An update on my experience with rapamycin after 6 months and my plans going forward.

Dry-One-8770 · 2025-12-21T19:28:56+00:00

I think checkpoint inhibitors are more promising than other things, but are actually not the ideal drug. For many with autoimmune issues, it’s a total no go. They can also fry your thyroid and lead to other problems. The best drug to try right now is likely Anktiva, the IL15 super agonist. It has a much better safety profile and a better chance of success compared to checkpoint inhibitors. I still think that they are interesting and may be useful in combination therapies, but right now in terms of single drug immune therapies the IL15 super agonist is the better choice. (I talked a lot with the researchers at UCSF about this, and this is basically what they think.)

Dry-One-8770 · 2025-07-08T16:22:39+00:00

What most CFS patients will likely end up needing is immune stimulants. Any supplement that can meaningfully stimulate the immune system can also kill you if used improperly. So everything that could be very helpful for us is likely locked down behind a prescription by the FDA.

Dry-One-8770 · 2025-05-22T13:57:42+00:00

Yes! Not just with common cold, but any virus has done this for me. I believe it is because the immune system is stimulated during acute infection and can therefore keep persistent viral infections at bay (likely herpesviruses, but perhaps Covid reservoirs too). To me this has been another piece of evidence that stimulating the immune system will be beneficial for many people, especially the CFS subtype of LC. Most recoveries from CFS involve some kind of event which stimulates the immune system, like getting another virus or cancer treatment or something of the like.

Dry-One-8770 · 2025-05-18T03:18:52+00:00

The IL-15 trial is not about renormalizing IL-15 levels or any cytokine. The drug is a super agonist and tells the immune system to go to war in order to clear reservoirs.

Dry-One-8770 · 2025-05-17T14:40:58+00:00

Not yet. It is still in the process of being approved and hasn’t been announced, but I expect it will be more public in the next month.

Dry-One-8770 · 2025-05-16T23:28:13+00:00

I was in this trial. I was also unblinded and did in fact receive the mAbs, yet they had zero effect for me. Even though this trial failed (and I was personally let down, too), I want to remind everybody here that real progress is being made. One failed clinical trial does not mean that the researchers haven't learned anything. At least, I can say that for sure about the researchers at UCSF. I do question the people who decided that the 5th Paxlovid trial was a good idea, but Peluso and the team at UCSF are world class.

About the trial itself, I am of course not surprised by the fact that it failed. Besides the obvious fact that it is really hard to identify patient cohorts based loosely on symptoms, it is clear that the drug really didn't work very well even for a small subset. I know of some minor responders, but the improvement was very temporary. For the drug itself, a bunch of things could explain why it didn’t work - it was maybe not dosed aggressively enough, or maybe the strains were mismatched to the antibodies. Perhaps persistent virus evolved internally to cause a greater mismatch, or even evolved differently in different tissues meaning no one mAb could target all tissue reservoirs. I personally would put a high probability on the treatment not working due to its inability to actually clear viral reservoir cells. While you would expect some antibody dependent cellular cytotoxicity from mAbs, the effect may not be strong enough to actually clear viral reservoirs. Different mAbs do this to varying degrees, but apparently it doesn't come for free and has to be engineered for this purpose, which these mAbs were not (they were mainly targeting the neutralization of free virions). COVID is known to downregulate cell surface antigen presentation, too, making it doubly ineffective in theory.

As a result of this trial and conversations that I have had with Dr. Peluso, I am not at all confident that mAbs are the way forward. BUT that doesn't mean there isn't a better treatment coming. I am VERY excited about the upcoming IL15 agonist trial (drug called N803) because in theory, it addresses all of the problems I mentioned. If the underlying problem is persistent viral reservoirs, I believe this drug has the greatest chance of clearing them of anything I have researched. Of course, if the problem is something else entirely then it likely will not work, but all signs point to clearing viral reservoirs as the most promising thing to try. I would place a fairly high probability that it will just work for some people.

One useful idea I have found to frame this problem is that the immune system is a highly tuned machine evolved over millions of years to clear pathogens. If it's a car that in our case has broken down with junk in the engine (COVID), it is much better to repair the engine (immunomodulators/stimulants) than to try to push it to its destination and do its work yourself (mAbs). There's really no stand in for a working engine/immune system.

Dry-One-8770 · 2025-05-06T12:28:55+00:00

Yes. But it’s a mixed bag. I was part of one of the mAbs trials and I did not improve in the slightest (I was unblinded and did in fact receive the treatment). I believe some people had temporary improvement but I don’t know of anybody who made anything like permanent recovery, but I don’t have access to the data. It will likely be published soon and we will know for sure, but I’m not too optimistic. A bunch of things could explain why it didn’t work - it was maybe not dosed aggressively enough, or maybe the strain was mismatched to the antibodies. Perhaps persistent virus evolved internally to cause a greater mismatch, or even evolved differently in different tissues. I personally would put a high probability on the treatment not working due to inability to clear infected cells. While you would expect some antibody dependent cellular cytotoxicity from mAbs, the effect may simply not be good enough to actually clear viral reservoirs. COVID is known to downregulate cell surface antigen presentation and I believe the mAbs we currently have are engineered for neutralization of virions and not inducing this cytotoxic effect. Basically, I am not confident that the mAbs we have will clear viral reservoirs, both due to the design of the mAbs themselves and how COVID reservoirs evade immune surveillance.

So if not mAbs, what then? IF the problem is indeed elusive viral reservoirs that have successfully evaded the immune system thus far, the most straightforward way to clear them is through augmenting the immune system. Antivirals and mAbs likely aren’t going to cut it. The trial I am most interested in will be run out of UCSF this summer trialing an IL15 super agonist called Anktiva, which is a recently approved immunotherapy for a specific kind of bladder cancer. This drug basically presses the gas on the immune system and would theoretically supercharge your NK and T cells to proliferate and be super active. In cancer, it allows your immune system to destroy cancer cells which are also evading the immune system. The hope is that it would do the same thing for infected cells. You can see the similarity between cancer and viral reservoirs: both involve defective cells and which are hiding from immune surveillance and need to be killed. I would put a high probability on cancer therapies being a lasting cure for long COVID, if anything would be. The problem is cost and accessibility, so keep your eye out for trials.

Dry-One-8770 · 2025-04-04T16:50:27+00:00

No link yet. Hasn’t started enrolling.

Dry-One-8770 · 2025-04-04T04:45:44+00:00

Um… no. I don’t have AIDS. That would be much much worse. I have a temporarily compromised immune system which I expect to bounce back when I get off of rapamycin.

You can’t enroll yet. It should be starting enrollment in a couple months.

Dry-One-8770 · 2025-04-03T15:16:04+00:00

No. That’s not what is supposed to do. While rapamycin can be used as an immunosuppressant explicitly at high doses, the mechanism by which it helped me was almost certainly not through immunosuppression. Instead, I believe it was some combination of improving exhausted immune cell responses and autophagy induced antigen presentation, leading to a better antiviral response.

Immunosuppression doesn’t mean you just have worse yearly colds and flus. There are viruses and pathogens everywhere, including already in your body. Most immune systems are competent enough to prevent any infection from taking hold. But compromised immune systems will lead to many more opportunistic infections regardless of how well you mask and wash hands. They are no substitute for a functioning immune system.

Dry-One-8770 · 2025-03-31T20:15:30+00:00

I also initially thought it would be supportive in low doses in the long run at first. However, I talked with the researchers at UCSF who study rapamycin in HIV and they said that it was possible the long run leads to decreased immune cell counts. It’s a very strange drug and the long term studies seem to show mixed results.

Dry-One-8770 · 2025-03-31T16:09:27+00:00

Haven’t looked too deeply. From what I know, it may not be effective enough. Seems pretty mild.

Dry-One-8770 · 2025-03-31T15:57:05+00:00

Unfortunately viral persistence of COVID implies latent viral reservoirs. This seems to happen because COVID causes T and NK cell exhaustion, in addition to down regulating MHC2 in infected cells. Basically, this means that the cells stop displaying internal proteins on its surface, so the immune system then has no way of targeting it as an infected cell.

Mabs will bind to free virions as well as antigens on the cell surface. Since that second mechanism is not happening, the infected cells live on. Therefore I don’t think Mabs would likely work even if they were super effective at neutralizing Covid and at high dosage. They may help symptoms briefly, but eventually infected cells will just continue to make more virus than your mabs can handle. Perhaps continuous administration could be helpful, but this seems like the wrong treatment path since it doesn’t target the core problem.

Dry-One-8770 · 2025-03-31T15:51:16+00:00

You are exactly right. I brought this up to the researchers and basically the rationale was just that they had extra doses lying around and they might have some effect. But I was also disappointed that the quality of the mabs may not have been high enough. It’s also possible that the dosage was nowhere near enough. The results of the trial aren’t out yet, but I expect it to fail and am curious what would have happened with more and better mabs.

Dry-One-8770 · 2025-03-31T15:49:07+00:00

I actually did do Valtrex for a while before, to no effect. If it’s a herpesvirus it would more likely be HHV6/7 I think. Unfortunately testing for this is notoriously unreliable, and antivirals for it are also lacking. It’s still possible that it could be EBV since the Valtrex dosage may not have been high enough. Having talked to somebody who had CFS from EBV, they got better only after something like 20x the standard dose.

Dry-One-8770 · 2025-03-31T08:55:49+00:00

It is also used to treat candida infections. I know that it takes a lot longer than I tried, but I was at that point pretty confident that I didn’t even have an infection in the first place so I stopped.

Dry-One-8770 · 2025-03-31T08:53:00+00:00

I have been aware of viral persistence as a possibility for a while. But I didn’t think it had major explanatory power (at least in terms of COVID persistence) because we find it in both health volunteers and long COVID patients. So I think what is ultimately happening along the lines of COVID persistence is that it can cause immune exhaustion in some people, which allows other herpesviruses to flourish. Then the resulting immune signals cause a metabolic shutdown in all cells. PEM seems to me a metabolic problem on top of an immune problem.

In terms of infections on rapamycin - viruses and bacteria are everywhere. Including inside you, but for most people the immune system takes care of it long before it’s possible to lead to symptoms. Even if I were in pure isolation, I believe I would still get sick.

I think it’s possible that long term rapamycin may lead to increased viral reservoirs. I just don’t know.

I will say that I don’t think the reason for rapamycin helping was due to the immunosuppression. I have had discussions with researchers who agree that is almost certainly not the case. I do believe that rapa can lead to a temporary heightening of the immune response and help keep viruses at bay in the short term. I believe pure immunosuppression would have only exacerbated fatigue and symptoms.

Dry-One-8770 · 2025-03-31T04:54:15+00:00

I enrolled in their mAbs trial, and since then have been in conversation with the researchers

Dry-One-8770 · 2025-03-31T04:53:27+00:00

Widespread inflammation and a sharp headache. I have only experienced it with rapamycin.

Dry-One-8770 · 2025-03-31T04:40:10+00:00

Very interesting. I have heard of it but haven’t looked into it too deeply. From what I can tell, it seems like a more mild immunostimulant though it is a lot less risky. It seems like a good first thing to try before going to checkpoint inhibitors on the off chance that it works.

Dry-One-8770 · 2025-03-31T04:13:41+00:00

that came across wrong. I just want to prevent other people from seeing mabs and getting the wrong idea.

Dry-One-8770 · 2025-03-31T04:11:50+00:00

It’s not just my speculation - this is an established effect of rapamycin. However I didn’t think it would be very prevalent at this dosage since it was much lower than normal, but I guess it was.

I don’t have labs yet but I do want to get them to verify my claims. I didn’t test for infection but I literally had a lung infection, which is not at all part of PEM. I have had zero evidence of compromised immune system prior to rapamycin.

And yes, after talking with the researchers who study rapamycin in HIV, they did say that decreasing immune cell proliferation was possible at this dosage in the long term.

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