High Prevalence of
Active Human Herpesvirus Six Variant A Infection in CNS and Lymphoid Tissue of
Patients with MS
Konstance K. Knox, Ph.D. and Donald R. Carrigan, Ph.D.
Institute for Viral Pathogenesis, 10437 Innovation Drive, Milwaukee, Wisconsin
53226
Presented at the 125th Annual Meeting of
the American Neurological Association
October 16, 2000
Boston, Massachusetts
Abstract
Studies
by our laboratory have documented that the majority of patients with MS have
active HHV-6 infections in their CNS and lymphoid tissues. There are two
distinct variants of HHV-6, HHV-6A and HHV-6B, that differ in their biologic and
pathogenic properties. In these studies, we utilized variant specific monoclonal
antibodies to detect the active HHV-6 infections. Of the 8 patients whose CNS
tissues contained cells actively infected with HHV-6, 4 had infections with both
HHV-6A and HHV-6B, 2 had only HHV-6A infected cells present, and 2 had only
HHV-6B infected cells in their tissues. Three (50%) of the 6 patients with
active infection of their lymphoid tissues were positive for both HHV-6A and
HHV-6B. One patient’s lymphoid tissue contained only HHV-6A, and two
patients’ tissues contained only HHV-6B. These relatively high rates of HHV-6A
infection in patients with MS, i.e. 75% and 67% in CNS and lymphoid tissues,
respectively, stand in contrast to the low rates ( < 20%) of HHV-6A detection
in normal individuals and immunocompromised patients. Thus, HHV-6A may play a
special role in the pathogenesis of MS.
Introduction
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HHV-6
is perhaps the most neuroinvasive member of the human herpesvirus family.
-
Work
from our laboratory (Knox et al.; Clin Infect Dis 2000; in press) has
documented that most patients with MS have active HHV-6 infections in
CNS, peripheral lymphoid tissues, and peripheral blood.
-
Within
the CNS the HHV-6 infected cells are found in areas of active
demyelinative disease.
-
HHV-6
viremia significantly correlates with clinical disease relapses in patients
with relapsing remitting MS (LJ Lobeck et al.; submitted)
-
The
term HHV-6 actually encompasses two distinct variants of the virus,
designated the A (HHV-6A) and B (HHV-6B) variants (table below).
-
Results
presented here suggest that HHV-6A may play a special role in MS.
Patients and
methods
Click
thumbnail to view larger version of figure.
Patients
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Paraffin
blocks of CNS tissues obtained at autopsy from patients with definite MS
were obtained from the Rocky Mountain MS Center in Englewood, Colorado.
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Paraffin
blocks of lymph node tissues from patients with definitive MS were obtained
from Dr. Steve Jacobson of the NIH and from the Armed Forces Institute of
Pathology.
-
Consecutive
serial sections of these tissues were immunohistochemically stained with
monoclonal antibodies specific for HHV-6A and HHV-6B.
Estimation of
the Prevalence of HHV-6A infection in Adults
-
The
prevalence of HHV-6A infection is unknown since serological tests cannot
distinguish between HHV-6A and HHV-6B. HHV-6B is ubiquitous.
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A
search of the Medline data base for the MESH term "herpesvirus six,
human" and for the word "variant" was performed.
-
Fifty-four
articles in peer-reviewed journals were identified in which HHV-6 DNA was
detected in a patient specimen and the viral variant was identified.
Results
Prevalence
of HHV-6A DNA in Specimens from Normal Controls and Various Patient Populations
Click
thumbnail to view larger version of figure.
Figure
1: The prevalence of HHV-6A DNA is significantly higher in normal adults
compared to normal children.
Click
thumbnail to view larger version of figure.
Figure
2: The prevalence of HHV-6A DNA is less than 30% in all patient groups and less
than 20% in normal controls
Prevalence
of Active HHV-6A infections in the CNS and Lymphoid Tissues of Patients with
MS
Click
thumbnail to view larger version of figure.
Figure
3: 75% (6/8) of the MS patients studied had active HHV-6A infections within
their CNS tissues
Click
thumbnail to view larger version of figure.
Figure 4: Of actively infected CNS tissue sections from these patients, 60% (12/20) of the active infections involved HHV-6A.
Click
thumbnail to view larger version of figure.
Figure 5: HHV-6 A infections were involved in 67% (4/6) of the lymphoid tissue infections present
Conclusions
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Infection
with HHV-6A is over-represented in the CNS and lymphoid tissues in patients
with MS.
-
The
natural history of HHV-6A is poorly understood, but it is likely that it is
acquired later in life than HHV-6B.
-
Unlike
HHV-6B, HHV-6A is only rarely present in saliva making other routes of
transmission, e.g. sexual, likely.
-
The
acquisition of HHV-6A in late adolescence or early adulthood could help to
explain several epidemiological features of MS.
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HHV-6A
is more neurotropic than HHV-6B (CB Hall et al.; Clin Infect Dis 1998;
26:132-137).
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HHV-6A
can productively infect numerous cell types including hematopoietic and
glioblastoma cells, human astrocytes and human diploid fibroblasts. The host
range of HHV-6B is more limited and is largely restricted to human T
lymphocytes.
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HHV-6A
is more destructive of the cells that it infects than is HHV-6B.
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Involvement
of HHV-6A in the pathogenesis of MS may allow productive infection of a
wider variety of CNS cell types and a more destructive infection process
than if HHV-6B infection alone was present.
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TNFa
has been proposed as a mediator of demyelination in MS, TNFa producing
cells have been identified in MS lesions and the expression of TNFa by
blood mononuclear cells in patients with MS correlates with disease
activity. HHV-6A is a powerful inducer of TNFa production in blood
mononuclear and bone marrow cells, a property that is not shared by other
members of the herpesvirus family, including HHV-6B.
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