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The full provisional PDF file of *XMRV: Usage of Receptors and
potential Co-receptors* is attached for private members, but can
also be found at:
http://www.virologyj.com/content/pdf/1743-422X-8-423.pdf
~jvr
````
BioMed Central
The Open Access Publisher
Virology Journal
This Provisional PDF corresponds to the article as it appeared upon
acceptance. Fully formatted PDF and full text (HTML) versions will
be made available soon.
XMRV: Usage of Receptors and potential
Co-receptors
Virology Journal 2011, 8:423
doi:10.1186/1743-422X-8-423
Mohan Kumar Haleyur Giri Setty
(Mohan.Haleyurgirisetty@fda.hhs.gov)
Krishnakumar Devadas (Krishnakumar.Devadas@fda.hhs.gov)
Viswanath Ragupathy (Viswanath.Ragupathy@fda.hhs.gov)
Veeraswamy Ravichandran
(Veerasamy.Ravichandran@fda.hhs.gov)
Shixing Tang (Shixing.Tang@fda.hhs.gov)
Owen Wood (Owen.Wood@fda.hhs.gov)
Durga Sivacharan Gaddam (Durga.Gaddam@fda.hhs.gov)
Sherwin Lee (Sherwin.Lee@fda.hhs.gov)
Indira K Hewlett (Indira.Hewlett@fda.hhs.gov)
ISSN 1743-422X
Article type Short report
Submission date 12 July 2011
Acceptance date 6 September 2011
Publication date 6 September 2011
Article URL http://www.virologyj.com/content/8/1/423
This peer-reviewed article was published immediately upon
acceptance. It can be downloaded, printed and distributed freely for
any purposes (see copyright notice below).
Articles in Virology Journal are listed in PubMed and archived at
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Virology Journal
=A9 2011 Haleyur Giri Setty et al.; licensee BioMed Central Ltd.
This is an open access article distributed under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
XMRV: Usage of Receptors and potential
Co-receptors
Mohan Kumar Haleyur Giri Setty1, Krishnakumar Devadas1,
Viswanath Ragupathy1, Veerasamy Ravichandran1, Shixing
Tang1, Owen Wood1, Durga Sivacharan Gaddam1, Sherwin
Lee1, Indira K. Hewlett1*
1 Center for Biologics Evaluation and Research, Food and Drug
Administration, Bethesda, MD 20892, USA.
*Corresponding Author: Dr. Indira Hewlett
Bld. 29B, Room. 4NN16, Laboratory of Molecular Virology, DETTD,
OBRR, CBER, FDA, Bethesda, MD 2089
2
Phone: (301) 827-0795
Fax: (301) 827-0998
Email: indira.hewlett@fda.hhs.gov
Abstract
Background
XMRV is a gammaretrovirus first identified in prostate tissues of
Prostate Cancer (PC) patients and later in the blood cells of
patients with Chronic Fatigue Syndrome (CFS).
Although XMRV is thought to use XPR1 for cell entry, it infects
A549 cells that do not express XPR1, suggesting usage of other
receptors or co-receptors.
Methods
To study the usage of different receptors and co- receptors that
could play a role in XMRV infection of lymphoid cells and GHOST
(GFP- Human osteosarcoma) cells expressing CD4 along with
different chemokine receptors including CCR1, CCR2, etc., were
infected with XMRV.
Culture supernatants and cells were tested for XMRV replication
using real time quantitative PCR.
Results
Infection and replication of XMRV was seen in a variety of GHOST
cells, LNCaP, DU145, A549 and Caski cell lines.
The levels of XMRV replication varied in different cell lines showing
differential replication in different cell lines.
However, replication in A549 which lacks XPR1 expression was
relatively higher than DU145 but lower than, LNCaP.
XMRV replication varied in GHOST cell lines expressing CD4 and
each of the co- receptors CCR1 - CCR8 and Bob.
There was significant replication of XMRV in CCR3 and Bonzo
although it is much lower when compared to DU145, A549 and
LNCaP.
Conclusion
XMRV replication was observed in GHOST cells that express CD4,
and each of the chemokine receptors ranging from CCR1- CCR8
and Bob suggesting that infectivity in hematopoietic cells could be
mediated by use of these receptors.
Introduction:
A new gamma retrovirus, Xenotropic Murine leukaemia Virus-related
virus (XMRV), was identified in 2006 and its association was
claimed with prostate cancer (PC) and chronic fatigue syndrome
(CFS).
A series of studies from disparate geographical areas have failed to
substantiate these claims.
Recent studies have suggested that XMRV may have arisen in
mice through recombination of two proviruses [1].
Regardless of the controversies, XMRV is a culturable virus capable
of infecting different cell types like T and B Lymphocytes, NK
cells, etc., [2].
Intravenous inoculation of Rhesus Macaques with XMRV showed
organ-specific cell tropism, infecting CD4 T cells in lymphoid
organs including the gastrointestinal lamina propria, alveolar
macrophages in lung, and epithelial/interstitial cells in other
organs, and cells of the reproductive tract [3].
Many retroviruses are pathogenic (HIV-1) causing severe disease
but at the same time they have been used in gene therapy which
requires targeting of the virus to the host cell through interactions
between viral envelope proteins and cell surface proteins.
It is important to determine the mode of its cell entry to define
tropism, and understand virus transmission and pathogenesis.
Biological process involves highly specific interactions and infection
of cells by viruses is no exception.
Such interactions are of major importance in pathogenic viruses as
they are potential drug targets.
One such classic example is the entry of HIV-1 through a series of
interactions between the viral gp120 and cellular receptor CD4 and
co-receptor such as either CCR5 or CXCR5 [4].
The xenotropic/polytropic subgroup of mouse leukemia viruses
(MLVs) all rely on the XPR1 receptor for entry, but these viruses
vary in tropism, distribution among wild and laboratory mice,
pathogenicity, strategies used for transmission, and sensitivity to
host restriction factors [5].
XMRV is closely related to xenotropic murine leukemia viruses
MLVs (X-MLVs) [6].
The X-MLVs and polytropic MLVs (P-MLV) use Xpr1 as a receptor
for cell entry [4, 7, 8], and so does XMRV [9, 10, 11].
The recent identification of MLV and XMRV in human prostate
cancer tissues, peripheral blood mononuclear cells (PBMCs) of
chronic fatigue syndrome patients, and the respiratory tract of
immunocompromised patients [12] raises the concern of a
potential threat to public health from cross-species transmission of
MLV related viruses.
Results and discussion
Infection and replication of XMRV was observed in a variety of
GHOST cells, LNCaP, DU145, A549 and CaSki cell lines (Fig 1
and 2).
The levels of XMRV replication varied in different cell lines.
However, replication in A549 which lacks XPR1 expression was
relatively high compared with DU145 but lower than levels observed
in LNCaP (Fig 1C and 2C).
These findings suggest that perhaps other molecules could serve
as receptors for this virus in addition to Xpr1.
XMRV replicated less efficiently in GHOST cell lines expressing
CD4 and each of the co- receptors CCR1 =96 CCR8 and Bob
compared with A549 and LNCaP.
However, among the GHOST cell lines there was significant
replication of XMRV in CCR3 and Bonzo expressing cells ( Fig 1C
and 2C).
XMRV infection of GHOST cells that express CD4 and each of the
chemokine receptors ranging from CCR1- CCR8 and Bob suggests
that infection and tropism for hematopoietic cells could be
mediated by use of these receptors as XPR1 is not expressed in
blood cells and very weakly expressed in bone marrow (Gene
Atlas).
Replication of XMRV in A549 cells lacking XPR1 was much higher
when compared with DU145 which express XPR1.
Furthermore, the cell line 293T expresses XPR1 but did not support
XMRV replication.
These findings clearly indicate the possibility of other receptors for
XMRV than XPR1.
Interestingly CCR1, CCR2, and CCR3 are expressed in A549 and
Bonzo in PC-3, DU145, LNCaP and A549 [13, 14].
More research may be needed to fully understand the scope and
extent to which this mouse derived virus uses other receptors to
enter human cells and cross species susceptibility in line with its
xenotropic nature.
~~~~
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