HHV-6 Mediated Mitochondrial Modulation and Its Association to ME/CFS

A project summary as written by Bhupesh Prusty:

Infections are frequently associated with chronic disease development and likely, play crucial roles in
the onset or progression of several human disorders that are not classified as infectious diseases.
Myalgic encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is one such example. However, the
precise role of pathogens in ME/CFS development remains, predominantly, uncharacterized. Human
Herpesvirus 6 (HHV-6) is frequently associated with several human diseases including ME/CFS. Work
from my laboratory as well as from others have shown that HHV-6 frequently integrates into human
chromosomes in order to achieve latency (ciHHV-6). Originally, ciHHV-6 was thought to be the dead
end for the virus. However recent publications demonstrate that certain timely triggers like
circumstances of immune suppression or influence of various drugs and/or pathogenic infections can
activate the integrated virus.

Our preliminary work shows that HHV-6 targets the cell’s energy reserve, the mitochondria, during
both active infection and activation from latency leading to mitochondrial dysfunction, a condition that
is also frequently associated with ME/CFS. Using a unique latent and chromosomally integrated
HHV-6 cell culture model, we have observed down regulation of a small non-coding human microRNA
in response to viral infection that induces expression of tumor suppressor protein p53 and
subsequently that of Drp1 leading to mitochondrial fragmentation. Because of these events,
mitochondria from the infected cells tend to have lower ATP generation capacity and reduced
efficiency for maintaining calcium homeostasis. In this proposal, we aim to dissect out the contributing
factor from HHV-6 that is directly responsible for the signaling processes leading to host cell
mitochondrial alteration. We have identified several viral miRNAs that are specifically expressed
during both active infection and viral activation. We hypothesize that these viral miRNAs play a key
role in alteration of mitochondrial fission-fusion dynamics. Our final aim is to link HHV-6 and
mitochondrial alterations using ME/CFS patient materials. Molecular mechanisms behind direct
association between HHV-6 and human mitochondria have never been studied before. The proposed
project aims to elucidate the molecular mechanism(s) by which HHV-6 infection actuates mitochondrial
dysfunction in ME/CFS patients, likely, resulting in the development/progression of ME/CFS.

The anticipated outcome of this pioneering research idea is the elucidation of a novel infectioninduced
mechanism for the onset and/or progression of ME/CFS. Understanding etiology of
mitochondrial modulation from thus far unknown causative agents will open new targets for drug
development. Infectious agents behind mitochondrial modulation in ME/CFS are poorly characterized
and the proposed research aims to address this unexplored avenue. The idea that a common virus
like HHV-6 could associate with host cell mitochondria and modulate its function (and contribute to
disease) has not been hypothesized before. I believe that my project has tremendous potential to
revolutionize the preconceived theories about pathogenic causes behind ME/CFS and is in line with
the Solve ME/CFS Initiative’s mission as well as funding objectives.

16 comments on “HHV-6 Mediated Mitochondrial Modulation and Its Association to ME/CFS

  1. Hi Bhupesh
    ME for 26 years here. Great that you are doing this research. HHV-6 looks like a promising avenue for sure.
    I’m slightly concerned that the thinking goes: fatigue -> energy systems -> mitochondria.
    If we don’t start with fatigue, we might look elsewhere.
    Anyone suffering from ME recognises the viral connection. The idea that HHV-6 remains latent and is periodically, often continually, triggered seems to fit well with the experience.
    I just wonder whether we should be looking at other manifestations rather than simply fatigue, energy systems, mitochondria, ATP. Whatever it is, it makes sufferers primarily feel ill rather than tired. Shame about the name.

    • Hi, Thanks for your comments. I agree with your concerns. But I believe that the most important factor here is mitochondrial modulation. It is not always necessary that less ATP is responsible for fatigue. When the mitochondrial function is altered, it leads to variety of changes like alteration is Calcium signalling and changes in transportation of metabolites through mitochondrial membrane. This can also contribute to fatigue. Hence if we start from fatigue we may not reach to causes of mitochondrial modulation as many factors can modulate mitochondria. Our focus is to dissect the exact mechanism of virus-mediated mitochondrial modulation. We have developed excellent in vitro tools to study this. Now we can use that to see if we create similar conditions like fatigue just by expressing viral RNAs in cells. If we can correlate these data to the same in patients, we can target to inhibit fatigue by regulating viral factors. Please free to write me if you have different thoughts. It’s always good to discuss.

      • Thanks, Bhupesh. Your work can only move knowledge and science forward…please keep going! My comments are seated in a frustration that the ‘fatigue’ thinking has allowed some less scrupulous operators to concoct a de-conditioning model. I am far from de-conditioned, yet still unwell and performing at about 15% of pre-illness levels.
        I’m UK-based. It will be great if you and fellow researchers can collaborate with UK researchers, although difficult still for them to get funding here. Best wishes, Steve

        • Hi Steve, I have several collaborations going on with UK based researchers. But never got a chance to work on CFS together with UK based researchers. Have you ever thought of testing for HHV-6?

          • ME…ok, if I must, CFS research in UK is less than career-enhancing 😉
            I am currently pursuing testing and possible AV therapy via the NHS. This is not in NICE guidelines of course, so it is an uphill struggle. Any NHS resources assigned to ME/CFS are (at best) wasted on graded exercise therapy and CBT. It is great timing for your research given that the PACE trial will now in due course be retracted and eventually the existing NICE guidelines will be completely trashed. I’ve waited 26 years so far, kept myself very fit to be ready for AV treatment.

    • Hi Angela, The proposed project is a pilot study and focuses mainly on linking HHV-6 to mitochondria and CFS. As a part of this project we will test a small group of patients without any bias. Our aim here is to see if we can find the specific HHV-6 encoded small non-coding RNAs in CFS patients or not. Using this data we will see if a particular type or group of patients show association with HHV-6 or not. This will help us to design future studies using specific patient groups.

      • I think Angela’s question may relate more to diagnostic criteria for selection. Most stakeholders wanting an outcome beneficial to sufferers would hope that the main criterion is PEM or PENE…post-exertional malaise / post-exertional neurological exhaustion, probably associated with other classic viral symptoms.
        Also, can you reliably test (negatively or positively) for HHV-6? What is the confidence in a result?

  2. in my experience (and that of my unfortunately very alternative treatment) it’s not just HHV6 that can perform the metabolism-shut-down-trick but also EBV, mycoplasma, lyme, and so on.. and it’s not really the blood/whole body that it infects but particular places like brain (hypothalamus area mostly), heart, thyroid, anything where there’s lots of nerves where it can hide and which the body hás to preserve since one can’t grow a new set of nerves usually ;/ whatever metabolic failure is found elsewhere is just a symptom, not a cause imho

    • I agree with you and this is what we are trying to argue all the times that blood may not be an ideal place to search for HHV-6 infection or any other infection to link it to CFS. Many pathogens shuts down mitochondria and many also need to increase mitochondrial function. But all the herpesviruses associated with CFS probably has a similar mechanism of damaging mitochondria. We use HHV-6 and HHV-7 as a model to know how they shuts down mitochondria. We are almost there. Then we will start looking for similar mechanism used by other viruses. We are not searching for HHV-6 and HHV-7 in CFS patients. We are only trying to establish how viruses or possibly other pathogens target mitochondria. This is so far not completely known.

      Regarding ineffectiveness of Ganciclovir, this antiviral inhibits viral DNA replication, but we do not believe that viral DNA replication is necessary for the disease contribution. Its something else that damages mitochondria.

      • thanks for the answer even though you must be superbusy 😉 one last thing/guess; could it have anything to do with hypoxia and have you heard about “stealth viruses”?

        • I doubt about hypoxia. HHV-6 and HHV-7 are also stealth viruses. That’s what is our interest. Almost everyone have it but we are trying to understand what makes them active again in some of them.

          • in me it was low vitamin D + boron and thyroid hormone T5 activated it when my FT4 went below 16

            the hypoxia is just in me then, perhaps because mycoplasma can be anaerobe, was on ABX for it for a year

            oops I said “one last thing” haha

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