XMRV & MLV-Related Viruses -Disease Associations

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Pathogens in the Blood Supply

Tuesday, March 29, 2011

1:00 PM - 5:00 PM

The New York Academy of Sciences

Presented by the Emerging Infectious Diseases &

Microbiology Discussion Group (http://bit.ly/hWRshI)

Abstract

Disease Associations of

XMRV and MLV-Related Viruses

Judy A. Mikovits, PhD,

Whittemore Institute for Neuro-Immune

Disease

A new human retrovirus first associated with QQ

variant RNaseL a gene in the hereditary prostate

cancer gene locus, in prostate cancer in 2006.

Detection of integration sites in unmanipulated

prostate tissue; demonstration of neutralizing

antibody and in situ hybridization for XMRV, supports

XMRV as a human retroviral infection associated with

prostate cancer.

Although in the absence of direct sequencing it

cannot be rule out the reactivity can be to related

MLV viruses.

In 2009 using a classical virology approach of viral

isolation and transmission, electron micropscopy,

serology and PCR, Lombardi et al demonstrated the

first isolation of XMRV from blood from patients with

chronic fatigue syndrome (CFS) predominately from

the west coast of the United States.

In 2010, Lo et al. extended these studies by

detecting nucleic acids of MLV-related variants in the

peripheral blood mononuclear cells of CFS from the

northeastern United States suggesting additional

strains capable of infecting humans exist.

In a study of 300 CFS patients, 13 developed

lymphoproliferative disorders.

Of those tested, 11/11 were positive for XMRV and

9/9 positive for clonalTCR gamma rearrangements.

Spontaneous development of four immortalized B

cells lines occurred during culture of cells from CFS

patients.

Three developed from B cells isolated from the

peripheral blood (two of whom had B cell lymphoma)

and one from a bone marrow biopsy.

The B cell lines have a mature CD20+, CD23+

phenotype and produce infectious XMRV.

Virus production occurred despite extensive

hypermutation of the proviruses in these cells by

APOBEC3G.

Therefore, XMRV infection may accelerate the

development of B cell malignancies by either indirect

chronic stimulation of the immune system and/or by

direct infection of the B-cell lineage.

Since viral load in peripheral blood is low, these data

suggest that B cells in tissues such as spleen and

lymph nodes could be an in vivo reservoir for XMRV.

We have also identified an inflammatory cytokine

and chemokine signature that distinguishes XMRV

infected CFS patients from healthy controls with 94%

sensitivity and specificity.

Monitoring immune dysfunction affords the

opportunity to begin to understand the pathogenesis

of XMRVs.

In addition to these data, recent advances in

developing tests for detection and characterization of

XMRV–variants will be also be discussed.