Emerging Infectious Disease Agents/XMRV/Transfusions

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Xenotropic murine leukemia virus-related
virus (XMRV)
Disease Agent:
• Xenotropic murine leukemia virus-related virus (XMRV)

Disease Agent Characteristics:

• Family: Retroviridae; Subfamily: Orthoretrovirinae; Genus:
Gammaretrovirus; Species: Xenotropic murine leukemia
virus-related virus (XMRV)
• Virion morphology and size: Virions have a complex construction
and consist of an envelope, a nucleocapsid, and a
nucleoid. Virions are spherical to pleomorphic measuring
80-100 nm in diameter. Virions have a buoyant density in
sucrose of 1.15-1.17 g cm
-3.
• Nucleic acid: The genome is a dimer of linear, positivesense,
single-stranded RNA, 8300 nucleotides long.
• Physicochemical properties: As enveloped retroviruses, the
virions should be susceptible to heat, detergents and many
disinfectants such as 1% sodium hypochlorite, 2% glutaraldehyde,
formaldehyde and ethanol.

Disease Name:

• Evidence of association, but not causation, has been
reported for XMRV infection with the following conditions:
Prostate cancer
Chronic Fatigue Syndrome (CFS)

Priority Level:

• Scientific/Epidemiologic evidence regarding blood safety:
Theoretical; although pathogenic retroviruses (i.e., HIV and
HTLV) are clearly transfusion transmitted, such transmission
of XMRV has been neither demonstrated nor alleged.
There are no data suggesting an association of prostate
cancer or CFS with transfusion.
• Public perception and/or regulatory concern regarding
blood safety: Moderate based on the characteristics of other
retroviruses and the early stage of investigations of the clinical
associations of human infection with this agent. Concern
has been publicly expressed regarding transfusion transmission
of XMRV following publication of data associating it
with CFS.
• Public concern regarding disease agent: Low at least partly
based on lack of familiarity with a virus only very recently
associated with any prevalent human disease; however, may
be higher in groups with diseases associated with XMRV.

Background:

• A diverse range of mammalian species is susceptible to infection
by gammaretroviruses. These are simple retroviruses
whose genomes encode only
gag, pro, pol, and env genes.
They include murine leukemia virus, feline leukemia virus,
koala retrovirus, and gibbon ape leukemia virus that cause
leukemia and other syndromes in their host species.
• Evidence of human infection with gammaretroviruses was
lacking until 2006 when genomes of a previously undescribed
gammaretrovirus, XMRV, were detected in a cohort
of US men with a familial aggregation of an aggressive form
of prostate cancer. The hypothesis was that these men, who
harbored a homozygous mutation of the antiviral enzyme
RNase L, were unusually susceptible to the oncogenic potential
of the virus. However, in a subsequent study, XMRV DNA
or proteins were found in 6 and 23%, respectively, of malignant
prostates irrespective of the RNase polymorphism.
Studies in a German cohort did not detect XMRV infection
in nearly 600 prostate cancer samples.
• In 2009, a statistical association of XMRV infection with CFS
was reported. Peripheral blood mononuclear cells (PBMC)
from 67% of stringently defined CFS patients contained the
proviral DNA of XMRV compared to 3.7% of healthy controls.
These patients did not have the RNase L polymorphism
mentioned above. Secondary infections in tissue
culture could be established from PBMCs, B and T cells and
plasma of patients. The study concluded, “(T)hese findings
raise the possibility that XMRV may be a contributing factor
in the pathogenesis of CFS.”
• Whether the association of XMRV infection with these syndromes
is causal or is confounded by factors like geographic
variability of the prevalence of the virus or the presence of
unusual susceptibility to viral infection in the clinical cohorts
studied is unknown. Published studies lack a complete
description about selection of the CFS patient and control
cohorts.

Common Human Exposure Routes:

• Unknown

Likelihood of Secondary Transmission:

• Unknown

At-Risk Populations:

• Unknown

Vector and Reservoir Involved:

• Unknown

Blood Phase:

• A perspective accompanying the original CFS study concluded
“(G)iven that infectious virus is present in
plasma and in blood cells, blood-borne transmission is a
possibility.”

Survival/Persistence in Blood Products:

• Unknown

Transmission by Blood Transfusion:

• Unknown

Cases/Frequency in Population:

• In the CFS study referred to above, 3.7% of healthy controls
harbored viral DNA sequences in PBMCs; however, the
expression pattern of viral genes in the infected controls
appeared to differ from those among the CFS population so
the relevance of the observation must be explored.

Incubation Period:

• Unknown

Likelihood of Clinical Disease:

• Unknown

Primary Disease Symptoms:

• If causal relationships are confirmed, symptoms will be
those of the associated diseases.
Many prostate cancers are asymptomatic, but symptoms
of urinary obstruction and metastatic spread
occur with advancing disease.
CFS (also called, more descriptively, myalgic encephalitis)
is characterized by persistent or recurrent fatigue,
diffuse musculoskeletal pain, sleep disturbances, and
subjective cognitive impairment of 6 months duration
or longer. Symptoms are not caused by ongoing exertion,
are not relieved by rest, and result in a substantial
reduction of previous levels of occupational, educational,
social, or personal activities. Alterations of
immune, neuroendocrine, and autonomic function
may be associated with this syndrome, but none
is diagnostic. There is considerable overlap between
this condition, fibromyalgia, and some affective
disorders.

Severity of Clinical Disease:

• The original cohort of prostate cancer patients harboring the
homozygous mutation in the RNase L gene had aggressive
prostate cancer. The strength of this association will require
more investigation.
• CFS produces very significant disability with substantial disruption
of activities of daily living among those meeting
strict case definitions.

Mortality:

• Unknown, but XMRV has been associated with a more
aggressive form of prostate cancer in one study that awaits
Confirmation

Chronic Carriage:

• Chronicity is a feature of the Retroviridae family

Treatment Available/Efficacious:

• Unknown.

Agent Specific Screening Question(s):

• No specific question is in use for blood donors and is not
indicated because transfusion transmission has not been
demonstrated.
• No sensitive or specific question is feasible.
The high apparent prevalence of infection reported in
healthy control subjects and the high prevalence of
chronic fatigue in the population are expected to make
donor history screening unreliable.
The rate at which potential donors carrying a criteriabased
diagnosis of CFS present to donor centers is
unknown, but probably low in light of the associated
disability.

Laboratory Test(s) Available:

• No FDA-licensed blood donor-screening test exists.
• Standards for the diagnosis of XMRV infection have not been
established.
• Research assays include PCR, cell culture, flow cytometrybased
immunoassay, and immunohistochemical analyses.

Currently Recommended Donor Deferral Period:

• No FDA Guidance or AABB Standard exists for blood
donors.
• Current practice is to accept donors who are healthy at the
time of donation.
• Pending the availability of further data, prudent practice
would be indefinite deferral of donors who have received a
diagnosis of XMRV infection.

Impact on Blood Availability:

• Agent-specific screening question(s): Not applicable
• Laboratory test(s) available: Not applicable

Impact on Blood Safety:

• Agent-specific screening question(s): Not applicable
• Laboratory test(s) available: Not applicable

Leukoreduction Efficacy:

• The initial studies in CFS suggest there is plasma viremia, so
leukoreduction is unlikely to be completely effective.

Pathogen Reduction Efficacy for Plasma Derivatives:

No specific data are available but presumed to be robust as the
agent is an enveloped virus that should be sensitive to many
measures used in the fractionation process.

Other Prevention Measures:

• Unknown

Suggested Reading:

1. Coffin JM and Stoye J P. Perspectives: A new virus for old
diseases? Science. 2009;326:530-1.
2. Dong B, Kim S, Hong S, Das Gupta J, Malathi K, Klein EA,
Ganem D, Derisi JL, Chow SA, Silverman RH. An infectious
retrovirus susceptible to an IFN antiviral pathway from
human prostate tumors. Proc Natl Acad Sci U S A. 2007;104:
1655-60.
3. Fischer N, Hellwinkel O, Schulz C, Chun FK, Huland H, Aepfelbacher
M, Schlomm T. Prevalence of human gammaretrovirus
XMRV in sporadic prostate cancer. J Clin Virol.
2008;43:277-83.
4. Hohn O, Krause H, Barbarotto P, Niederstadt L, Beimforde
N, Denner J, Miller K, Kurth R, Bannert N. Lack of evidence
for xenotropic murine leukemia virus-related virus (XMRV)
in German prostate cancer patients. Retrovirology. 2009;
6:92.
5. Hong S, Klein EA, Das Gupta J, Hanke K, Weight CJ,
Nguyen C, Gaughan C, KimKA, Bannert N, Kirchhoff F,
Munch J, Silverman RH. Fibrils of prostatic acid phosphatase
fragments boost infections with XMRV (xenotropic
murine leukemia virus-related virus), a human retrovirus
associated with prostate cancer. J Virol. 2009;83:6995-
7003.
6. Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R,
Howlader N, Altekruse SF, Feuer EJ, Huang L, Mariotto A,
Miller BA, Lewis DR, Eisner MP, Stinchcomb DG, Edwards
BK (eds).
SEER Cancer Statistics Review, 1975-2006, National
Cancer Institute. Bethesda, MD. http://seer.cancer.gov/
csr/1975_2006/. Accessed November 5, 2009.
7. Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen
KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C,
Gold B, Dean M, Silverman RH, Mikovits JA. Detection of an
infectious retrovirus, XMRV, in blood cells of patients with
chronic fatigue syndrome. Science 2009;326:585-9.
8. Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR.
XMRV is present in malignant prostatic epithelium and is
associated with prostate cancer, especially high-grade
tumors. Proc Natl Acad Sci U S A. 2009;106:16351-6
9. Silverman RH. A scientific journey through the 2-5A/RNase
L system. Cytokine Growth Factor Rev. 2007;18:381-8.
10. Smith WR, Noonan C, Buchwald D. Mortality in a cohort
of chronically fatigued patients. Psychol Med. 2006;36:
1301-6.
11. The Universal Virus Database, v3. http://www.ncbi.nlm.nih.
gov/ICTVdb. Accessed November 4, 2009.
12. Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G,
Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D,
Silverman RH, DeRisi JL. Identification of a novel gammaretrovirus
in prostate tumors of patients homozygous for
R462Q RNASEL variant. PLoS Pathog. 2006;2:e25.