REPORT:
http://www.hhv-6foundation.org/Baltimore-HHV-6-Lay.pdf By Anthony Komaroff, MD
Summary of the 6th International
Conference on HHV-6 & -7
The 6th International Conference on HHV-6 & 7 was
held in Baltimore, Maryland, on June 19- 22, 2008. A
satellite conference on Viruses in Chronic Fatigue
Syndrome and Post-Viral Fatigue followed the main
conference.
Biology of Human Herpesvirus-6 (HHV-6)
In order to best diagnose and treat diseases caused
by a virus, it is essential to learn as much as
possible about the virus-its genes and the proteins
made by those genes, as well as how it infects cells
and reproduces itself.
It is known that the first step by which HHV-6 infects
a cell is attachment to a receptor on the surface of
the cell called CD46. New research found that the
CD46 receptor is located on what is called a "lipid
raft", and that the raft carries the virus inside the
cell where it then can make new copies of itself.
It has been unclear where, inside a cell, new viruses
are assembled. One group reported that this occurs
inside little "bubbles" called multivesicular bodies
(MVBs). The MVBs float toward the surface of the cell
and then exit the cell to go on and infect other cells.
Proteins that are unique to HHV-6 were reported
(particularly one called U94), and two proteins
(called IE 1 and IE2) were shown to distinguish the
variants (A and B) of HHV-6.
When cells are infected by HHV-6, the virus
multiplies much more rapidly if the cell is also
infected with another "cousin" herpesvirus, human
cytomegalovirus, or if the infected cell is placed next
to a cell called a dendritic cell.
Chromosomally Integrated HHV-6 (CIHHV-6)
Most herpesviruses remain as little circles of DNA
inside infected cells, separate from the DNA of the
cell's chromosomes. Several years ago it was
reported that HHV-6 could sometimes integrate itself
into a cell's chromosomes, including the
chromosomes of sperms and eggs making it possible
for HHV-6 to be inherited from a parent. At first,
scientists were very skeptical of this, but subsequent
studies convinced most scientists that it was true:
some people had chromosomally integrated HHV-6
(CIHHV-6).
How common is CIHHV-6? Evidence presented at the
conference confirmed earlier reports that CIHHV-6 is
present in about 1% of people.
Does CIHHV-6 cause any medical problems? One
reason to think that it could is that in the 99% of
humans without CIHHV-6, only a very small number
of cells are infected with HHV-6. In CIHHV-6, since
the viral DNA was inherited from the sperm or egg of
a parent, the viral DNA is present in every cell.
Nevertheless, many scientists have been skeptical
that CIHHV-6 causes any medical problems. First of
all, there has not been strong evidence that the
complete virus is integrated into the chromosomes,
or that it can produce proteins or make copies of
itself-things viruses typically must do in order to
cause medical mischief.
Several preliminary reports at the conference
indicated that CIHHV-6 may indeed lead to the
production of multiple copies of the virus, and may
cause disease. One research team repeatedly
measured the "viral load"-the amount of viral DNA
in the blood-from a group of patients with CIHHV-6.
If the virus was not capable of reproducing multiple
copies of itself, then it would be expected that the
viral load would remain constant over time. Instead,
the research team found extremely large differences
from one sampling to another, indicating that
sometimes the virus was making many copies of
itself, and sometimes it was not.
Even more compelling were two small studies. One
study involved three patients with CIHHV-6 and
chronic fatigue syndrome. The research team found
that when the three patients were given the antiviral
drug valganciclovir, which kills HHV-6 in laboratory
("test tube") studies, the viral load in their blood
went way down, and their symptoms improved.
Another study involved one patient with CIHHV-6
who suffered from acute encephalitis (inflammation
of the brain, usually caused by an infection), a
neurological condition called myoclonus, and loss of
consciousness. The patient was given another
antiviral drug that kills HHV-6, foscarnet, and
completely recovered. Still, it will take randomized
trials of these antiviral drugs (or others effective
against HHV-6) in patients with CIHHV-6, evidence
of active HHV-6 infection, and illness that could
plausibly be caused by HHV-6 to prove that CIHHV-6
can cause illness.
Diagnostic Tests
Some progress was reported in diagnostic tests that
distinguish active infection from inactive (latent)
infection with HHV-6, tests to distinguish the A
strain of the virus from the B strain, and tests to
quantify the amount of virus present in a sample.
Still, the field has not reached the point where all
experts can agree on what the best tests are in
specific clinical circumstances.
HHV-6 in Brain Diseases
Soon after HHV-6 was discovered, it became clear
that the virus could cause infection of brain
cells-glial cells and neurons. That raised the
possibility that HHV-6 might play a role in some
brain diseases.
Encephalitis.
For several years it has been clear that HHV-6 could
produce encephalitis in patients with compromised
immune systems (such as people placed on immune
system suppressing drugs during organ
transplantation, or patients with AIDS). It also has
been clear that the virus can cause temporary
encephalitis in young children when they are first
infected with the virus.
The conference reported increasing evidence that the
virus also can cause encephalitis in adults with
normal immune systems. A study of adults with
encephalitis of unknown cause-people who tested
negative for all known causes of encephalitis-found
that HHV-6 DNA could be identified in the spinal fluid
of 40% of them. In one patient in whom a brain
biopsy was performed, the virus was also found in
the brain.
Multiple sclerosis.
In multiple sclerosis (MS), the "insulation" wrapped
around a nerve cell, called myelin, is damaged by an
autoimmune attack (an attack by one's own immune
system on some part of one's body), compromising
the function of the nerve cell. In 1995, a research
report suggested that HHV-6 might be one trigger of
multiple sclerosis (MS). Since that time, the majority
of the published papers on this subject have been
consistent with the first report.
At the Conference, the following additional
supportive evidence was presented: 1) antibodies
(called "oligoclonal bands") specifically against
HHV-6 were found in the spinal fluid of a minority of
patients; 2) HHV-6 was found to cause a disease like
MS in a monkey (a marmoset); 3) HHV-6 was found
to damage cells called oligodendroglial precursor
cells, cells that repair damage to myelin.
Epilepsy.
For about 10 years doctors have recognized that
when infants are first infected with HHV-6 the virus
can trigger seizures. At the Barcelona Conference in
2006, preliminary evidence was presented that
HHV-6 might be a trigger for temporal lobe epilepsy
in adults. At the Baltimore Conference, impressive
evidence was presented by many different scientists
that HHV-6 is the most common cause of seizures
occurring when a child has a fever ("febrile
seizures"). It also appears to be the most common
cause of uncontrollable seizures in children (a
condition called "status epilepticus"). It is unclear if
these childhood seizures triggered by HHV- 6 make
the child more vulnerable to seizures or other
neurological conditions in adulthood, although a
study of that question is underway.
More evidence was presented that HHV-6 may trigger
some cases of temporal lobe epilepsy. The strongest
evidence involves brain tissue that has been
surgically removed as a treatment for epilepsy. Two
different research groups reported finding large
amounts of the virus in that brain tissue, particularly
in a region of the brain known to be involved in
temporal lobe epilepsy-the CA1 region of the
hippocampus. The infection primarily involved brain
cells called astrocytes.
Mood disorders.
A team from Japan reported that HHV-6 makes a
protein called SITH-1, and that this protein appears
to cause mood disorders. When, using genetic
engineering, a mouse was modified in such a way
that brain cells called glial cells made large amounts
of SITH-1, the mice behaved in a manic (hyperactive)
way.
Antibodies to SITH-1 were found circulating in the
blood of most patients with major depression,
bipolar disorder ("manic-depression"), and chronic
fatigue syndrome-whereas such antibodies were not
found in any adults without these conditions. In two
adults with mood disorders attributed to encephalitis
caused by HHV-6, unusually large amounts of the
messenger RNA that makes SITH-1 were found. This
preliminary study is intriguing, but much more work
is needed to determine whether HHV-6, or the
SITH-1 protein that it makes, are common causes of
mood disorders.
Chronic fatigue syndrome.
The possible role of HHV-6 in chronic fatigue
syndrome (CFS) is discussed in the summary of the
Viruses in Chronic Fatigue Syndrome and Post-Viral
Fatigue Conference.
HHV-6 and HHV-7 Reactivation in Transplant
Recipients
Many studies have shown that HHV-6 (and probably
HHV-7) are often reactivated in patients whose
immune systems have been suppressed by medicines
(such as in organ transplantation) or by diseases
(such as AIDS). New studies confirmed that: 1) such
reactivated HHV-6 infection can cause encephalitis;
2) disease is reduced by white blood cells called T
cells that are primed to attack HHV-6; 3) increased
levels of the immune system chemical called
interleukin-6 (IL-6) predict transplant patients that
are more likely to develop encephalitis (and might
therefore benefit from antiviral therapy).
HHV-6 in Drug-Induced Hypersensitivity Syndrome
Investigators reported that HHV-6, HHV-7 and other
herpesviruses are often reactivated during an
unusual and severe type of drug allergy, variably
called either DIHS or DRESS. The illness involves
many different organs (often the brain and the liver),
frequently leads to high numbers of white blood cells
called eosinophils, and is sometimes followed by the
development of type 1 diabetes or autoimmune
thyroid disease (thyroiditis). HHV-6 was found in
diseased tissues, including brain and liver,
suggesting that-once reactivated by the allergic
reaction-the virus might have contributed to the
disease.
Another report found that several of the medicines
that most often trigger the severe allergic syndrome
also cause reactivation of HHV-6, suggesting that
reactivation of the virus might even be a primary,
rather than a secondary, cause of the illness. HHV-6
and HHV-7 in Cancer
Several herpesviruses-particularly Epstein-Barr
virus-have been found to cause some kinds of
human cancer. The first step in suspecting a possible
role for a virus in causing cancer is to find the virus
inside the cells that are cancerous-but not in most
of the noncancerous cells nearby. Research groups
reported finding HHV-6 in cells of non-Hodgkin's
lymphoma, Hodgkin's lymphoma, brain tumors called
gliomas and in cells from cancer of the cervix. In
several of these reports, there was a greater amount
of virus in the more malignant cells. While these
reports could indicate that HHV-6 is a factor (or
co-factor, along with other cancer-causing viruses) in
causing these cancers, it also could be an "innocent
bystander", attracted to the cancerous tissue but not
really making the tissue turn cancerous.
Heart Diseases
Two possibly-related diseases of heart muscle,
myocarditis and dilated cardiomyopathy, have no
known cause. Several research teams reported that
HHV-6 (and several other viruses) could be found in
the heart muscle of patients with these diseases,
but only rarely in healthy heart muscle. These
patients often also had evidence of reactivated
HHV-6 infection in white blood cells. In one patient
treated with an antiviral drug effective against
HHV-6, the pumping power of the heart muscle
improved, suggesting that the viral infection might
be causally related to the heart muscle disease.
Even more provocative, one group reported that
HHV-6 can infect the inner lining (called the
endothelium) of the arteries of the heart (the
coronary arteries). Furthermore, they found that
HHV-6 infection causes inflammation in the wall of
the artery. A second group compared patients with
myocarditis that was associated with HHV-6 to those
with myocarditis not associated with HHV-6. There
was a greater tendency in the first group for the
coronary arteries to go into spasm.
Together, these results suggest the possibility that
patients with myocarditis caused by HHV-6 may also
have HHV-6 infection of the lining of their coronary
arteries. That, in turn, could mean that HHV-6 may
play a role in causing or worsening coronary artery
disease-the most important cause of premature
death in adults. While at this time a role for HHV-6
in coronary artery disease is just a remote
possibility, there is some evidence that its "cousin"
herpesvirus human cytomegalovirus-may play a role
in coronary artery disease. There also is strong
evidence that a related herpesvirus, Marek's disease
virus, causes coronary artery disease in birds.
Treatments for HHV-6
Several antiviral drugs-some already available to
treat other viruses and some still
experimental-appear to be very effective against
HHV-6 in laboratory testing. Whether these drugs
will work when used in people with illnesses caused
by HHV-6, and whether they will produce side
effects, remains to be seen.
Summary
When HHV-6 was discovered 20 years ago, its
remarkable ability to infect a wide variety of cells
suggested the possibility that it might be capable of
triggering a wide variety of diseases. At this
conference, the expanding spectrum of diseases
associated with HHV-6 (and, in some cases, HHV-7)
was remarkable. While none of these disease
associations has been proven, in every instance the
evidence in favor of the association of HHV-6 and the
disease was stronger than it had been in the past,
and no previously-suggested association was
contradicted by newer and better information.
This makes it imperative that a greater effort be
made to improve diagnostic testing and expand
available treatments.
---
Posts
