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Evidence of Herpes Virus in
Myalgic Encephalomyelitis
Clinical correlates of infection with human herpesvirus-6.
Krueger GR, Klueppelberg U,
Hoffmann A, Ablashi DV.
Immunopathology Section, University of Cologne,
Germany.
In Vivo 1994 Jul-Aug;8(4):457-85
Human herpesvirus-6 is a
lymphotropic virus which infects susceptible individuals during the first year
of life and usually causes life-long latency. In a variable percentage primary
infections are followed by a short acute disease, exanthema subitum. Older
individuals may suffer from infectious mononucleosis-like illnesses or
from Kikuchi-Fujimoto's disease. In addition, there is a fairly wide
spectrum of lymphoid and hematopoietic diseases or autoimmune disorders, which
are associated with elevated titers of HHV-6 antibody, and from which
replicating virus may be isolated. Such diseases include atypical polyclonal
lymphoproliferation, Hodgkin's disease, chronic fatigue syndrome and systemic
lupus erythematosus. The present article reviews the current knowledge of
such associations.
PMID: 7893974 PubMed - indexed Review, Review, Academic
____________________________
Dr Ablashi, an international authority in herpes virology provided further significant evidence of the importance of HHV6 in ME/CFS disease. Along with the leading clinician Dr Peterson and the eminent scientist Prof. Gupta of the University of California and others additional evidence showed the high rate of HHV6 infection in patients. This significant prevalence is consistent with several studies that have shown an association with HHV6.
HHV6
has been the most identified virus to be associated with ME/CFS since the first
major study of the Tahoe outbreak. In that extensive study conducted by some of
the most respected names in medicine, there was indication of HHV6 involvement
in 70% of patients.
This
study (below) also demonstrated significant improvement in patients that
underwent potent antiviral therapy that caused the elimination of the virus.
This
study tells us that antivirals hold great promise for the treatment of ME. The
variability of response also tells us that an antiviral that is specific for
our disease is yet to be identified and much more work is needed to find the
most effective antiviral for our disease.
HHV6
has not been universally found in all patients yet is the most consistently
identified virus in our disease. ME and HerpesVirus are both associated with
encephalitis, demyelination, destruction of NK cells and with the abnormal
RnaseL enzyme.
We
should realize that M.E. is a complex disease and HHV6 is an important and
dangerous part. And may be activating and reactivating along with other
infections and immune factors: urgent and massive investigation is needed.
I
believe we must DEMAND that the health authorities make immediate MAJOR
investment in pursuing the INFECTIONS and their TREATMENT. If we don't make
these demands then who will ?
The
numbers of us with this disease is growing everyday and has risen by more than
2,000.% over the last 20 years.
Quintero
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CHRONIC FATIGUE SYNDROME (CFS): HHV-6
REACTIVATION AND CLINICAL MANIFESTATIONS BEFORE, DURING, AND AFTER
ANTIHERPESVIRUS THERAPY
H. Eastman, M. Roman, C.
Owen, K. Olsen, K. Steininger, D. Peterson, S. Gupta, J. Whitman, and D.
Ablashi
OBJECTIVE: Over the years, many viral agents have been suspected in the etiology of CFS. Recently, HHV-6, a beta herpesvirus, has been reported to be involved in the pathogenesis of CFS. We investigated the active infection of HHV-6 in CFS patients using (1) short-term culture of peripheral blood mononuclear cells (PBMCs), (2) IgM and IgG antibody evaluation in the plasma, and (3) nested PCR on plasma, cerebral spinal fluid (CSF), and PBMCs. We also characterized the HHV-6 isolates obtained as being Variant A or B. Seven CFS patients showing active HHV-6 infection were treated with three different antiherpesvirus compounds (Foscarnet, Ganciclovir, Valciclovir) to see if control of HHV-6 infection would alter the clinical manifestations.
MATERIALS
AND METHODS: Specifically, we studied 24 CFS patients staged according to the
severity of the disease. These patients came from Sierra Internal Medicine,
Incline Village, NV, and the Medical Sciences Division, University of
California at Irvine, Irvine, CA. The immunovirological assays used (i.e., IFA
to detect HHV-6 antigen positive cells or to titer plasma for antibody) have
previously been described (Ablashi et al., J Clin Virol 16:129, 2000). PBMCs
from CFS patients were cultured (14 days) to detect HHV-6 infection using HHV-6
monoclonal antibodies. The modified nested PCR protocol used was based on the
method described by Secchiero el al. (J Clin Microbiol 33:2124, 1997). HHV-6
specific primers against the major capsid protein were used. These primers
generate a 258 bp fragment in the second stage PCR. DNA was isolated from
PBMCs, plasma, and CSF samples using QIAgen columns.
RESULTS: 1.
HHV-6 infection was detected in 14/24 (58.3%) of the CFS patients by the
methods described. HHV-6 infection was detected in the PBMCs in short-term
culture as early as three days, using IFA and HHV-6 early (p41) and late (gpl
16) monoclonal antibodies. The number of infected PBMCs varied from patient to
patient. 2. IgM antibody to
HHV-6 detected by IFA ranged from 1:20 to >1:160, and the IgG titer ranged
from 1:80 to 1:1280. The presence of HHV-6 IgM antibody correlated well with
the presence of HHV-6 in the PBMCs in 85% of the samples studied. 3. Nested PCR detected HHV-6 DNA in
15% of the plasmas and 25% of the CSF from the CFS patients. 4. Approximately 70% of the HHV-6
isolates from CFS patients were Variant A.
5. Out of the seven patients treated with antiviral compounds,
the patient treated with Foscarnet clinically improved, and no HHV-6 infection
was detectable. Of the four patients treated with Ganciclovir, only one showed
slight clinical improvement. However, HHV-6 infection could be detected in the
PBMCs of this patient. Of the two patients treated with Valciclovir, one
improved clinically with no HHV-6 infection detectable. The second patient
remained HHV-6 negative without any clinical improvement.
CONCLUSION: 1.
The data presented, although preliminary, show that the majority of CFS
patients studied have HHV-6 infection. 2.
It was surprising to find CFS patients exhibiting HHV-6 DNA in the CSF or
plasma as well as in HCBMCs infected with CSF from these patients. These data
suggest the presence of cell-free infectious virus in the CSF. In CFS, it is
possible that HHV-6 is invading the central nervous system and may participate
in the neurological manifestations associated with this disease. 3. Seventy percent of the HHV-6
isolates from CFS patients were classified as Variant A, which is more
neuro-tropic. 4. Potent
antiviral agents, such as Foscarnet and Valciclovir, are useful in suppressing
HHV-6, thereby resulting in improved patient condition. However, longitudinal
studies of more patients with CFS using newer antiviral agents which are less
toxic are required to determine what specific role HHV-6 infection plays in the
pathogenesis of this disease.
- - - - - - - - - - - - - -
Just a few of the Important Research reports on
ME/CFS and HHV6 see:
A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection.
Buchwald D, Cheney P, Peterson D, Henry B, Wormsley S, Geiger A, Ablashi D, Salahuddin S, Saxinger C, Biddle R, Kikinis R, Jolesz F, Folks T, Balachandran N, Peter J, Gallo R, Komaroff A,: Boston, Ma. USA
Ann Intern Med 1992 Jan 15;116(2):103-13
Symptoms, signs and laboratory findings in patients with chronic fatigue syndrome.
Kuratsune H, Yamaguti K, Hattori H, Tazawa H, Takahashi M, Yamanishi K, Kitani T., Osaka University. Japan
Nippon Rinsho 1992 Nov;50(11):2665-72
Infection of natural killer cells by human herpesvirus 6.
Lusso P, Malnati M, Garzino-Demo A, Crowley R, Long E, Gallo R. National Institutes of Health, Bethesda, Md. USA
Nature 1993 Apr 1;362(6419):458-62
Chronic fatigue syndrome: immune dysfunction, role of pathogens and toxic agents and neurological and cardial changes.
Hilgers A, Frank J , Dusseldorf, Germany
Wien Med Wochenschr 1994;144(16):399-406
Prevalence of IgM antibodies to human herpesvirus 6 early antigen (p41/38) in patients with chronic fatigue syndrome.
Patnaik M, Komaroff A , Conley E, Ojo-Amaize E, Peter J; Specialty Laboratories, Inc.: California, USA.
J Infect Dis 1995 Nov; 172(5):1364-7
Persistent active HHV-6 infections in patients with CFS.
Knox K, Brewer J and Carrigan D,
Fourth International AACFS Conference. Boston, MA. October, 1998.
Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients.
Ablashi D, Eastman H, Owen C, Roman M, Friedman J, Zabriskie J, Peterson D, Pearson G, Whitman J. Georgetown University, Washington, DC, USA.
J Clin Virol 2000 May;16(3):179-91
Evidence of Active HHV-6 Infection and Its Correlation with RNase L Low Molecular Weight Protein (37 KDa) in CFS Patients.
D. Ablashi, M. Roman, C. Owen, S. Gupta, C. Herst, D. Peterson, S. Levine, R. Harris, P. Frank, W. Philip, and J. Whitman; Advanced Biotechnologies Inc, Columbia, MD, USA: University of California, Irvine, CA, USA: R.E.D. Laboratories, Belgium: Sierra Internal Med, Incline Village, NV, USA : CFS Clinic, New York, NY, USA: CBI, Richmond, VA, USA: Vigen Laboratories, Wilmette, IL, USA
Third International M.E./CFS Research Conference Sydney Australia, Dec. 2001
Selective Reactivation of Human Herpesvirus
6 Variant A, Occurs in Critically Ill Immunocompetent Hosts.
Razonable R, Fanning C, Brown R, Espy M, Rivero A, Wilson J, Kremers W, Smith T, Paya C. Mayo Clinic Rochester, Minnesota
The Journal of Infectious Diseases 2002;185:110-113
---------------------------------
See ME Help Circle, 4 maart 2002
"HHV6 most Prevalent virus in ME/CFS patients"
__________________________________________
A chronic immune disease ?
Lusso the eminent herpes virus expert uncovers a new
mechanism of persistent immune suppression by herpes virus without apparent
active replication.
ME is a complex infectious neurological-immune- metabolic disease. The
final answers will be complex and require much new knowledge as is evident from
this report that shows us another novel piece. As well as demonstrating how
little we know.
Quintero
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Selective suppression of
IL-12 production by human herpesvirus 6.
Smith A, Santoro F, Di Lullo
G, Dagna L, Verani A, Lusso P.
Unit of Human Virology, DIBIT-San Raffaele Scientific Institute, Via Olgettina n 58, Milan 20132, Italy. paolo.lusso@hsr.it
Blood. 2003 Oct 15;102(8):2877-84.
Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that has been suggested to act as a cofactor in the progression of HIV disease. Exposure of human macrophages to HHV-6A or HHV-6B profoundly impaired their ability to produce interleukin 12 (IL-12) upon stimulation with interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS).
By contrast, the production of tumor necrosis
factor-alpha (TNF-alpha); regulated on activation, normal T-cell expressed and
secreted (RANTES); and macrophage inflammatory protein 1beta (MIP-1beta) was
not negatively affected. To exclude the involvement of IL-12-suppressive
cytokines, such as IL-10 and TNF-alpha, the viral stocks were fractionated by
ultra- centrifugation. The bulk of the suppressive activity was
recovered
within the virion-rich pelleted fraction that was virtually devoid of such
cytokines. IL-12 suppression was independent of viral replication, and the
effect was not abrogated upon ultraviolet-light inactivation of the viral
inoculum. The mechanism of HHV-6-mediated IL-12 suppression was investigated by
RNase protection assays, which demonstrated unaltered levels of IL-12 p35 mRNA
and only a modest reduction in p40 mRNA, which was insufficient to account for
the near-complete loss of both extracellular and intracellular IL-12 protein.
Moreover, both the IFN-gamma and the LPS signaling pathways were intact in
HHV-6-treated cells. These data suggest that HHV-6 can dramatically affect
the generation of effective cellular immune responses, providing a novel
potential mechanism of HHV-6-mediated immunosuppression.
PMID: 12829600
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_u=ids=12829600&dopt=Abstract
______________________________
Myalgic encephalomyelitis has become a
major worldwide epidemic in a short span of time. It is clear a massive
scientific effort will be necessary to unravel the complex science, and to undo
the massive destruction worldwide by the government propaganda and their efforts
to cover-up the infectious, contagious and epidemic nature of this
disease. This program of propaganda has
systematically contributed to the deaths of thousands of patients, and will
continue to fuel the millions of new cases that will become infected with the
Myalgic Encephalomyelitis contagion.
A central part of this cover-up
program has been to even deny the existence of the epidemic, or the identity of
this disease. Since 1988 the CDC has
promoted a massive program of false and misleading information upon the public.
Including the misleading information obscuring the viral cause of Myalgic
Encephalomyelitis, by suggesting that all these dedicated and highly respected
scientists from all over the world and their numerous, extensive and repeated
studies are wrong and that the CDC claims must be believed.
It is time for
patients to band together and Expose the Lies and Save Lives.
Quintero
The Paul-Bunnell Heterophile
Antibody Determinant in Epstein-Barr Virus-Associated Disease
Roberto
Patarca-Montero, MD, PhD and Mary Ann Fletcher, PhD
Journal of Chronic Fatigue Syndrome, Vol. 10 (3/4)
2002, pp. 51-86
ABSTRACT.
Reactivation of latent herpes
viruses (notably Epstein-Barr virus, human herpesvirus-6) is commonly seen in
chronic fatigue syndrome and it is believed to contribute to symptom
perpetuation. Epstein-Barr virus (EBV), which was fIrst isolated by Epstein,
Barr and Achong (1964) from a cultured Burkitt's lymphoma lymphoblast cell
line, is the etiological agent for infectious mononucleosis (IM), polyclonal and
oligoclonal lymphomas associated with primary and acquired immunodeficiencies,
and the complications of X-linked lymphoproliferative syndrome (XLP) (Cantani and Mastrantoni, 1989; Englund, 1988; Ernberg
et al., 1990; Jones and Straus, 1987; Okano et a1., 1988; Purtilo, 1987; Purtilo
et al., 1981; Rowe et al., 1986; Saemundsen et al., 1981) and nasopharyngeal
cancer (Pearson et al., 1984).
Furthermore, people who have had IM have higher rates of subsequent development
of malignant lymphoproliferative disorders (Abo
et al., 1982; Snydman et al., 1982) and Hodgkin's disease (Green et al., 1979; Mueller, 1987; Poppema et al.,
1985; Weiss et al., 1989), while patients with XLP have a higher
incidence of non-Hodgkin's malignant lymphoma (Harrington
et al., 1987). The precise role of EBV in these diseases or in CFS is
not well understood. Nonetheless, it is known that EBV infection triggers the
formation of heterophile antibodies that, for many decades, have formed the
basis for serologic diagnosis of IM. In this review, we discuss the discovery,
species variation, and structure of the erythrocyte membrane-associated
Paul-Bunnell (PB) heterophile antibody determinant, its implications to IM
diagnosis, and its potential contribution to defective immune surveillance,
such as that seen in chronic fatigue syndrome.
KEYWORDS.
Epstein-Barr virus, chronic fatigue syndrome, infectious mononucleosis, T-cell
proliferation, Hodgkin's disease
HERPESVIRUSES AND CHRONIC FATIGUE SYNDROME
Herpesviruses (Epstein-Barr virus, cytomegalovirus,
human herpes virus types 6 and 7, herpes simplex virus types 1 and 2) have been
associated with chronic fatigue syndrome (CFS). For instance, reactivation/replication
of a latent herpesvirus (such as Epstein-Barr virus) could modulate the immune
system to induce CFS (Glaser and Kiecolt-Glaser, 1998). In this respect,
serologically proven acute infectious illness due to Epstein-Barr virus (EBV)
is associated with a range of nonspecific somatic and psychological symptoms,
particularly fatigue and malaise rather than anxiety and depression (Bennett et
al., 1998). Although improvement in several symptoms occurs rapidly, fatigue
commonly remains a prominent complaint at 4 weeks, and resolution of fatigue is
associated with improvement in cell-mediated immunity. A prospective cohort
study of 250 primary care patients also revealed a higher incidence and longer duration
of an acute fatigue syndrome, and a higher prevalence of CFS, after glandular
fever as compared to after an ordinary upper respiratory tract infection (White
et al., 1998). In another study, anti-EBV titers were higher among CFS patients
and were associated with being more symptomatic (Schmaling et al., 1996).
However, testing of 548 chronically fatigued, including patients with CFS, for antibodies
to 13 viruses (herpes simplex virus 1 and 2, rubella, adenovirus, human
herpesvirus 6, Epstein-Barr virus, cytomegalo-virus, and Coxsackie B virus, types
1-6 in patients) found no consistent differences in any of the seroprevalences
compared with controls (Buchwald et al., 1996).
Cloned DNA obtained from the culture of an African
green monkey simian cytomegalovirus-derived stealth virus contains multiple discrete
regions of significant sequence homology to portions of known human cellular
genes (Martin, 1998). The stealth virus has also been cultured from several CFS
patients and a cytopathic stealth virus was also cultured from the cerebrospinal
fluid of a nurse with CFS. The findings lend support to the possibility of
replicative RNA forms of certain stealth viruses (Martin, 1997). Review of the clinical
histories and brain biopsy findings of 3 patients with severe stealth virus
encephalopathy showed that the patients initially developed symptoms consistent
with CFS (Martin, 1996a). One patient has remained in a vegetative state for
several years, while the other two patients have shown significant, although
incomplete, recovery. Histological and electron-microscopic studies revealed vacuolated
cells with distorted nuclei and various cytoplasmic inclusions suggestive of
incomplete viral expression. There was no significant inflammatory response. Viral
cultures provided further evidence of stealth viral infections occurring in
these patients (Martin, 1996a). Partial sequencing of a stealth virus segments isolated
from a CFS patient revealed a fragmented genome and sequence microheterogeneity,
which suggest that both the processivity and the fidelity of replication of the
viral genome are defective (Martin, 1996b). An unstable viral genome may provide
a potential mechanism of recovery from stealth viral illness.
Some studies suggest an association between human
herpesvirus-6 (HHV -6) (Roseolovirus genus of the betaherpesvirus subfamily)
and CFS (Braun et al., 1997; Cuende et al., 1997; Marsh et al., 1996; Tripathy
et al., 1996). One study found that a high proportion (50% by antibody testing
and up to 80% by nested-PCR detection of viral DNA but not RNA) of CFS patients
were infected with HHV-6 but with low viral load. The latter results do not
support HHV-6 reactivation in CFS patients (Cuende et al., 1997). Use of the
supernatant fluid from HHV-7 infected cells as antigen in immunoassays yielded
high and low HHV-7 antibody in sera from chronic fatigue patients and healthy donors
as controls, respectively (Ablashi et al., 1998).
Transfer
factors (TF) with specific activity against herpesviruses have been documented
in CFS. With some studies suggesting that persistent viral activity may play a
role in perpetuation of CFS symptoms, there appears to be a rationale for the
use of TF in patients with CFS, and recent reports have suggested that transfer
factor may play a beneficial role in this disorder (Ablashi et al., 1996; De
Vinci et al., 1996; Hana et al., 1996; Levine, 1996). For instance, specific
HHV-6 TF preparation, administered to two CFS patients, inhibited the HHV-6
infection (Ab1ashi et al., 1996). Prior to treatment, both patients exhibited
an activated HHV-6 infection. TF treatment significantly improved the clinical
manifestations of CFS in one patient who resumed normal duties within weeks,
whereas no clinical improvement was observed in the second patient. Of the 20 patients
in a placebo-controlled trial of oral TF, improvement was observed in 12
patients, generally within 3-6 weeks of beginning treatment (De Vinci et al.,
1996). However, in this study herpes virus serology (EBV and HHV-6) seldom
correlated with clinical response. Treatment with TF of a group of 222 patients
suffering from cellular immunodeficiency (CID), frequently combined with CFS
and/or chronic viral infections by EBV and/or CMV, showed that age but not gender
substantially influenced the failure rate of CID treatment using TF (Hana et
al., 1996). In older people, it is easier to improve the clinical condition
than CID: this may be related to the diminished number of lymphocytes; however,
a placebo effect cannot be totally excluded.
---
Roberto Patarca-Montero is Co-Director of the E.M. Papper
Laboratory of Clinical Immunology and Molecular Biology and Assistant Professor
of Microbiology and Immunology. University of Miami School of Medicine.
Mary Ann Fletcher is Director of the E.M. Papper Laboratory
of Clinical Immunology and Molecular Biology and Professor of Medicine, Microbiology
and Immunology, and Psychology, University of Miami.
Address correspondence to: Mary Ann Fletcher, E.M. Papper
Laboratory of Clinical Immunology, Departments of Medicine. and Microbiology
and Immunology, University of Miami School of Medicine, P.O. Box 016960 (R-42),
Miami, FL 33101.
(c)2002 by The Haworth Press, Inc. All
rights reserved.
Journal of Chronic Fatigue Syndrome, Vol. 10 (3/4) 2002, pp.
51-86
The above is an excerpt,
the Complete article are available
for a fee from The Haworth Document Delivery Service: 1-800-HAWORTH. E-mail address: mailto:getinfo@haworthpressinc.com
Website: http://www.haworthpressinc.com/store/product.asp?sku=J092
]
Posted November 2002
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See
these reports -
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