XMRV: Usage of Receptors and potential Co-receptors

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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@...)

Krishnakumar Devadas (Krishnakumar.Devadas@...)

Viswanath Ragupathy (Viswanath.Ragupathy@...)

Veeraswamy Ravichandran

(Veerasamy.Ravichandran@...)

Shixing Tang (Shixing.Tang@...)

Owen Wood (Owen.Wood@...)

Durga Sivacharan Gaddam (Durga.Gaddam@...)

Sherwin Lee (Sherwin.Lee@...)

Indira K Hewlett (Indira.Hewlett@...)

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

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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:

Fax:

Email: indira.hewlett@...

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 – 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.