Hypothesis ME/CFS as a sickness behaviour-like response to HSV-1 infection within the brain: A hypothesis, 2025, Campbell

[forestglip]

ME/CFS as a sickness behaviour-like response to HSV-1 infection within the brain: A hypothesis

John Campbell

[Line breaks added]

Highlights
• Subset of ME/CFS cases proposed to be caused by a ‘noisy’ latent HSV-1 infection within the brain.
• HSV-1 proposed to cause local sickness behaviour-like response in the brain.
• IL-1β, IL-6, TNF-α in the brain proposed to increase sensations of fatigue and pain.

Abstract
This work presents the hypothesis that a Herpes Simplex Virus 1 (HSV-1) infection in the brain is a significant contributor to the symptoms experienced by a subset of ME/CFS patients. In these patients, an HSV-1 infection has spread from the trigeminal ganglia to the brain, leading to a sickness behaviour-like response that amplifies sensations such as fatigue, pain, and nausea.

The hypothesis proposes that ME/CFS is a heterogeneous condition, with a ‘noisy’ latent HSV-1 infection of the brain, and an enduring sickness behaviour-style immune response, an underlying factor for a subset of patients.

Web | Medical Hypotheses | Paywall

 

[Peter T]

The idea that ME/CFS is related to some form of ongoing viral infection either a persistent infection, perhaps as a virus reservoir in some part of the body inaccessible to testing as with say Ebola persisting in such as the eyeball, or a novel or poorly understood virus such as retroviruses has a long history. I do not know enough about the current status of virology to say if, given the number of years we have been looking, it is reasonable or not to say, if a persisting virus was the cause of our ongoing symptoms, it would already have been found.

Proponents of some form of persisting virus theory have explained previous lack of success in terms of it either persisting in some hard to test location or a novel virus. Does this paper explain the previous failure of viral related explanations in terms of it only relating to a subgroup of those with ME/CFS?

I don’t know enough to evaluate this paper, but I do know it is reasonable to be cautious given the number of times this field of research has claimed ‘the answer’ only for it to amount to nothing.

However I am also puzzled by the finding (previously?currently?) reported in the UK MEA’s big purple book that a course of antivirals helps a proportion of people with ME/CFS, which seems to just sit there ignored or forgotten. For some years I had languishing on my to do list looking out the research on this to discuss with my GP the pros and cons of a year or more on antivirals, but have never got that far along any iteration of my ‘list’.

[edited to correct typos]

 

[Rick Sanchez]

However I am also puzzled by the finding (previously?currently?) reported in the UK MEA’s big purple book that a course of antivirals helps a proportion of people with ME/CFS, which seems to just sit there ignored or forgotten. For some years I had languishing on my to do list looking out the research on this to discuss with my GP the pros and cons of a year or more on antivirals, but have never got that far along any iteration of my ‘list’.

I go back all the way to the Phoenix Rising days and always thought the idea of anti-virals was silly. If they worked, then surely everyone would be taking them? I mean even now, you barely hear any anti-viral ´´success`` stories compared to LDN and LDA ´´success`` stories. Then around two years ago got guilt tripped into taking some Valaciclovir by my parents because the ME clinic I was at suggested taking some, and for the only time in my entire life I felt like I tried something that actually worked. Was able to feel sleepy, fall asleep immediately and breathe through my nose within 3 days and all my symptoms continued to improve afterwards. Felt like genuine divine intervention. Slowly stopped working around 3 months in though, until all improvement had ceased 9 months in.

Yet, despite my own experience. What I fear is that anti-virals have been a red herring for some MECFS researchers and clinicians. A lot of them seem to have heard of, or believe to have seen for themselves stories like mine. But what if the improvements like mine were merely a) randomly fluctuations, or b) had nothing at all to do with the cause itself of MECFS? Maybe the anti-virals merely gave a temporary break from whatever is causing MECFS.

I`ve tried to track down other patients who also experienced massive improvements following anti-viral treatment, and honestly it has been incredibly difficult to find any at all!! A lot of the stories simply sound like random fluctuations, especially the ones where it took months for it to ´´work``, and where the ´´effect´´ seemed minimal. Honestly just sounds like the classic LDN or alternative therapy stories. The very very few stories similar to mine, where massive improvement took place quickly, all seem to have relapsed.

MECFS clinics have an ungrateful job, but I think they have sadly helped feed the anti-viral narrative. Flugge and Mella have shown through their studies how wildly MECFS symptoms can fluctuate, especially in the milder parts of the MECFS populations who make up the majority compared to the more stable severe patients. This naturally leads to a lot of red herrings with a chronic illness like MECFS, where patient and practitioner believe something is working that simply isn`t.

The only interesting anti-viral study I was able to find was a recent one by Dr. Chia. Although the reason I found it interesting was because ultimately it did not work out. The patients relapsed within two to nine months. However that was precisely why I found it interesting. Compared to MECFS null result studies, it was interesting how quickly the patients ´´improved`` and then relapsed. Because usually when you hear of the MECFS bogus treatments you always hear, oh yeah, you have to try this for months or whatever before it starts working (convenient!!). You even hear this about the treatments at MECFS clinics. Looking at Flugge and Mella studies, some MECFS patients will randomly have improved abit after 3-6 months (or they will believe they have improved), so suddenly, it might appear like these bogus treatments are working!!

Lipkin also made a comment about anti-virals recently which I found when I was going down the anti-viral rabbit hole:

The other thing is, there are a group of patients who have persistent infections who respond to Ampligen
They just do
Regardless of the fact that some people don`t believe it
I`ve seen it
It`s real
Dan Peterson, who`s been sort of pioneer in this area, has show unequivocally that there are certain markers that he can identify which allow him to say, this is somebody who`s going to respond, and this is somebody who won`t

Personally I fear it is all a red herring, and that even if in cases like mine there was genuine temporary improvement (and not just random fluctuation), then it ultimately won`t have anything to do with the cause of MECFS.

 

[duncan]

Proponents of some form of persisting virus theory have explained previous lack of success in terms of it either persisting in some hard to test location or a novel virus. Does this paper explain the previous failure of viral related explanations in terms of it only relating to a subgroup of those with ME/CFS?

You won't see it much, but there's a theory of immune tolerance that might.

 

[Peter T]

@Rick Sanchez, a very interesting post, thank you for sharing.

 

[ScoutB]

On the one hand, a pesky virus in the brain doesn’t seem out of the question to my layman’s logic. (My understanding is the evidence for HIV as the cause of AIDS looked similarly unclear and contradictory for many years so just because a viral theory has been around for a long time without proving itself doesn’t necessarily mean it’s totally wrong).

On the other hand, is the paper’s author the same YouTube guy spreading misinformation per this thread?

 

[PageofME]

I go back all the way to the Phoenix Rising days and always thought the idea of anti-virals was silly. If they worked, then surely everyone would be taking them? I mean even now, you barely hear any anti-viral ´´success`` stories compared to LDN and LDA ´´success`` stories. Then around two years ago got guilt tripped into taking some Valaciclovir by my parents because the ME clinic I was at suggested taking some, and for the only time in my entire life I felt like I tried something that actually worked. Was able to feel sleepy, fall asleep immediately and breathe through my nose within 3 days and all my symptoms continued to improve afterwards. Felt like genuine divine intervention. Slowly stopped working around 3 months in though, until all improvement had ceased 9 months in.

Yet, despite my own experience. What I fear is that anti-virals have been a red herring for some MECFS researchers and clinicians. A lot of them seem to have heard of, or believe to have seen for themselves stories like mine. But what if the improvements like mine were merely a) randomly fluctuations, or b) had nothing at all to do with the cause itself of MECFS? Maybe the anti-virals merely gave a temporary break from whatever is causing MECFS.

I`ve tried to track down other patients who also experienced massive improvements following anti-viral treatment, and honestly it has been incredibly difficult to find any at all!! A lot of the stories simply sound like random fluctuations, especially the ones where it took months for it to ´´work``, and where the ´´effect´´ seemed minimal. Honestly just sounds like the classic LDN or alternative therapy stories. The very very few stories similar to mine, where massive improvement took place quickly, all seem to have relapsed.

MECFS clinics have an ungrateful job, but I think they have sadly helped feed the anti-viral narrative. Flugge and Mella have shown through their studies how wildly MECFS symptoms can fluctuate, especially in the milder parts of the MECFS populations who make up the majority compared to the more stable severe patients. This naturally leads to a lot of red herrings with a chronic illness like MECFS, where patient and practitioner believe something is working that simply isn`t.

The only interesting anti-viral study I was able to find was a recent one by Dr. Chia. Although the reason I found it interesting was because ultimately it did not work out. The patients relapsed within two to nine months. However that was precisely why I found it interesting. Compared to MECFS null result studies, it was interesting how quickly the patients ´´improved`` and then relapsed. Because usually when you hear of the MECFS bogus treatments you always hear, oh yeah, you have to try this for months or whatever before it starts working (convenient!!). You even hear this about the treatments at MECFS clinics. Looking at Flugge and Mella studies, some MECFS patients will randomly have improved abit after 3-6 months (or they will believe they have improved), so suddenly, it might appear like these bogus treatments are working!!

Lipkin also made a comment about anti-virals recently which I found when I was going down the anti-viral rabbit hole:



Personally I fear it is all a red herring, and that even if in cases like mine there was genuine temporary improvement (and not just random fluctuation), then it ultimately won`t have anything to do with the cause of MECFS.

Hi Rick
I am one of those patients like you. And so far I have met three other patients "personally" online who also responded well to acyclovir and had their flares fully suppressed. Anecdotal evidence for the activity of acyclovir in some ME patients has been around since the 80ies.

It's interesting that here in this thread I see for the first time that someone has recently proposed HHV-1 brain inflammation as the cause of ME.

I have known of Jacquline Cliff's and others work on HHV-6B for some time. Acyclovir is not the standard drug to treat HHV-6B reactivation in patients with severe immuno deficiencies because there are other anti-herpes-virals that are more effective. But acycloivr has "good" activity against HHV-6B according to the textbooks and therefore I believe that I do have HHV-6B flares and that that's the cause of ME at least for my subgroup.

I attended the last CureME call in the end of July 2025 and had a chance at directly ask Jackie about her work. She said that they needed a couple of years but then will be able to understand the role of HHV-6B in ME fully.

What's important about herpes viruses: They do not disappear in the host after infections but they go "latent". They hide in different cell types and are able to wake-up again. Therefore your idea that acyclovir does not work because patients sooner or later relapse is inadequate.

I use acyclovir differently from how it was prescribed to you and I am very glad that I have found your story to confirm my idea that it isn't a good idea to go on large daily amounts of the drug continually and begin working again. But instead continue with my disciplined pacing with which I have managed to access a slow recovery process and use acyclovir only for an emergency.

About three years ago I had an exchange with a doctor who decided to go back to work on the drug. When we chatted she was on that regime for about a year. It was not only that she had to increase dosage but she also said that the side effects began to become unbearable. It also seemed to me that she was not building skill at pacing properly and thus was overstraining her organism.

So what I do is that I only use it as an emergency medication. For example I had a mild flare three weeks ago that I would usually manage with increased bed rest and bring to full control in very few days. However, since I was abroad and had planned to travel back home by train in a ten hours journey from door to door I decided to go on the drug because on the day of travel I wouldn't have been able to rest and pace well enough and probably would have ended up worse in the evening or the next day.

As soon as I had settled in back home I went off the drug, staying on a preventative dose of 2x400mg for two more days to help me find back into pacing my daily life and then went off.

Herpes viruses build resistancies to anti-virals fast. It is therefore very important to always take a high enough dose in order to prevent the virus from forming new resistant variations. So this might be an explanation why it stopped working for you after three months.

I find a bit weird that you were prescribed acyclovir at that clinic without being informed about the danger of the forming of resistancies of the herpes viruses. Because this information helps patients to understand that it's extremely important to never forget a dose and be very disciplined around the schedule of administering it.

 

[PageofME]

ME/CFS as a sickness behaviour-like response to HSV-1 infection within the brain: A hypothesis

John Campbell

[Line breaks added]

Highlights
• Subset of ME/CFS cases proposed to be caused by a ‘noisy’ latent HSV-1 infection within the brain.
• HSV-1 proposed to cause local sickness behaviour-like response in the brain.
• IL-1β, IL-6, TNF-α in the brain proposed to increase sensations of fatigue and pain.

Abstract
This work presents the hypothesis that a Herpes Simplex Virus 1 (HSV-1) infection in the brain is a significant contributor to the symptoms experienced by a subset of ME/CFS patients. In these patients, an HSV-1 infection has spread from the trigeminal ganglia to the brain, leading to a sickness behaviour-like response that amplifies sensations such as fatigue, pain, and nausea.

The hypothesis proposes that ME/CFS is a heterogeneous condition, with a ‘noisy’ latent HSV-1 infection of the brain, and an enduring sickness behaviour-style immune response, an underlying factor for a subset of patients.

Web | Medical Hypotheses | Paywall

This is very interesting and brings back some difficult memories for me as well. When I had my first ME/CFS episode in the spring of 2017 for six weeks I was quite certain from the beginning that I had a form of herpes reactivation. I had suffered from opportunistic HSV-1 reactivations since I was a child and the character of that flu-like new illness felt very similar.

I was then a mild patient for several years. Certain that I had some annoying herpes reactivations every now and then because of stress and soon realised that they went away quickly with some bed rest and some mugs of herbal infusion. Since my GP couldn't help me explain what was going on except to let me know that you couldn't do anything against herpes anyway I left it at that.

When I began to deteriorate faster since the autumn of 2020 I began to research different types of herpes to figure out what I could have. Because of a sore throat and flu-like symptoms I went to see a throat-nose-ears doctor who ruled out an infection in the area of her specialty. This I took as a confirmation that I had smoldering, sub-acute herpes brain inflammation. From now on I clearly felt my brain simmering behind my forehead, and I also connected my beginning neurological problems to that sensation.

I wrote with a infectiologist in my family to ask her about smoldering "benign" herpes brain inflammation and she came up with the idea of Mollaret meningitis. An acute but benign and self-ending form of HSV-1 reactivation in the meninges.

I went back to the TNE doctor and begged her to prescribe acyclovir on speck to me on the idea of HSV-1 meningitis. She agreed and I got on the drug. It worked. After one hour on 800mg the flu-like feeling, the low fever and the inflammatory sensations behind my forehead stopped.

I thought I had it all figured out, of course. I'll leave it at that for the moment. I have already written before here that I now think that my ME is caused by HHV-6B founded on the research results of Prusty, Cliff and many more.

 

[Rick Sanchez]

Hi Rick
I am one of those patients like you. And so far I have met three other patients "personally" online who also responded well to acyclovir and had their flares fully suppressed. Anecdotal evidence for the activity of acyclovir in some ME patients has been around since the 80ies.

It's interesting that here in this thread I see for the first time that someone has recently proposed HHV-1 brain inflammation as the cause of ME.

I have known of Jacquline Cliff's and others work on HHV-6B for some time. Acyclovir is not the standard drug to treat HHV-6B reactivation in patients with severe immuno deficiencies because there are other anti-herpes-virals that are more effective. But acycloivr has "good" activity against HHV-6B according to the textbooks and therefore I believe that I do have HHV-6B flares and that that's the cause of ME at least for my subgroup.

I attended the last CureME call in the end of July 2025 and had a chance at directly ask Jackie about her work. She said that they needed a couple of years but then will be able to understand the role of HHV-6B in ME fully.

What's important about herpes viruses: They do not disappear in the host after infections but they go "latent". They hide in different cell types and are able to wake-up again. Therefore your idea that acyclovir does not work because patients sooner or later relapse is inadequate.

I use acyclovir differently from how it was prescribed to you and I am very glad that I have found your story to confirm my idea that it isn't a good idea to go on large daily amounts of the drug continually and begin working again. But instead continue with my disciplined pacing with which I have managed to access a slow recovery process and use acyclovir only for an emergency.

About three years ago I had an exchange with a doctor who decided to go back to work on the drug. When we chatted she was on that regime for about a year. It was not only that she had to increase dosage but she also said that the side effects began to become unbearable. It also seemed to me that she was not building skill at pacing properly and thus was overstraining her organism.

So what I do is that I only use it as an emergency medication. For example I had a mild flare three weeks ago that I would usually manage with increased bed rest and bring to full control in very few days. However, since I was abroad and had planned to travel back home by train in a ten hours journey from door to door I decided to go on the drug because on the day of travel I wouldn't have been able to rest and pace well enough and probably would have ended up worse in the evening or the next day.

As soon as I had settled in back home I went off the drug, staying on a preventative dose of 2x400mg for two more days to help me find back into pacing my daily life and then went off.

Herpes viruses build resistancies to anti-virals fast. It is therefore very important to always take a high enough dose in order to prevent the virus from forming new resistant variations. So this might be an explanation why it stopped working for you after three months.

Thank you a lot for your very interesting post, and contribution to the discussion.

I continued taking a high dose throughout, being very mindful of taking it at the best possible times to maximize the effect. I come from a somewhat privileged family, and know a lot of doctors and people who work in pharma, and everyone I have talked to think the idea of resistance being the reason for my regression very unlikely. They could all be wrong of course.

Having been active in the MECFS community for over a decade now, I have read a lot of stories about people who had a remission and then claimed to ´´overdo it`` and have their symptoms worsen. So I was obsessed with never overexerting when I was getting better. Yet I still regressed.

I think there is a lot of victim blaming amongst MECFS patients, and people will sometimes wrongly attribute worsening of symptoms to overdoing it, when in fact the worsening was always going to happen. I think this is also the case in a lot of failed recovery stories. Don`t get me wrong of course a lot of MECFS patients can directly attribute their ´´permanent`` worsening of symptoms to overexertion or graded exercise. However I think patients like all human beings become too obsessed with cause and effect. Not every case of worsening symptoms is due to overexertion. Some patients just crash and get worse, and there was absolute nothing that could have been done to prevent this from happening.

The latent virus thing is of course true, and the possibility of resistance is genuine. However some of the other patients I have been in contact with have tried other and more ´´serious`` anti-virals afterwards, and none had any effect whatsoever, when the virus should not have built resistance to these? At least as I understand it with my sadly pathetic knowledge of medicine.

Some long covid researchers seem obsessed with the latent virus stuff so we will see if anything comes from it in the following years. I personally doubt anything will come from this route taken, but would be delighted if proven wrong.

One last thing. Very interesting how quickly you responded!!

 

[PageofME]

Thank you a lot for your very interesting post, and contribution to the discussion.

I continued taking a high dose throughout, being very mindful of taking it at the best possible times to maximize the effect. I come from a somewhat privileged family, and know a lot of doctors and people who work in pharma, and everyone I have talked to think the idea of resistance being the reason for my regression very unlikely. They could all be wrong of course.

Having been active in the MECFS community for over a decade now, I have read a lot of stories about people who had a remission and then claimed to ´´overdo it`` and have their symptoms worsen. So I was obsessed with never overexerting when I was getting better. Yet I still regressed.

I think there is a lot of victim blaming amongst MECFS patients, and people will sometimes wrongly attribute worsening of symptoms to overdoing it, when in fact the worsening was always going to happen. I think this is also the case in a lot of failed recovery stories. Don`t get me wrong of course a lot of MECFS patients can directly attribute their ´´permanent`` worsening of symptoms to overexertion or graded exercise. However I think patients like all human beings become too obsessed with cause and effect. Not every case of worsening symptoms is due to overexertion. Some patients just crash and get worse, and there was absolute nothing that could have been done to prevent this from happening.

The latent virus thing is of course true, and the possibility of resistance is genuine. However some of the other patients I have been in contact with have tried other and more ´´serious`` anti-virals afterwards, and none had any effect whatsoever, when the virus should not have built resistance to these? At least as I understand it with my sadly pathetic knowledge of medicine.

Some long covid researchers seem obsessed with the latent virus stuff so we will see if anything comes from it in the following years. I personally doubt anything will come from this route taken, but would be delighted if proven wrong.

One last thing. Very interesting how quickly you responded!!

Rick, thank you for your interesting reply.

I think that the most important thing I wanted to say was how important your experience was for me. Because you are only the second person I have the chance to chat with who did try a continual acyclovir treatment.

It was of course an idea that I thought about too. The main reason that it didn't happen was that neither my TNE doctor, nor my GP, or my ME specialist wanted to take the responsibility to try a herpes drug off-label. They all mentioned the risk of the forming of resistancies. That was before I knew about the HHV-6B hypothesis in ME.

Since I really wanted it for an emergency situation I found a way to get a hand on it myself. I informed my GP and my specialist which they appreciated as a sign of my trust in them, and probably understood well. Maybe thinking that they would do just the same if they had ME.

I realise my post to you went a lot in to the direction of educating you about the charateristics of herpes viruses and the high risk of resistancies. When my main internal response was more of the sort of relief that I didn't had the chance to go on acyclovir continually because of the caution of my doctors around off-label prescriptions generally, and their great awareness of the forming of resistancies in bacteria and viruses towards antibiose/antivirals.

You wrote a lot about remission and deterioration that can happen to patients even when they rest and pace really well. I know about that. In the German speaking countries the idea that with pacing 80% of patients / in 80% of the time patients can reach stabilisation with a disciplined energy management is widespread. So I am very aware of the 20% where patients do not have control of the course of the illness.

When I wrote that that doctor who I chatted with possibly didn't do enough to learn to rest and pace it was inferred from my own experience on acyvlovir. I am completely at a loss very fast when I am on the drug for a couple of days to understand what's a sensible amount of activity that I should do.

I have therefore decided for myself that I want to treat that case as sick days. I try to plan as little activity and a lot of rest. Just as if I was ill with every other infectional illness. And I remind myself that I am not recovered or healthy even though it feels like that. It's only under the influence of a very potent drug that I feel that way. In reality my theory goes that my T-cells are too exhausted, too few, too degenerated to effectively fight off HHV-6B reactivation. Hence I tell myself that even when I don't feel like it especially during the first couple of days on the drug where I feel that I'm in complete remission of ME/CFS which is euphorising, in reality, I am very sick.

I think that that's just an other mindset than that of that doctor I chatted with who decided to continue working as a doctor in a stressful job with long hours and a lot of responsibilty. The driven doctor's mindset, if you will.

Since we have "socialism" in Switzerland when it comes to financial social security and nobody has to live in the streets who doesn't want to, there is a real choice for us whether we want to take care of ourselves when we're ill. And I think that that might have helped me to resist the desire to start my work rehabiliation on a potent drug that's not a cure but just suppresses symptoms.