Friday, May 13, 2011

Lombardi: Distinct Inflammatory Signature

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Below you will find the abstract and the
Introduction-section of:

*Xenotropic Murine Leukemia Virus-related
Virus-associated Chronic Fatigue Syndrome
Reveals a Distinct Inflammatory Signature*

By Lombardi et al.

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in vivo 25: 307-314 (2011)

Xenotropic Murine Leukemia
Virus-related Virus-associated
Chronic Fatigue Syndrome
Reveals a Distinct Inflammatory


1Whittemore Peterson Institute, University of
Nevada, Reno MS 0552, 1664 N. Virginia St., Reno,
NV 89557, U.S.A.;
2Triad Medical Center, 4600 Kietzke Lane M242,
Reno, NV 89502, U.S.A.;
3Nevada Center for Health Statistics and Informatics,
University of Nevada, 1664 N. Virginia St., Reno, NV
89557, U.S.A.;
4University of Nevada Reno, Department of
Microbiology and Immunology Applied Research
Facility,1664 N. Virginia St., MS 199, Reno, NV 89557



The recent identification of xenotropic murine
leukemia virus-related virus (XMRV) in the blood of
patients with chronic fatigue syndrome (CFS)
establishes that a retrovirus may play a role in the
pathology in this disease.

Knowledge of the immune response might lead to a
better understanding of the role XMRV plays in this

Our objective was to investigate the cytokine and
chemokine response in XMRV-associated CFS.

Materials and Methods:

Using Luminex multi-analyte profiling technology, we
measured cytokine and chemokine values in the
plasma of XMRV-infected CFS patients and compared
these data to those of healthy controls.

Analysis was performed using the Gene Expression
Pattern Analysis Suite and the Random Forest tree
classification algorithm.


This study identifies a signature of 10 cytokines and
chemokines which correctly identifies XMRV/CFS
patients with 93% specificity and 96% sensitivity.


These data show, for the first time, an
immunological pattern associated with XMRV/CFS.



Chronic fatigue syndrome (CFS) is a poorly
understood disease of unknown etiology, which is
commonly characterized by innate immune defects,
chronic immune activation and dysregulation, often
leading to neurological maladies [reviewed in (1)].

It can also involve other biological systems such as
the musculoskeletal, gastrointestinal and
endocrinological systems (2-4).

Although several common symptoms are primarily
reported and predominate, they may differ among
individuals, are often intermittent and can persist for
years, frequently resulting in substantial disability

Some of the most commonly reported physical
symptoms include muscle weakness and pain, tender
or swollen lymph nodes and chronic flu-like
symptoms (6).

Memory and concentration impairment, blurred
vision, dizziness and sleep abnormalities represent
some of the cognitive symptoms typically observed
while immunological symptoms often manifest
themselves through viral reactivation, RNase L
dysregulation, decreased natural killer (NK) cell
function and susceptibility to opportunistic infections

NK cell dysregulation may be associated with viral
reactivation or viral persistence and may also lead to
malignancy (13, 14).

Indeed, clinical observations corroborate pathological
manifestations in CFS as viral reactivations,
particularly herpes virus such as cytomegalovirus
(CMV), Epstein-Barr virus (EBV) and human herpes
virus-6 (HHV-6), are common occurrences (15-17).

Moreover, epidemiological studies have reported
increased incidences of lymphoma associated with
CFS outbreaks (18).

These clinical observations suggest that a
compromised innate immune system may play a role
in CFS pathology.

The completion of the human genome project
enabled positional cloning studies to identify the
RNASEL gene as the hereditary prostate cancer
allele-1 (HPC1) (19).

This discovery prompted Robert Silverman and his
colleagues to search for a viral component to
hereditary prostate cancer.

Using a viral micro-array and tissue biopsies from
individuals with hereditary prostate cancer they
identified and sequenced the complete genome of a
novel human gammaretrovirus, very similar in
sequence to xenotropic murine leukemia virus and
therefore termed the new virus xenotropic murine
leukemia virus-related virus (XMRV) (20).

Subsequent studies performed in our laboratory
identified and isolated infectious XMRV in the blood
of 67% of CFS patients (21).

This work was performed using multiple techniques
including PCR, electron microscopy showing budding
viral particles, Western blot analysis of viral proteins
and serology confirming that infected patients
express antibodies to XMRV envelope proteins.

In addition, gene sequencing and phylogenetic
analysis confirmed these patients were indeed
infected with XMRV that was >99% identical to
previously published sequences but was obviously
distinct from the only existing XMRV molecular clone,
VP62 (20).

Taken together, this work clearly rules out any
possibility of gross contamination and additionally,
represents the first identification and isolation of
naturally occurring infectious XMRV.

The connection between CFS and XMRV was further
supported by the studies of Lo et al., who identified
murine leukemia virus (MLV)-related sequences in
the blood of 86% of CFS patients, further
establishing a retroviral association with CFS (22).

Presently, three families of retroviruses are known to
infect humans; the human immunodeficiency viruses
(HIV), the human T-cell leukemia viruses (HTLV) and
now the human murine leukemia-related viruses.

Both HIV and HTLV are known to dysregulate the
innate immune system and promote the production
of inflammatory cytokines and chemokines (23, 24).

In light of the association between XMRV and CFS, it
is not surprising that some of the most salient
observations in CFS are the differences in cytokines
and chemokines when compared to healthy controls

Previous reports, however, addressing the role of
these molecules in CFS have produced conflicting

Much of this emerges from such hindrances as small
sample size, a limited number of cytokines surveyed
at one time, insufficient patient population
stratification, and insufficient negative control

This has resulted in inconsistent reports in the
literature for a number of cytokines including
interleukins (IL) 6, 10 and 12.

In spite of these conflicting results, a number of
cytokines and chemokines have consistently been
show to be associated with different subgroups of

For instance, Natelson et al. showed elevated levels
of IL-8 and IL-10 in the cerebral spinal fluid of
patients with sudden, influenza-like onset CFS when
compared to healthy controls (25).

Additionally, Chao et al. have show neopterin and
IL-6 to be up-regulated in subsets of CFS patients,
indicative of a pro-inflammatory immune condition

However, these studies did not analyze the complex
relationships between multiple cytokines and clinical

By applying conventional statistical analysis and
'machine logic' algorithms to the multiplex data, it is
possible to identify cytokines and chemokines that
are differentially expressed between two groups.

To support this premise, we have used the xMap®
multi-analyte profiling technology that allows
simultaneous measurements of multiple biomarkers
in serum or plasma.
In this study, a panel of 26 cytokines, chemokines
and growth and angiogenic factors were analyzed in
blood plasma of CFS patients and healthy control

This study revealed a signature of 10 cytokines and
chemokines, which showed a specificity of 93% and
sensitivity of 96% in diagnosing XMRV-associated
CFS in this patient cohort.

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