14 October 2008
The 6th International Conference on HHV-6 & 7 and satellite conference on
Viruses in CFS held in Baltimore June 19- 23rd were very successful, with
over 230 scientists and clinicians in attendance.
Anthony Komaroff, MD of Harvard University kindly prepared a lay summary
(suitable for patients) of each conference that can be downloaded at the
links below. Scientific summaries will be published soon.
Summary of the 6th International Conference on HHV-6 & 7, June 20-23rd, 2008
http://www.hhv-6foundation.org/Baltimore-HHV-6-Lay.pdf
Summary of the Viruses in CFS conference, June 23-24th, 2008
http://www.hhv-6foundation.org/Baltimore-CFS-Lay.pdf
===============================================================
Summary of the Viruses in Chronic Fatigue Syndrome & Post-Viral Fatigue
Conference
===============================================================
The Viruses in Chronic Fatigue Syndrome & Post-Viral Fatigue Conference was
held in
Baltimore, Maryland, on June 22-23, 2008. Investigators from around the
world examined
evidence for the possible role of several different viruses in initiating
and perpetuating chronic
fatigue syndrome (CFS).
=======================================
Post-Infectious Fatigue Syndrome (PIFS)
=======================================
For over 60 years, scientists have reported sporadic cases of a chronic
fatiguing illness
developing in the wake of a well-documented infection. Nevertheless, it is
only in the last few
years that scientists have systematically studied this PIFS. These studies
have begun by
identifying all cases of a well-documented type of infection in a large
group of people. Then, the
research team carefully follows the patients for a long time thereafter,
evaluating symptoms, and
performing physical examinations and laboratory testing.
In 2006, a landmark study of post-infectious fatigue syndrome that was
conducted in Dubbo,
Australia, was published. The team studied people with each of three
different kinds of
infections-Epstein-Barr virus infection, Ross River virus infection, and
infection with a
bacterium, Coxiella burnetii, the cause of a disease called Q fever. The
study showed that about
10% of patients in each of the three groups developed a post-infectious
fatigue syndrome that
met the Centers for Disease Control and Prevention (CDC) criteria for CFS.
At the Conference, the team reported in detail on this study. The chronic
illness was most likely
to develop in those patients who were sickest at the time of the initial
infection: demographic,
psychological and microbiological factors did not predict who would develop
PIFS. Although
final results were not presented, the team reported that the activity of a
handful of genes
predicted who would become most severely ill with PIFS, and that genes were
plausible
candidates to explain the symptoms of PIFS. In particular, the team found
variations in the genes
for two immune system chemicals that affect inflammation
(cytokines)-interferon-ã and
interleukin-10.
=====================================
Human Herpesvirus-6 (HHV-6) and HHV-7
=====================================
For almost 20 years, studies have found evidence associating HHV-6 with
chronic fatigue
syndrome (CFS). Most human beings are permanently infected with HHV-6,
although the virus
usually remains "asleep" (inactive) inside certain cells and is not making
copies of itself.
However, sometimes the virus "reawakens" and begins to multiply-a condition
called active
infection.
Any human being with an inactive infection-which is to say, most human
beings-will have
detectable antibodies against the virus in their blood. People with active
infections can be
identified by tests of antibodies, virus antigens, and viral nucleic acids
in the blood. Most
researchers who have studied it report that patients with CFS more often
have active infection
with HHV-6 than either healthy people or people with other illnesses than
can cause fatigue.
At the Barcelona Conference in 2006, a preliminary study reported that
patients with CFS and
evidence of active infection with HHV-6 and/or a related virus, Epstein-Barr
virus, improved
when treated with an antiviral drug, valganciclovir (ValcyteR). However,
that study did not give
some patients the antiviral drug and other patients a placebo (i.e., sugar
pill), and so it could not
prove that the treatment actually helped . At the Baltimore Conference, the
same group from
Stanford University reported on a randomized, placebo-controlled trial. The
study had ended
just before the conference began, and only a small amount of the data had
been analyzed. The
patients who received the valganciclovir seemed to improve more than the
patients given
placebo, but further analysis of the data is required to determine the
results of the study.
A team from Latvia reported that latent (inactive) infection with HHV-7 was
present more often
in patients with CFS than in healthy control subjects. The team also found
that active infection
with HHV-6 was present in many more patients with CFS than in healthy
control subjects.
==================
Epstein-Barr Virus
==================
In the mid-1980's, some cases of (what came to be called) CFS were
associated with reactivated
Epstein-Barr virus (EBV) infection.
At the Baltimore Conference, one team reported that a protein made by EBV
during active
infection stimulates the production of several cytokines. These cytokines
can produce many of
the symptoms of CFS. The team reported that the mechanism by which EBV
induces the
production of these cytokines is through triggering an immune system "master
switch" called
NF-êB.
==========
Parvovirus
==========
PIFS following infection with parvovirus B19 has been reported for more than
a decade. A team
from Japan followed over 200 patients immediately after they had been
infected with the virus.
PIFS was not associated with continued presence of viral DNA in the blood,
but levels of
complement-proteins involved in inflammation-were.
Another study found that people experiencing a lot of stress at the time
they developed a new
infection with parvovirus were more likely to go on to develop a PIFS that
met criteria for CFS.
In addition, as was found in the Dubbo study (above), patients whose immune
system cells
produced high levels of inflammatory cytokines at the time of initial
infection were also more
likely to go on to develop a PIFS.
=============
Enteroviruses
=============
Enteroviruses include three families of human viruses: Coxsackievirus,
echovirus and poliovirus.
These viruses can infect the cells of the brain and spinal cord, respiratory
tract, muscle and gut
cells, and have been suspected as a possible cause of CFS for many decades.
A research team reported finding enterovirus RNA (viral genetic material)
and high levels of
antibodies against enteroviruses more often in patients with CFS than in
healthy control subjects.
Stomach biopsies were performed in some patients with CFS who had abdominal
symptoms:
enterovirus antigens were found much more often in their stomach tissue than
in stomach tissue
from patients who had biopsies for reasons other than CFS (like possible
stomach ulcers). In
patients with enterovirus antigens in the stomach, enterovirus RNA was also
found.
===================
Borna disease virus
===================
Borna disease virus has long been recognized to infect animals that are in
close contact with
humans-horses, cattle, dogs and cats. It causes infection of the brain,
particularly the limbic
system, which is involved in emotion, behavior, and long-term memory. A team
from Germany
reported the latest research from its laboratory indicating that the virus
also can infect humans,
and may cause various mood disorders.
The team reported that it had isolated Borna disease virus from the blood of
a U.S. patient with
CFS. In the test tube, they found that the virus was killed by an antiviral
drug called amantadine.
They then found that a German patient with CFS and evidence of Borna disease
virus infection
improved clinically with amantadine treatment.
A team from Japan reported finding evidence of Borna disease virus in about
10% of patients
with CFS.
=======================
Endogenous retroviruses
=======================
Nested among each of our genes are sequences of DNA that may make viruses
called
endogenous retroviruses. These DNA segments have been inherited from our
parents, and
entered the human genome millions of years ago. Most of them are thought to
be unable to
actually make retroviruses.
One research team reported that a particular endogenous retrovirus called
human endogenous
retrovirus-K18 (HERV-K18) can be induced to make viruses when a cell is
infected with
Epstein-Barr virus or stimulated by a chemical called interferon-á (which is
both a natural
chemical and a drug used to treat various diseases). Three different
variants of HERV-K18 exist.
The team reported that one variant, K18.3, is found more often in patients
with CFS.
The possibility that HERV-K18 might trigger CFS in some people is plausible:
HERV-K18
makes a protein called a "superantigen" that triggers a strong immune
response and dysregulates
the immune system. Such a response could theoretically trigger the symptoms
of CFS. This
research is preliminary, but intriguing.
=================================
Immunological and genetic studies
=================================
Gene polymorphisms
Contemporary biology allows scientists to do something that was
impossible only 30 years ago: to easily identify gene variations. Some genes
exist in several
subtly different forms, called polymorphisms. The polymorphisms were caused
by a mutation,
typically one that occurred in a distant ancestor and was passed on to
future generations. Tiny
mutations in a gene can change the function of the protein made by the gene,
and that can lead to
disease.
A team using genetic data collected by the CDC reported that several
polymorphisms in genes
that are part of the brain hormone system ("neuroendocrine system") are
found much more often
in people with CFS. It is well known that the brain hormone system "talks"
to the immune
system, through various chemical signals. The team showed that the
communication between
these two systems was quite different in patients with CFS than in healthy
control subjects.
Gene expression studies.
Contemporary biology also allows scientists to do something else that
was impossible only 20 years ago: to identify every gene in a cell, and
determine if it is turned on
or off. Genes that are turned on are said to be "expressed": they are making
the protein that they
were built to make. For example, scientists can take a group of cells-like
white blood cells in
patients with a particular disease, or diseased tissue (such as a particular
type of cancer)-and
see which of the roughly 22,000 human genes are being expressed, and which
are not: a "gene
expression fingerprint".
A research team from England reported that 88 genes (out of the
approximately 22,000 human
genes) were uniquely expressed in the white blood cells of patients with
CFS: 85 genes were
turned on, and 3 were turned off. The 88 genes typically involved biological
functions that are
central to the immune response to infection-which is consistent with the
idea that CFS can be
triggered and/or perpetuated by certain infections.
Immunological abnormalities and symptoms.
One presentation summarized the immunological
measurements that distinguish patients with CFS from healthy controls,
including: increased
numbers of activated T cells (a type of white blood cell); impaired function
of T cells and natural
killer cells (NK cells), another type of white blood cell; TH2 cytokine
shift (a change in the type
of cytokines produced); increased levels and production of inflammatory
cytokines; reduced
amounts of a molecule called soluble CD26; and increased amounts of a
molecule called NPY.
But did these measurable abnormalities have any connection to the symptoms
that patients with
CFS were experiencing? Data were presented indicating that diminished T cell
and NK cell
function correlate with cognitive impairment and reduced level of function.
=======
Summary
=======
CFS was named and defined only 20 years ago, although a similar illness had
been described in
the medical literature for hundreds of years. The possibility that CFS is
often triggered by
infectious agents has been widely discussed and debated. Few scientists have
argued that a
single novel infectious agent is responsible for CFS, in the way that HIV is
the central and
necessary cause of AIDS. Indeed, most illnesses caused by infectious agents
can be caused by
multiple different types of infectious agents. For example, bronchitis,
gastroenteritis, hepatitis,
urinary infections, and the common cold are each caused by multiple
infectious agents.
This conference presented evidence that a handful of infectious agents are
plausible triggers of
CFS. The evidence was both direct-associations between an infectious agent
and CFS-and
indirect-evidence of an immune response in CFS that suggests the body may be
attempting to
battle an infectious agent.
Altogether, both proponents and opponents of the theory that CFS can be
triggered by infectious
agents had much food for thought.
-----------------
http://www.hhv-6foundation.org/aboutus.html
About the HHV-6 Foundation
The HHV-6 Foundation in a non-profit entity founded by Kristin Loomis and
Annette Whittemore in 2004 to encourage scientific exchange between
scientists and to provide pilot grants for promising scientific and clinical
research.
The first priority of the Foundation is to support efforts to develop better
laboratory tests that can differentiate between chronic active and latent
infection. Since this virus can retreat to the brain and other tissues and
disappear from the serum, finding a sensitive diagnostic tool is a
challenge. The Foundation is working hard to promote efforts to develop
better techniques.
Another important priority for the Foundation is to encourage efforts to
find antiviral compounds that are appropriate for long-term use. The
Foundation has supported several in-vitro studies of antiviral efficacy at
both commercial and academic laboratories, including a comprehensive
screening done for us at the Rega Institute in Belgium and the Laboratory of
Virology at the University of Paris in France.
The Foundation sponsors a large international conference every other year
and encourages collaboration between scientists. Our 2006 International
Conference on HHV-6 & 7 in Barcelona was attended by 165 scientists from 19
countries. The Foundation supports basic research by funding pilot grants
and has funded a dozen grants tp date. (See Research Grants Awarded
http://www.hhv-6foundation.org/researchfunded.htm) These awards allow
investigators the seed funds to gather preliminary data in order to apply
for larger grants. The Foundation maintains a repository of patient samples
and valuable reagents that scientists need for research (purified virus,
monoclonal antibodies, cell lines, etc.)
Dharam Ablashi, co-discoverer of the HHV-6 virus and veteran of the National
Cancer Institute, is the Institute's Scientific Director. Kristin Loomis, a
graduate of Harvard Business School, serves as the President and Executive
Director.