Yeah, right; most folks are unaware of these things further posted
here.
Herpes virus can be a serious problem in certain individuals.
Defining the herpes virus as "nothing serious", in my personal opinion
is a big error.

Depending upon certain circumstances, this virus can be a start point
towards a devastating complication and such.
Perl Molson

http://www.the-scientist.com/yr2000/may/research_000501.html
RESEARCH

Does Multiple Sclerosis Have a Herpesvirus Connection?
HHV-6 seems to play a role, but the mechanism is far from clear
By Douglas Steinberg

Editor's Note: This is the second of two articles on the difficulties
of proving that a virus contributes to a disease. The first article,
on mouse mammary tumor virus and human breast cancer, appeared in the
April 17 issue of The Scientist.1

Donald R. Carrigan and Konstance K. Knox
--------------------------------------------------------------------------------

Someone once said that if you want to ruin your reputation, go into MS
[multiple sclerosis] research, quips Jacqueline E. Friedman, a senior
research associate at Rockefeller University. But Friedman, who deals
with the disease as both a clinician and a scientist, isn't just being
flippant. She notes the complexity of MS and how it "may actually be
different diseases all lumped together."

In MS, certain neurons in the central nervous system lose their myelin
sheaths, which are made by glial cells known as oligodendrocytes.
Typically diagnosed as a person turns 30, MS afflicts an estimated
300,000 Americans. During its earlier relapsing-remitting phase,
attacks come and go, while its later chronic progressive phase is
marked by slow decline. MS leads to debilitation but not death.

Years of research have yielded many ideas but little certainty about
the cause of the disease.2 The general view is that demyelination
results from an autoimmune, inflammatory reaction.3 But what triggers
that reaction? And what chain of events leads to the destruction of
myelin?

Given the apparent involvement of the immune system in MS, viruses
have long been suspected as contributory agents. "The first slide I
give in my talks is a survey of all the viruses that have been
associated with MS for the past 50 years," says Steven Jacobson, chief
of the viral immunology section at the National Institute of
Neurological Disorders and Stroke. The list--only a partial one, he
stresses--includes 17 viruses, among which are rabies, measles, and
several herpesviruses.4

Do these viruses help cause MS, or does MS just facilitate viral
infections? Thanks to research in the last five years, some by his
lab,5 Jacobson now accepts that human herpesvirus 6 (HHV-6) is
associated in some way with MS. But at pains to underscore his
cautious stance, he adds, "I have a slide that says 'Association is
not causation.'"

 

Support for an MS Link
Discovered in 1986,6 HHV-6 is a DNA virus belonging to the herpesvirus
family by virtue of its molecular makeup, biological characteristics,
and immunological cross-reactivity. The virus has A and B variants,
which may be distinct species.7 It infects almost all infants or
toddlers.
Herpesviruses are implicated in a witch's brew of human ills, and
HHV-6, in particular, is known to cause encephalitis in
immunosuppressed patients, and roseola infantum, a febrile disease, in
children. Some evidence suggests that HHV-6 also plays a role in AIDS
and chronic fatigue syndrome.

Efforts to link HHV-6 to MS began in earnest in 1995 when a team at
PathoGenesis Corp. in Seattle reported that HHV-6 was present in 78
percent of MS brains, as detected by PCR. About a dozen other viruses
weren't found at all in MS brains, while herpes simplex virus 1 was
present in fewer than 10 percent. The team also discovered that
oligodendrocytes stained positive for the virus in MS brains but not
in the brains of controls, who suffered from neurological diseases
other than MS or from nonneurological diseases.8

The study wasn't ideal proof of a link between HHV-6 and MS: PCR
turned up traces of HHV-6 in 74 percent of control brains, too.
Staining of neurons for HHV-6, moreover, wasn't entirely specific for
MS and hasn't been confirmed by other groups. Yet the PathoGenesis
paper "probably was pivotal," says Donald R. Carrigan, an HHV-6
researcher at the Institute for Viral Pathogenesis in Milwaukee. "Its
main effect was to introduce the idea that HHV-6 might be involved in
MS in a top-line journal."

But the study "didn't convince anyone," Carrigan recalls, so other
groups set out to test the virus-disease connection further. Most of
the 15 to 20 papers on the subject report a link between HHV-6 and MS.

Conflicting Results
These studies have generally taken three approaches to testing the
blood, cerebrospinal fluid, and tissue samples of MS patients and
controls: scoping out HHV-6 DNA with PCR; assaying for antibodies
against HHV-6 produced by the subjects' immune systems; and staining
tissues with nonhuman antibodies against HHV-6. (Unfortunately for
scientists, the most valuable samples, autopsied brains from
early-stage MS, are rarely available.)

Traces of HHV-6 infection have been found in anywhere from 30 to 70
percent of MS patients, significantly more than in control subjects.

Several labs, however, have failed to link HHV-6 with MS. Some have
detected little or no viral DNA in both MS and control subjects.9
Jacobson suggests that these studies used methods--primary PCR instead
of nested PCR, for example--that may not have been sensitive enough.10

Other labs have seen signs of HHV-6 in too many controls.11 According
to Carrigan, these studies may not have differentiated between latent
and active HHV-6 infection. He contends that because the virus infects
most people in childhood, signs of latent virus in control subjects
can swamp signs of active infection in MS patients.

An additional deficiency may be the failure of some studies to
distinguish between the A and B variants of HHV-6. In March,
Jacobson's lab published a paper on lymphoproliferation, which
indicates prior exposure to a pathogen. The lab found that T
lymphocytes from 67 percent of MS subjects proliferated in vitro in
response to the A variant of HHV-6, compared to 33 percent of healthy
controls. There was little difference in response to the B variant.12

Philip E. Pellett, chief of the herpesvirus section at the Centers for
Disease Control and Prevention (CDC) in Atlanta, says that
inconsistencies in the MS/HHV-6 findings might be resolved if
researchers shared panels of patient samples representing diverse
geographical areas and different stages of the disease. But he warns
against the standardization of assays because the field is too new to
foreclose a diversity of approaches.

 Image from D.V. Ablashi et al., "Human herpesvirus-6 (HHV-6)
infection in multiple sclerosis: a preliminary report," Multiple
Sclerosis, [6]:490­6,1998.

Short-term culture of peripheral blood mononuclear cells from an MS
patient in relapse
--------------------------------------------------------------------------------


No NIH Funding
At a meeting in Winnipeg, Man., two months ago, about 25 researchers
discussed how to improve HHV-6 diagnostics by evaluating assays and
establishing panels of patient samples. The gathering was organized by
Graham A. Tipples, a section head in Canada's Laboratory Centre for
Disease Control. A meeting of similar magnitude and depth hasn't been
held in the United States--and there are no current plans for one.

Indeed, while scientists in Japan and Europe have been publishing many
papers on HHV-6, Americans seem to be far less active on this research
front. An oft-cited reason is lack of money and personnel. Once,
Pellett recalls, 10 people in his lab worked on HHV-6; now it's just a
graduate student and a guest researcher. As for funding, interviewees
for this article praised the National Multiple Sclerosis Society for
its cautious but receptive approach, but most had given up on the
National Institutes of Health as a source of financial support.

Trying to explain NIH's attitude toward HHV-6, Carrigan speculates
that "the edict came down from the upper echelons of [the National
Institute of Allergy and Infectious Diseases] that since this virus is
ubiquitous, it can't cause any disease."13 Pellett says that HHV-6
research "somehow was not deemed cool" at NIH and hasn't received
enough support from disease-specific lobbying groups.

But Jacobson, who is at NIH and says he sits on a lot of funding
committees, is concerned that grant applicants rely too heavily on a
single approach such as testing for antibodies. "I really believe good
projects will always be funded," he asserts.

General skepticism about a tie between HHV-6 and MS has also
contributed to the reluctance to fund research. The problem isn't so
much the inconsistent findings by different labs. "People, I think,
appreciate that it takes time to really get a consensus," says
Friedman, the physician-scientist at Rockefeller. More damaging in her
view is the multitude of viruses blamed for MS over the decades.

 Image from D.V. Ablashi et al., "Human herpesvirus-6 (HHV-6)
infection in multiple sclerosis: a preliminary report," Multiple
Sclerosis, [6]:490­6,1998.

HHV-6 particles at various stages of development
--------------------------------------------------------------------------------


Proposed Mechanisms
How then is HHV-6 linked to MS? "If you already have virus acquired in
your body when you are a child and it's latent there, it becomes very
difficult to prove that this virus is a causative agent," says Dharam
V. Ablashi, a codiscoverer of the virus6 and director of her- pesvirus
programs at Advanced Biotechnologies Inc. in Columbia, Md. Instead, he
adds, HHV-6 "may be a contributing agent," potentiating the disease by
inducing such cytokines as IL-6, TNF-a, and IL-1ß.

According to Ablashi, HHV-6 remains latent in monocyte-macrophages
until the onset of MS. Then these immune-system cells carry the virus
into the central nervous system where it merges with target cells.
"Latency is a big headache," he acknowledges. "You don't know how the
virus gets activated from latency."

Carrigan and Konstance K. Knox, his colleague at the Institute for
Viral Pathogenesis, posit the following: MS patients have a genetic
defect impeding the ability of their immune systems to respond to
HHV-6. At MS onset, unchecked HHV-6 directly infects and kills
myelin-making oligodendrocytes. When MS shifts from its
relapsing-remitting stage to its chronic progressive stage after 10 to
15 years, patients' immune systems have begun to respond to the virus.

"But at the same time," Carrigan continues, "there's a
cross-reactivity between the viral protein and their own brain
proteins. And so at this point, the disease changes from basically an
infectious disease to an autoimmune disease."

Friedman's hypothesis requires two events to occur. "We think that, at
least intermittently, HHV-6 antigens are expressed on
oligodendrocytes," she says. "And that may come and go without any
problems. But if the immune system gets stimulated by whatever cause,
and the blood-brain barrier breaks down, memory cells will then see
the antigens." Thus, when expression of HHV-6 antigens coincides with
immune-system stimulation, oligodendrocytes get attacked.

 

Transgenics and Drugs
Some experimental work has been done exploring the relationship
between HHV-6 and MS. The virus infects cultured oligodendrocytes and
other glial cells.14 CD46 was recently identified as a cellular
receptor for HHV-6.15 Found on apparently all human cells, CD46 also
acts as a receptor for measles virus, another suspect in MS etiology.
Jacobson is now examining whether MS patients express the receptor
differently than controls do.

Michael J. Lyons, an adjunct faculty member in the Laboratory of
Clinical Microbiology and Immunology at Rockefeller University, just
generated transgenic mice expressing an HHV-6 structural protein only
in oligodendrocytes. The viral gene was hitched to the myelin basic
protein promoter.

Lyons says he and Michael B. Oldstone at the Scripps Research
Institute in La Jolla, Calif., plan to infect double-transgenic mice
with another virus, enabling inflammatory cells to cross the
blood-brain barrier. Lyons won't disclose details of the project, but
it may look at whether cells expressing the HHV-6 transgene are
especially vulnerable to immune-system attack.

Given the daunting complexity of MS, some researchers argue that an
effective antiviral treatment may be the best attainable proof of
involvement of HHV-6 or another virus in the disease. In a 1996 study,
acyclovir was administered to relapsing-remitting MS patients. The
results were mixed. While the treated group failed to show a
convincing letup in neurological deterioration, exacerbations, or
flare-ups of symptoms, did decrease if the data were analyzed in a
certain way.16

Since 1997, Friedman has been conducting a double-blind study in which
50 MS patients receive either pills containing the Glaxo Wellcome
antiviral drug Valtrex (valacyclovir hydrochloride) or placebos.
Treatment lasts two years, and results, including MRI scans, are
expected in 2001. "Valtrex may not be the most effective [drug]
against HHV-6 but it's probably the safest," Friedman says. She
explains that "since we haven't got an exact cause and effect yet for
the virus, we didn't want to put the patients in any danger."

Carrigan and Knox, meanwhile, have been trying to set up a study using
Roche Pharmaceuticals' more toxic--but possibly more
effective--antiviral drug, ganciclovir. According to Carrigan, the
project has been hamstrung by a host of problems. For example, the
researchers now have access only to the liquid form of ganciclovir.
Twice-daily intravenous injections are required, which is a burden in
a long-term study and a hindrance to patient recruitment.

Effective antiviral treatments may prove that HHV-6 contributes to MS
in an undetermined way. But the drugs may not necessarily be a cure.
Carrigan notes that HHV-6 can develop drug resistance. "It's not clear
that any one thing is going to be the cure for MS," concludes
Friedman. "I think it's ultimately going to be a combination."S

 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1
2742867&dopt=Abstract

Association of serum antibodies to herpes simplex virus 1 with
cognitive deficits in individuals with schizophrenia.

Dickerson FB, Boronow JJ, Stallings C, Origoni AE, Ruslanova I, Yolken
RH.

Sheppard Pratt Health System, Baltimore, Md, USA.

BACKGROUND: Cognitive deficits are a characteristic feature of
schizophrenia and contribute to the profound disabilities associated
with this illness. Some of the cognitive deficits that occur in
individuals with schizophrenia are similar to those found in
individuals who have recovered from central nervous system infections
with human herpesviruses. METHODS: We measured cognitive functioning
and serologic evidence of infection with human herpesviruses in 229
outpatients with schizophrenia. We evaluated cognitive functioning
with the Repeatable Battery for the Assessment of Neuropsychological
Status. For each patient, serum IgG class antibodies with
specificities for the following potentially neurotropic human
herpesviruses were measured by means of a solid-phase immunoassay:
herpes simplex viruses 1 and 2, cytomegalovirus, Epstein-Barr virus,
human herpesvirus 6, and varicella-zoster virus. We determined the
association between serologic evidence of herpesviruses infection and
cognitive functioning by univariate and multivariate analyses,
including demographic and clinical factors associated with cognitive
functioning. RESULTS: We found that serologic evidence of infection
with herpes simplex virus 1 is an independent predictor of cognitive
dysfunction in individuals with schizophrenia. Discriminant function
analysis indicated that much of the difference in cognitive
functioning could be attributed to immediate memory. We found no
significant association between cognitive dysfunction and serologic
evidence of infection with other human herpesviruses. CONCLUSION:
Serologic evidence of herpes simplex virus 1 infection is associated
with cognitive impairment in schizophrenia.

http://freedomantiviral.addr.com/about_herpes.htm
Schizophrenia Cause Shows Link to Genital Herpes

Preliminary research shows there may be a link between children born
to mothers who had HSV-2 or genital herpes while pregnant being at
greater risk of developing the brain disorder schizophrenia.
The disease alters an individual's emotions, thought processes and
perceptions of reality. Approximately one percent of the world's
population is affected. Typically, symptoms appear during the late
teen and 20s.

The study centered around stored blood samples from the mothers of 27
adults with schizophrenia and those from the mothers of 54 healthy
adults. These samples had been collected at the end of each woman's
pregnancy.

The analysis between the two groups uncovered an association between
antibodies for HSV-2 in a mother's blood and a child's later
development of the disorder. The researchers wrote that they "did not
find significant differences" between the groups when other infections
were looked at in comparison.

They also said they did not know if infection with genital herpes is a
direct cause or simply a factor in developing schizophrenia. (Archives
of General Psychiatry, Nov. 2001)