| Human Herpesvirus 6 (HHV-6) and Chronic Fatigue Syndrome
Human Herpesvirus 6 (HHV-6) is one of eight known members of the human
herpesvirus family. The virus, which was discovered in 1986 at the NCI,
infects cells of the immune and central nervous system.
Serologic testing demonstrates that more than 95% of the worlds population
is positive for antibodies to HHV-6, indication an immune response to
infection by the virus. After initial infection, HHV-6 viral DNA remains
latent within the cell nuclei in blood and other body tissue.
Two variants of HHV-6 are recognized: HHV-6A and HHV-6B. Primary infection
with HHV-6B causes roseola in children and more than 95% of the population
has antibodies to this variant. Primary infection with HHV-6A is believed
to occur late childhood or adulthood and may occur without symptoms. The A
strain is much more pathogenic and attacks the brain and immune system. The
prevalence of HHV-6A infection is not known.
HHV6-A reactivation in adulthood can result in illness. Normally,
reactivations are kept in check by the immune system and the virus resumes
latency. Reactivation in adults has been associated with mononucleosis
syndrome, autoimmune disorders, and nervous system diseases. HHV-6 has been
specifically linked to MS, AIDS and CFS.
In individuals whose immune system has been compromised by disease (AIDS)
or medical treatments (chemotherapy or immunosupressive drugs), a
reactivation of HHV-6 can result in suppression of bone marrow function or
inflammation and cause damage in tissues such as brain, liver, or lungs.
Recent studies have revealed active HHV-6 infections in single random blood
samples taken from MS patients (54% positive) and CFS patients (39%
positive). After testing a second sample from patients who were negative,
24% tested positive for active infection. Results showed that on average
these samples were positive 50% of the time. This suggests that active
infection of HHV-6 may be intermittent, with the viral load changing over
time.
Normal healthy controls were negative for active HHV-6. This demonstrates
that active HHV-6 infections are abnormal and not found in healthy people
without disease associations.
Dr. Ablashi found that 70% of the HHV-6 isolates from patients were variant
A, which is more neurotropic. He found that CFS patients exhibited HHV-6
DNA in the cerebrospinal fluid (CSF) and was able to infect cord blood
cells with CSF from these patients. He concluded that HHV-6 may well
account for the neurological manifestations in CFS patients.
In addition there is a wide spectrum of lymphoid, hematopoetic and
autoimmune diseases which are associated with elevated titers of HHV-6,
from which replicating virus has been isolated. Such diseases include
atypical polyclonal lymphoproliferation, Hodgkin's disease, CFS and
systemic lupus erythematosis.
Contrary to the findings of the CDC, HHV-6 can account for many of the
clinical symptoms of CFS. The problem with the CDC testing, says Knox and
Cartrigan, is that "it tested both patient and control groups using serum
samples, lymphocytes and three PCR methods." These are not adequate means
of detecting active HHV-6 infection.
The ability of HHV-6 to induce high level production of proinflammatory
cytokines, combined with its frequent infection of the brain and spinal
cord and its ability to infect and destroy all types of lymphocytes
(including NK cells whose function is known to be impaired in CFS patients)
can account for a range of clinical abnormalities that define CFS.
Whether or not these agents are causative, many studies have suggested that
persistent viral activity plays a role in the perpetuation of symptoms. The
good news is that the possibility exists that CFS may be effectively
treated with currently available anti-viral medications. Longitudinal
studies of antivirals are required to determine precisely what role HHV-6
infection plays in the pathogenesis of the disease.
Jill McLaughlin
Executive Director
National CFIDS Foundation, Inc.
Needham, MA 02492
References
Salahuddin, SZ et al. Isolation of a new virus, HBLV, in patients with
lynphoproliferative disorders. Science 1986; 234:596-601.
Ablashi D., et al. Human Herpesvirus 6 strain groups: A nomenclature. Arch
Virology 1993; 129: 363-366.
Krueger GR, et al, Clinical correlates of infection with human herpesvirus
6. In Vivo 1994; 8: 457-485.
Singh N and Carrigan DR, Human Herpesvirus 6 in transplantation: An
emerging pathogen. Ann Internal Med 1996; 124: 1065-1071
Lusso P. Human herpesvirus 6 (HHV-6). Antiviral Res 1996 Jun;31(1-2):1-21.
Braun DK, Dominiguez G and Pellet PE, Human Herpesvirus 6. Clinical
Microbiology Rev 1997;10:521-567.
Knox KK, Brewer JH and Carrigan DR, Persistent active HHV-6 infections in
patients with CFS. Fourth Internationsal AACFS Conference. Boston, MA.
October, 1998.
Ablashi D, Testing and clinical manifestation of HHV-6 in CFS. Fifth
Intenational AACFS Conference. Seattle, Washington, 2001
Reeves WC, et al, Human herpesvirus 6 and 7 in chronic fatigue syndrome: A
case-control study. Clinical Infectious Diseases 2000; 31:48-52.
Chronic Fatigue Syndrome and Herpesviruses: the Fading Evidence.
Journal: Herpes 2000 May;7(2):46-50
Authors: Soto NE, Straus SE.
Affiliation: National Institute of Allergy and Infectious Disease,
National Institutes of Health, Bethesda, Maryland, USA.
NLM Citation: PMID: 11867001
Herpesviruses, in particular Epstein-Barr virus (EBV), cytomegalovirus
(CMV) and human herpesvirus 6 (HHV-6), have, for the past two decades,
come under considerable scrutiny as aetiological agents of chronic
fatigue syndrome (CFS).
However, virological findings of herpesviruses in CFS have not been
consistent between different studies, and the unusual patterns of
serological responses to EBV, CMV and HHV-6 have not been specific for
CFS, being observed also in asymptomatic individuals.
In addition, patients with symptomatology suggestive of CFS do not appear
to have an increased frequency of these herpesviruses, as detected by
culture or polymerase chain reaction, compared with controls, which
argues against an ongoing active herpetic infection.
Studies have also shown that the presumable elevation of antibody titres
to EBV, CMV or HHV-6 in CFS are not observed only with these viruses, but
also with other organisms such as herpes simplex virus and measles.
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. AACFS - 5th International
Research Conference, at Seattle, Washington 2001
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