HHV-6 and ME/CFS - David S. Bell MD Lyndonville News, June 2008

[Guest guest]

HHV-6 and ME/CFS

 

 

 

Introduction:

 

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.

 

 

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 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 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.

 

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.â€

 

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 significance.

 

Comment: A disappointing result overall, definitely not a “home-runâ€.

Furthermore, few CFS patients have these kinds of antibody titers from standard

laboratories.

 

 

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 illness.

 

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

insurance.

 

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 “cureâ€, I

am sorry. But do not give up hope. One of these days…..

 

 

 

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 – if those interested in ME/CFS do not make it

happen, it is not going to happen.

 

© 2008 David S. Bell

 

 

 

 

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