HHV6 M.E./CFS summary of latest data

Discussion in 'Fibromyalgia Main Forum' started by Bluebottle, Jun 26, 2008.

  1. Bluebottle

    Bluebottle New Member

    This is from today's Co-Cure digest:

    Lyndonville News

    Information and Support for the ME/CFS/FM

    David S. Bell MD, FAAP, Editor

    Volume 5, Number 3: June 2008

    Web site: http://www.davidsbell.com

    HHV-6 and ME/CFS


    This issue of the Lyndonville News is a summary of
    the latest data on HHV-6 (human herpes virus #6).
    As many of you know this has long been debated as
    having a prominent role in ME/CFS. And over the past
    two years there has been increased excitement
    because of the anticipation of the Stanford Study
    results. The conference was the 6th International
    Conference of the HHV-6 Foundation, Baltimore, MD
    June 19-22 2008.


    HHV-6 is a virus in the Herpes family, and has long
    been a suspect in causing or perpetuating ME/CFS.
    Discovered by Dr. Dharam Ablashi and Dr. Robert
    Gallo, it seemed to act a lot like a fellow herpes
    virus, including Epstein-Barr virus. It was found to
    cause the common childhood infection, Roseolla, and
    there is no vaccine effective in preventing it. HHV-6
    is present in a wide range of patients and situations,
    and has characteristics that indicate it is a serious
    pathogen. Yet questions have lingered: is it the
    cause of ME/CFS, a cause of some cases of ME/CFS,
    an innocent bystander, or some mixture - a
    contributor to serious illness. Going into the
    conference I had several questions:

    1. Should HHV-6 be measured in the clinical
    evaluation of persons with chronic fatigue, and if
    so, what is the best method to measure it?

    2. How can active central nervous system infection
    with HHV-6 be measured?

    3. If HHV-6 is a trigger to set off ME/CFS, what is the
    mechanism, and how can it be interrupted?

    4. HHV-6A or HHV-6B?

    5. Is there an established link between HHV-6
    infection and mitochondrial disease other than a
    non-specific cytokine relationship?

    6. Does treatment for HHV-6 improve patients with

    A daunting range of goals, and I will give my opinion
    to them at the end of this edition. A note of caution:
    I am presenting my hearing of these lectures and my
    interpretation of the data. Others might disagree,
    and only time will tell. Many of the lectures
    concerned the biology of HHV-6 and were not specific
    to ME/CFS. I present snippets of wonderful science
    that caught my attention, in no particular order.

    Introductory Session

    Dr. Robert Gallo

    HHV-6 was discovered in Dr. Gallo's lab in 1986 with
    Dr. Dharam Ablashi very prominent in the scientific
    work. It was assumed initially that the virus led to
    some cancers by promoting gene expression of other
    viruses such as HIV. However while having an affinity
    for T cells and nerves, it is not found in tumor cells.
    HHV-6A, HHV-6B, and HHV-7 are extremely similar.
    It appears that HHV-6 is a co-factor in many
    illnesses because it increases inflammatory cytokines
    TNF? and IL-1? (Flammand et al, Virol. 1991). As will
    be discussed later inflammatory cytokines are felt to
    be important in the mechanism of symptoms of

    Overview of HHV-6 infection

    Dr. P Pellett

    HHV-6 is a ubiquitous virus causing Roseolla in
    young children, and like other herpesviruses, can
    re-activate with certain stresses. The problem has
    been to link infection with HHV-6 to specific illnesses
    and this has been difficult to do. In multiple
    sclerosis there is an increasing concentration of
    HHV-6 in serum, spinal fluid, and plaque; this has
    helped to define its rolE here. The key will be to find
    a good predictive marker that points to disease
    involvement of HHV-6.

    The Role of CI-HHV-6 in congenital HHV-6 infections

    Dr. C. B. Hall

    Roughly 1% of newborns will have infection with
    HHV-6 at birth, and it has long been assumed that
    these infants have transplacental infection, meaning
    that the virus from the mothers' blood crosses the
    placenta to cause infection in the infant. However,
    one important aspect of this virus is that it can be
    integrated into the human genome, chromosomeal
    integration of HHV-6 or CI-HHV-6. In this study, it
    turns out that 86% of those infants infected (1% of
    all babies) have CI-HHV-6, and the remaining 14%
    are transplacental. Of the CI-HHV-6, one third are
    variant A and two thirds are variant B. One potential
    problem here is that the CI-HHV-6 infants have
    extremely high viral loads, so much so that
    practically every leukocyte has virus. There is not
    much difference between serum titers of antibody in
    the two groups. The babies have been followed for a
    few years now and so far seem to be doing well with
    no obvious disease. Ongoing studies will examine
    this in the future.

    A Comparison of Diagnostic Assays for characterizing
    infections with HHV-6

    Dr. M. T. Caserta

    The problem with the measurement of HHV-6 is that
    it is necessary to distinguish active replication
    causing illness from chromosomal integration, from
    passive detection, meaning that at some time in the
    past a person has had Roseolla or exposure to
    HHV-6. Thus the standard tests are of very little
    value because they do a poor job of differentiating
    these states. Furthermore, antibody titres do not
    distinguish variant A from B. The "gold standard" or
    most accurate test to date, is viral replication in
    culture. That is, to show that the virus is actively
    growing and replicating in cells.

    Antigenemia Assay: In this assay the products of
    replication are being sought. There are two big
    hurdles; first, there is no separation between
    HHV-6A and B. Secondly, this assay requires a laser
    scanning microscope which are expensive and
    difficult to find

    Antigen Capture Assay: This assay is also looking for
    active replication, and it detects variant A and B core
    protein in cell free fluid. It detects both acute and
    convalescent infection with HHV-6 but is not positive
    in normal donors.

    LAMP Assay: This method amplifies DNA under
    "isothermal" conditions, making it easier to do than
    PCR. It will detect primary infection but not latent
    infection. It is not yet known if it will be of value in
    detecting CI-HHV-6 or reactivation, and ability to
    distinguish variants unknown.

    RT-PCR: This PCR technique measures the reverse
    transcriptase, essentially looking at the messenger
    RNA from an active, replicating virus. Probably just
    as good as culture.

    Quantitative PCR: This PCR assay looks to determine
    the number of comies present, or the viral load.
    There are probably 100 papers out on this, but each
    paper uses different primers and it is very hard to
    compare different assays.

    In concluding, Dr. Caserta suggests a combination of
    assays would be most helpful to distinguish active
    viral infection to latent infection.

    Comment: For those readers interested in ME/CFS
    who are not scientists, the synopsis is this: we still
    do not have a good easy test to distinguish variant A
    from B that will universally be covered by your
    insurance company. The tests used in research are
    improving, and the big question remains: if you test
    positive for A or B by a good research test, what are
    you going to do about it?

    Early Antigens in HHV-6 Infection

    Dr. L. Flammand

    In this paper Dr. Flammand looks at several of the
    early signals given off by HHV-6 infection, some of
    which will probably be important to measure in the
    years to come. What caught my attention was his
    statement that the early proteins of HHV-6 infection
    alter mitochondrial membrane potential.

    New Developments in Therapeutics for HHV-6

    Dr. MN Prichard

    In this session, Dr. Pritchard reviews the anti-virals
    with known activity against HHV-6. Unfortunately the
    three available, cidofivir, foscarnet, and gancyclovir
    have relatively poor ability to treat HHV-6 infections,
    none are specifically approved for this use, and
    resistance is emerging. The most optimistic
    statement was that these agents "may be of some
    use." On the other hand there are many agents in
    the developmental pipeline that may have good and
    specific activity against HHV-6.

    Comment: Do not hold your breath for these new
    agents. Even if we knew for sure that HHV-6 either
    caused ME/CFS or was an important co-factor, it will
    be many years before these agents come to public
    use, and even more years before your insurance
    company will allow you to have them.

    The Association of HHV-6 in Diseases of the Nervous

    Dr. S Jacobson

    In this overview, Dr. Jacobson touches on the
    associations between HHV-6 (particularly HHV-6A)
    and CNS disease. HHV-6, like other herpes viruses, is
    a ubiquitous agent, acquired early in childhood, but
    clear relationships or associations with specific
    nervous system diseases are emerging. He stresses
    that "association is not causation." There are four
    ways to demonstrate an association between a
    ubiquitous agent and a clinical disorder: a)
    immunological b) molecular analysis c) clinical and d)

    In multiple sclerosis there is clearly more HHV-6
    (variant A) in brain tissue and plaque than there
    should be. However, is it there because underlying
    inflammation draws the cells that go into the plaque
    to the area? In a disease called mesial temporal lobe
    epilepsy, a portion of the brain is surgically removed
    and is thus available for study. In seven out of seven
    temporal lobes studied, all had active, replicating
    HHV-6. The importance of this is that this form of
    epilepsy is not an inflammatory disease, so it leads
    more weight to the presence of the virus in Multiple

    Testing can be an enormous, even insurmountable
    problem. In some clinical conditions, blood and
    spinal fluid show little HHV-6, even though the brain,
    on autopsy, is loaded with virus.

    Comment: This last point is critical for ME/CFS. Brain
    biopsy is not an option, so how can we know if
    HHV-6 (HHV-6A) is causing a/the problem?

    Overview of HHV-6 and Chronic Fatigue Syndrome

    Dr. Anthony Komaroff

    Active infection with HHV-6 is more common in
    ME/CFS than in matched controls. In the opening
    overview, Dr. Komaroff reviewed the nine studies
    showing increased incidence of active infection, and
    the two studies that did not. He mentioned the
    different ways to assess active infection: PCR, IgM
    antibodies to HHV6 early antigen, cytopathic effect
    in culture, and viral isolation.

    Overview of CFS

    Dr. A Komaroff

    In this session Dr. Komaroff lists, in a very
    convincing way, the studies that are clearly abnormal
    in CFS. This may be an illness of different subsets,
    yet the data proving that it is real is
    incontrovertable. He reviewed the abnormal findings
    in CD8 cells, NK cells, Proteomics. Genomics, MRI,
    SPECT, autonomic nervous system, both sympathetic
    and parasympathetic, hypothalamic-pituitary axis,
    EEG, upregulation of pro-inflammatory cytokines.

    In regard to HHV-6 Dr. Komaroff said that this agent
    is "One infectious agent capable of triggering and
    perpetuating CFS."
    Comment: Is it possible that there are medical care
    providers who do not "believe" in CFS?

    HERV-K18 as a Risk Factor in CFS

    Dr. Huber

    In this very interesting talk, Dr. Huber discussed
    HERV (human endogenous retro virus) K18. The
    presence of an endogenous retrovirus is not that
    exciting as it is estimated that 8% of the human
    genome is made up of HERV's. What is interesting is
    that this particular one is transactivated by both EBV
    and ? interferon. What's more, the Env gene of this
    HERV encodes a superantigen. This latter fact is
    possible to become a dominant topic in the near
    future, as superantigens cause a massive T cell
    activation. Some diseases such as "toxic shock
    syndrome" are known to be caused by superantigens
    (not the same one as we are discussing here). In
    this study three different groups of CFS patients
    were examined: Dr. Miller at Emory (interferon
    related), Dr. Levine in NYC (idiopathic), and recently
    with the EBV portion of Dubbo study. All showed a
    relationship leading to the conclusion that CFS risk
    may be related to specific HERV-K18 genotype in
    subsets of patients.

    A Randomized, Double Blind, Placebo-controlled
    Study on the Use of Valganciclovir in Patients with
    CFS and Elevated HHV-6 and EBV Antibodies

    Dr. J.G. Montoya

    This is the first report of the study since the good
    results from a pilot study were released a year ago
    January on the use of valgancyclovir. This drug is a
    competitive inhibitor of viral DNA polymerase, and
    while there were no serious adverse events during
    this trial, it should not be considered a completely
    benign medication. Anyone taking it should be
    followed carefully for toxicities.
    The entry criteria for this study were elevated levels
    of anitbody to both EBV and HHV-6. Over 130
    persons were screened, and thirty were in the study,
    20 on drug and 10 on placebo. The entry antibody
    levels were as follows: HHV-6 IgG ? 640; EBV IgG ?
    640, and EBV EA ? 160. There were many indicators
    used for end points, but discussion here revolved
    around only three: MFI-20 indicating fatigue severity,
    CDC SI relating to symptoms; and a global
    assessment of physical and cognitive functioning.
    The only value that improved to statistical
    significance was the cognitive portion of overall
    functioning. The other measures pointed to a
    positive trend but did not reach statistical

    Comment: A disappointing result overall, definitely
    not a "home-run". Furthermore, few CFS patients
    have these kinds of antibody titers from standard

    The Dubbo Infection Outcome Study

    Dr A Lloyd

    This session was a further review of studies
    presented earlier, but clarifying new data. Essentially
    this study looks at "nested" case-control studies of
    patients followed after acute infection with
    Epstein-Barr virus, Ross River virus and Q fever. As
    was presented earlier, all three infections had similar
    rates of illness resolution. Roughly 5% of each had
    fatigue and other symptoms at one year and this
    decreased somewhat by year two. The severity of
    acute illness was the best predictor of persisting

    Why do some resolve and some do not? The first
    hypothesis is due to persistence of the infecting
    agent. Their studies showed no evidence of
    persistence of EBV, RRV or Q fever, despite an
    aggressive search. Interestingly, IgM and IgG
    antibodies were of no use predicting in any of the
    three. Second hypothesis is that immunity was
    different with antigen-specific T cells and again no
    differences were found. Dr. Lloyd concluded that
    there was no aberrant immune response.

    Cytokines in Post-Infective Fatigue

    Dr. Vollmer-Conna

    This session continued the Dubbo findings from Dr.
    Lloyd's talk and looked at cytokine expression as a
    mechanism of symptom expression. She briefly
    reviewed the many inconsistent cytokine studies of
    the past. At the beginning of the Dubbo infections
    IL-1? and Il-6 seemed to correlate with symptom
    severity, particularly fatigue. However the best
    association with symptom persistence was increased
    IFN?, and decreased Il-10.

    Comment: The cytokine data does not look
    convincing in explaining symptom persistence. There
    was a large gap between symptom severity at onset
    and the increased IFN?/decreased Il-10. But these
    two talks tell us a great deal about what is going on

    Summary and Personal Comments about HHV-6
    and Conference.

    This summary was not presented at the conference,
    but represents my personal conclusions about the
    relationship between HHV-6 and ME/CFS. As always,
    every observer could come to different conclusions.

    A) HHV-6 has two variants, A & B, and is a
    ubiquitous agent. It causes Roseolla in young
    children, and everybody is exposed to it at one time
    or another.

    B) Roughly 1% of babies are born with the virus,
    most with it integrated into chromosomes and have
    high viral loads. It is not known yet if this will cause
    any problems. Because children do not usually
    develop ME/CFS until after age 10, we will have to
    wait another few years to get any early information
    on this point.

    C) HHV-6, particularly HHV-6A has a strong
    association with many diseases of the central
    nervous system.

    D) In ME/CFS, the only way to know if HHV-6 is
    important is to treat it with an effective antiviral, or
    prevent it with a vaccine. The antivirals currently
    available are only partially effective and vaccine is
    not available (Note- the relationship between human
    papilomavirus and cervical cancer was only shown
    when the vaccine was shown to prevent the cancer)

    E) HHV-6 infects/resides in many tissues, including
    vascular endothelium, making it a good candidate for
    the variety of symptoms seen in ME/CFS.

    F) HHV-6 is one of many infectious agents that can
    precipitate and/or perpetuate ME/CFS.

    G) A trial of valgancyclovir was not very effective in
    reducing the fatigue and physical symptoms of
    ME/CFS. It did seem to help cognitive symptoms.

    Bottom Line: Many of my patients will want to know
    if I will be using valgancyclovir in regular clinical
    practice. As of this time I do not plan to use it in
    patients with ME/CFS. I may consider testing some
    persons with RT-PCR and quantitative PCR for HHV-6,
    but this can be expensive and not covered by

    In my practice, I plan to aggressively pursue the
    relationship between anaerobic threshold and
    mitochondrial function in some patients. For those of
    you hoping to hear that the valgancyclovir study was
    going to be the "cure", I am sorry. But do not give up
    hope. One of these days=85..

    My thanks go to Andy Detwiler who financed this trip
    to the HHV-6 conference, paying for the airline
    tickets, hotels, and conference fees. For all those
    who are grateful for this information summarized
    here, please thank Andy. He wishes to encourage
    interested persons to get involved in one way or
    another. I am in complete agreement =96 if those
    interested in ME/CFS do not make it happen, it is not
    going to happen.

    =A9 2008 David S. Bell
  2. LonelyHearts

    LonelyHearts New Member

  3. Goatwoman

    Goatwoman Member