locations and from both chronic fatigue syndrome
and prostate cancer patients are nearly identical: The viral
genomes differ by only a few nucleotides, whereas there are
hundreds of sequence differences between XMRVs and
xenotropic murine leukemia proviruses of laboratory mice.
Other evidence includes the presence of XMRV and high
amounts of antibodies to XMRV and other MLVs in chronic
fatigue syndrome and prostate cancer patients.

There is still much that we do not understand. Whether the
virus plays a causative role in either chronic fatigue syndrome
or prostate cancer is unknown. For example, XMRV infection
might, coincidentally, be more frequent in the same
geographical region as a cluster of patients with chronic
fatigue syndrome. And individuals with either disease might
be more readily infected due to immune activation. XMRV
might prefer to grow in rapidly dividing prostate cancer cells
(10), and the presence of rapidly dividing cells in either
condition might make infection more readily detectable. We
do not know how the virus is transmitted, and the suggestion,
based on indirect evidence, that there is sexual transmission
(8) is premature. Given that infectious virus is present in
plasma and in blood cells, blood-borne transmission is a
possibility. Furthermore, we do not know the prevalence or
distribution of this virus in either human or animal
populations, and animal models for infection and
pathogenesis are badly needed.

Two characteristics of XMRV are particularly noteworthy.
One is the near genetic identity of isolates from different
diseases and from individuals in different parts of the United
States. The two most distantly related genomes sequenced to
date differ by fewer than 30 out of about 8000 nucleotides.
Thus, all of the XMRV isolates are more similar to each other
than are the genomes isolated from any one individual
infected with the human immunodeficiency virus. In this
respect, XMRV more closely resembles human T cell
lymphotropic viruses (HTLVs) isolated from the same
geographic region (11). As in the case with HTLV, the lack
of diversity implies that XMRV recently descended from a
common ancestor, and that the number of replication cycles
within one infected individual is limited.

Another notable feature of XMRV is that the frequency of
infection in nondiseased controls is remarkably high-about
4% in both normal individuals from the same geographic
region as infected patients with chronic fatigue syndrome,
and in nonmalignant prostates. If these figures are borne out
in larger studies, it would mean that perhaps 10 million
people in the United Sates and hundreds of millions
worldwide are infected with a virus whose pathogenic
potential for humans is still unknown. However, it is clear
that closely related viruses cause a variety of major diseases,
including cancer, in many other mammals. Further study may
reveal XMRV as a cause of more than one well-known "old"
disease, with potentially important implications for diagnosis,
prevention, and therapy.

References
1. L. D. Devanur, J. R. Kerr, J. Clin. Virol. 37, 139 (2006).
2. V. C. Lombardi et al., Science 8 October 2009
(10.1126/science.1179052).
3. A. Urisman et al., PLoS Pathog. 2, e25 (2006).
4 R. Schlaberg, D. J. Choe, K. R. Brown, H. M. Thaker, I. R.
Singh, Proc. Natl. Acad. Sci. U.S.A. 106, 16351 (2009)
5. R. A. Weiss, in RNA Tumor Viruses, R. A. Weiss, N.
Teich, H. E. Varmus, J. M. Coffin, Eds. (Cold Spring
Harbor laboratory, Cold Spring Harbor, NY, 1982).
6. B. Dong et al., Proc. Natl. Acad. Sci. U.S.A. 104, 1655
(2007).
7. B. Dong, R. H. Silverman, E. S. Kandel, PLoS One 3,
e3144 (2008).
8. S. Hong et al., J. Virol. 83, 6995 (2009).
9. S. Kim et al., J. Virol. 82, 9964 (2008).
10. E. C. Knouf et al., J. Virol. 83, 7353 (2009).
11. S. Van Dooren et al., Mol. Biol. Evol. 21, 603 (2004).

Published online 8 October 2009;
10.1126/science.1181349
Include this information when citing this paper.

Path to human infection. Although xenotropic murine
leukemia virus (MLV)-derived from exogenous MLVs that
became established as proviruses in the mouse germ line-
can no longer infect mice, it can infect humans, apparently
leading to one or more cross-species infection events to
become XMRV.





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