Targeting the Monocytic-Endothelial-Platelet Axis with Maraviroc and Pravastatin as a Therapeutic Option to Treat Long COVID/ Patterson/PP

J

Jaybee00

Senior Member (Voting Rights)
Preprint

https://www.researchsquare.com/article/rs-1344323/v1


Post-acute sequelae of COVID (PASC), or long COVID, is a multisystem complication of SARS-CoV-2 infection that continues to debilitate millions worldwide thus highlighting the public health importance of identifying effective therapeutics to alleviate this illness.

The pathophysiology behind PASC may be attributed to the recent discovery of persistent S1 protein subunit of SARS-CoV-2 in CD16+ monocytes up to 15 months after infection. CD16+ monocytes, which express both CCR5 and fractalkine receptors (CX3CR1), play a role in vascular homeostasis and endothelial immune surveillance.

We believe targeting these receptors using the CCR5 antagonist, maraviroc, along with pravastatin, could disrupt the monocytic-endothelial-platelet axis that may be central to the etiology of PASC. Using five validated clinical scales (NYHA, MRC Dyspnea, COMPASS-31, modified Rankin, and Fatigue Severity Score) to measure 18 participants’ response to treatment, we observed significant clinical improvement in six to twelve weeks on a combination of maraviroc 300mg PO BID and pravastatin 10 mg PO daily.

Subjective neurological (p=0.002), autonomic (p<0.0001), respiratory (p=0.0153), cardiac (p=0.002) and fatigue (p<0.0001) symptoms scores all decreased which correlated with statistically significant decreases in vascular markers sCD40L and VEGF.

These findings suggest that by interrupting the monocytic-endothelial-platelet axis, maraviroc and pravastatin may restore the immune dysregulation observed in PASC and could be potential therapeutic options.

This sets the framework for a future double-blinded, placebo-controlled randomized trial to further investigate the drug efficacy of maraviroc and pravastatin in treating PASC.
 
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dreampop said:
No controls, why bother?
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That's probably a bit unfair. The study probably helped them develop their ideas and might give potential funders of a bigger blinded trial confidence. They say:
Abstract said:
This sets the framework for a future double-blinded, placebo-controlled randomized trial to further investigate the drug efficacy of maraviroc and pravastatin in treating PASC.
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It looks like they understand that this isn't proof that the treatments work.
 
I wish I had more to say, but I am currently about 50% certain that this combo is working for me after 6 weeks. See my previous threads for more info — I will post a real update after it has been a bit longer. Note that I probably have a history of tick borne illnesses, and do not fit CCC criteria for me cfs.

Normally I wouldn’t make an “improvement post” so soon, but it seems relevant here.

i have a lot of skepticism of the Patterson stuff but I have no choice but to give him the slight benefit of the doubt right now.
 
I've only skimmed the abstract and will try and read the pre-print on the weekend. I suspect (from what I've read in general so far) that some of these findings will prove useful to understanding LC. In particular, the demonstration of S1 spike protein in monocytes out to ~15 months seems important. On the treatment side, the implication of pathology relating to lipids might show wider application in ME in time. Agree with Hutan's comments above that pilot studies have to start somewhere, so that RCTs may follow on.

Circumspection around the COIs is required too. This looks like it might be an ongoing problem in LC research at this stage, while governments and national health providers are not moving with urgency or vision. Expect very similar issues will be present in any papers that might stem from the apheresis treatments too.

Hopefully, useful information will be gathered from all these sources and I am pleased to see progress being made. In the meantime anecdotal reports (incl. @5vforest just now :thumbsup:) of patient improvement maintain optimism, even if they don't yet represent scientific levels of evidence.
 
Assuming the S1 protein persistence is real, what are the implications? That there is a persistent infection? That the virus has somehow integrated itself into host DNA?
 
strategist said:
Assuming the S1 protein persistence is real, what are the implications? That there is a persistent infection? That the virus has somehow integrated itself into host DNA?
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Not necessarily persistent infection, but perhaps persistent viral components - in this case S1. The Patterson theory is that intermediate (CD14+, CD16+) and non-classical (CD14-, CD16+) monocytes ingest S1 and that this renders them very long-lived - well beyond their typical lifespan of a few days, but instead to months or years.

Previously the authors had said:
One possible explanation for S1 protein in non-classical monocytes could be that pre-existing CD14lo CD16+ cells could phagocytise virally infected apoptotic endothelial cells with subsequent degradation of the RNA and presentation of the S1 protein.
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Concluding then they said:
In summary, the mechanism of PASC proposed in this report suggests that intermediate monocytes remain in circulation due to low CCL4 levels extending their time to differentiate leading to an accumulation of non-classical monocytes.
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See our previous discussions about that earlier paper on this thread.

Some relevant quotes from the current paper (lightly edited for brevity/clarity) -

The introduction said:
Nonclassical monocytes are involved in phagocytosis and vascular adhesion by patrolling the endothelium under homeostatic and inflammatory conditions through B2 integrin, lymphocyte function-associated antigen-1 (LFA-1) and high levels of fractalkine receptors (CX3CR1). On the other hand, intermediate monocytes express high levels of C-C chemokine receptor type 5 (CCR5) and fractalkine receptors and are involved in antigen presentation, cytokine secretion and apoptosis regulation.

Since CCR5 and fractalkine receptors have been studied for various chronic inflammatory pathologies, we hypothesized that these receptors may also be therapeutic targets for PASC. CD16+ monocytes also produce high levels of various pro-inammatory cytokines which could be an explanation for the heterogenous symptomatology in PASC. Specically, elevations in C-C chemokine ligand 5 (CCL5)/RANTES, IL-2, IL-6, IFN-gamma and VEGF, along with decrease in CCL4 have been observed in patients and are hypothesized to be contributing to the pathophysiology of PASC.
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The discussion said:
Both intermediate and nonclassical monocytes, are known to interact significantly with the endothelium and platelets via the fractalkine pathway. This suggests that the pathophysiology of PASC may lie with the monocytic-endothelial-platelet axis. Fractalkine, which mediates cell adhesion and leucocyte recruitment, is a transmembrane protein expressed in the brain, colon, heart, and lung, along with endothelial cells and astrocytes.

Intermediate monocytes express high levels of both CCR5 and fractalkine receptors, whereas nonclassical monocytes express high levels of fractalkine receptors. This interaction between fractalkine and fractalkine receptors have been involved in the pathogenesis of atherosclerosis, vasculitis, vasculopathies, and inflammatory brain disorders and could also be contributing to vascular endothelialitis in PASC.

Endothelialitis leads to collagen exposure along with platelet activation and adherence via GPIb-IX-V with collagen-bound vWF. Activated platelets release soluble CD40 ligand (sCD40L) to recruit both neutrophils and monocytes to the vascular lesions, thus activating the coagulation cascade. Stimulated platelets also release RANTES which binds to endothelial cells and encourages monocyte adhesion to inflamed endothelial tissues and acts as a chemotactic agent for inflammatory cells.

Activated platelets and endothelial cells can also secrete VEGF which induces angiogenesis and microvascular hyperpermeability. VEGF is a diagnostic marker for vasculitic neuropathy and also contributes to a pro-inflammatory-prothrombotic environment. While the vascular effects of statins have been well documented, the protective role of maraviroc on the endothelium has also been similarly published. Hence, we targeted CCR5 and fractalkine receptors on the S1 protein expressing CD16+ monocytes using maraviroc and pravastatin, respectively.
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I'm no expert, but I personally don't favour this theoretical explanation and think it's too much of a stretch to immortalise monocytes from the usual days to years.

From The fate and lifespan of human monocyte subsets in steady state and systemic inflammation: "intermediate and nonclassical monocytes have longer circulating lifespans (∼4 and ∼7 d, respectively)."

I would think it's more likely the observed monocytes have ingested S1 recently: either from a reservoir of intact/active virus or of old/residual viral components.
 
Hutan said:
That's probably a bit unfair. The study probably helped them develop their ideas and might give potential funders of a bigger blinded trial confidence. They say:

It looks like they understand that this isn't proof that the treatments work.
Click to expand...

Yeah, I think my comment was unfair even with context. I can see the value in a "practice run" for safety, dosage, and I guess if I put my cynicism aside, timetable as the authors are doing here. Sometimes these papers can feel like they are made just to maintain a research cycle rather than for the research itself if that makes any sense.
 
If you already happen to be taking a statin, switching to pravastatin would seem to be an easy test. The study uses the common standard dosage. I'm already taking a statin. In a routine follow-up I explained my rationale to my doctor from a lipid clinic. He had no trouble making the switch.

As with others, I'm skeptical and going to wait quite a few weeks before assessing its effect.
 
Here goes anecdotal evidence.

I've been using pravastatin for about two months. It took about a month before there was a noticeable effect. As a geek, one of my metrics is how much a feel like programming. Suddenly I went from no interest in programming for many months to spending an hour or more a day at the computer. I wake up often now refreshed and with a mind that's actively planning and has some energy. Physically, when I go for walks my legs move without my having to stubbornly urge them on.

For a while I stopped taking most of my 'encourage the mitochondria' supplements. I've added them back, which works much better. This is in line with what Patterson has been doing.

I don't see this as a cure. In particular, PEM remains. It becomes more of a roller coaster, with many more highs and lows, but having this much improvement is amazing. That said, the concern is that it may end up being more of a short term stimulant with the potential to exhaust me.
 
Here is another talk, this time to a group of Australian doctors. It is a good and recent summary of his research, including insight into why they are following their current path.



As an aside (beware "works for me")

After I'd been taking pravastatin for a month or so, about an hour after taking it I noticed I was energized and practically driven to get out of bed. The results have been pretty consistent over time. My cholesterol specialist said it was reasonable in my case to increase the dosage to two pills a day. When I started that process I actually read the label on the bottle which indicated the pill should be taken at night. I started doing that. I switched back to taking one pill in the morning and another in the afternoon. The "energy effect" returned, now twice a day. I also couldn't understand why PEM was still there so much. The video explained the dosing, and why the other drug is needed even though they are both CCR5 inhibitors.
 
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