Posted by MERM on 6/26/2008, 12:45 pm
HHV-6 and ME/CFS
Introduction:
This issue 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.
Background:
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 ME/CFS?
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 TNFá and IL-1â (Flammand et al, Virol. 1991). As will be discussed later inflammatory cytokines are felt to be important in the mechanism of symptoms of ME/CFS.
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 infections 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 System 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) pathological.
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 sclerosis.
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