Yeah - that was the same speculation I offered at some point in the series, that real life dosage is earlier post-onset-of-symptoms than the trial and it doesn’t work well when gun = jumped
Just read this and your subsequent articles on Paxlovid. I can't thank you enough for these. I'm a physicist, not a biologist. I actually loathe molecular biology and find something chilling about it. But God bless you for going there. And then putting together your lockpicker sequences for those of us who can't bear to break life down into molecular steps!
A friend had been told by her doctor that this drug would protect her from hospitalization and death. I've offered her ivermectin; her doctor has told her it's elephant tranquilizer or something. She said she'd heard of the fails of Paxlovid but still ...says it's still better than hospitalization and death. Not sure if she'd appreciate your commentaries here but I sure do. Thank you, and thanks to Igor too.
What does this proposed mechanism tell us about the much-touted efficacy of ivermectin therapy for Covid-19? I thought one of Ivermectin's therapeutic pathways was supposed to be interference with nsp5.
Wanted to offer my experience this past week with my getting covid for the 3rd time in a year and treating with ivermectin per FLCCC protocol.
Had Delta Sept 21, nasty but bearable. Had very mild Omicron Jan 22, only knew I had it because niece with similar symptom tested positive and I'd just been with her. Just got what may be ba5 but who knows, Wednesday July 13, 22. This go round like a nasty cold, came on with scratchy throat, then sniffles and post nasal drip. Fever less than 2F, gone within 4-5 days.
On the second day of symptoms tested positive. Then started ivm 36 mg/day, along with D, zinc and C.
I can't prove the ivm made this end quickly but it sure feels like it turned out around fast.
I no longer think I won't catch this crap again. 68 yo, athletic, good diet, no comorbidities. But I'm paying the old fart tax and glad the ivm tabs were good to go.
Glad to hear of your recovery! So that's an anecdote affirming the "BA.5 = reinfection" meme. It's a very interesting question, actually, whether BA.1 is going to turn out to confer any sort of protection against the rest of the Omicron family due to its super-different spike structure, and general lack of immunogenicity per research I haven't had time to make a post about.
So the question may come down a lot more to T Cells. In this case the old fart tax is probably magnified, since T Cells are typically a lot less plastic as we age.
Apr 16, 2022·edited Apr 16, 2022Liked by Brian Mowrey
I just sat down with a cup of turmeric tea, just to see if there is anything new on Substack, and...
... drumroll...
OMG: THE MOST AMAZING POST showed up! Incredible.
I linked your post to mine and the interplay between them is most interesting and worthy of anyone's close attention.
Just FYI: I did NOT, in any way, selectively choose those reddit paxlovid posts. There is not that many on that subreddit. I always read all paxlovid posts on /r/COVID19Positive because I thought I would find something worth reporting, given Pfizer's reputation, and two things jumped to my attention
1) Horrible taste in mouth, which did not seem newsworthy enough
and
2) The story of Paxlovid NOT helping end the infection, which seemed extremely newsworthy to me, even if it seemed anecdotal and premature.
I am glad this got your interest and there is a cellular mechanism for this sort of turn of events.
I hope that someone very important, besides the two of us of course :-) notices this and tests the Paxlovid recipients more closely.
Ah - if these posts are just a snapshot of the most recent entries matching Paxlovid/Positive, then that definitely adds to the weight of the trend.
All the same, the most I'm comfortable with for now is offering a theory for what *might* be in reality's "hand" - not actually calling a bet, just yet!
I finally hunted down what I believe is the documentation for the assay used to quantify viral load (translate swab PCR Ct to load), and it looks sturdy. The official trial methods text is still a bit vague RE RNA quantification but overall I think the viral load figure should be accurate and translate to normal expectations about infection thresholds. I've added an annotated graph showing that threshold to footnote 2 of this post.
What's notable is 1) there are two Day 10 resurgers as well, though their immune systems seem to bring the virus back in check on Day 14. This only adds to what a robust signal the chart provides for "pausing" normal infection! 2) Some of the Day 14 resurgers went from undetectable to under 10 Ct on PCR. 3)Actually the n seems to be 97, so the overall percent of resurgers isn't crazy high and might be in line with false negatives on earlier time points, except that the Cts are so low so I don't think so
Apr 16, 2022·edited Apr 16, 2022Liked by Brian Mowrey
Actually just matching "paxlovid" on Reddit.
This -- that all or at least MOST paxlovid reddit posts providing more than 5 days of history, spoke about continued infection, is what made me write my article in the first place.
I obviously cannot guarantee total completeness of what I read and what am reporting, but it was so prevailing in reddit posts -- which are people asking for advice and help -- that made me almost jump when I saw the connection between them.
It is not "5 anecdotes out of 120", it is more like "5 out of not very many more than 5".
Brian, to be honest we need to make a lot of noise about it, this could be a story of the month, "how to turn a Covid patient into a Covid Mary using paxlovid". And how two substackers "Igor and Brian" discovered it. that kind of thing
Sorry, missed the alert for this one - Right, ~5 for ~5 is what I understood. Without personally having a feel for what's normal over in Reddit-space, I can't form a guess for whether this is still a reflection of some "unusual things tend to be posted more" bias.
Thank you very much for the flattering citation back on your post! I am happy to have my theory cited in any further reporting on the subject. I am not sure what kind of noise can be made until more reports of resurgence emerge, the evidence is still just theoretical / anecdotal for now - the real next step would be experimentation, esp. sequencing of samples from patients on Paxlovid who experience re-positive, which is one tool "our side" doesn't really have access to.
So, the conditions for being on Figure 2 are what's taking the most time to carefully parse. Best guess is: 1) Received treatment (~1039) + 2) RNA sequencing on Day 0 and Day 5 (97 of 1039) + 3) qPCR on Day 0 and 5 (428 of 1039, ? of 97), but it might just be 1 and 2 (97), even though the results are for qPCR, but I think it's all 3. So the n of subjects seems to be something lower than 97, maybe around ~60, but it's very hard to count the lines.
Either way, most of the condition-meeters continued to be qPCR'd up to Day 14 (few lines appear to end at Day 5 or 10), and so there doesn't seem to be any built in bias toward "still had something going on after day 5" here. Day 14 should be representative of whatever bias was built in to day 5 which should have nothing to do with resurgence susceptibility.
With no apparent bias, it seems like ~10-20% of this sample had a resurgence, depending on the total n. And since these are log values, these are often huge upswings (8 is 1,000,000X of 2, etc.). It's crazy that all the FDA has to say about this huge red flag is "not associated with mutations."
But viral kinetics in absence of Pax. are also important. I'm going through https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8908851/pdf/NEJMoa2118542.pdf now to see if there's any corresponding info for placebo (doesn't seem like it), as well as checking some other recent studies with longitudinal viral load plots.
Yes please make some noise! Tell Steve Kirsch on Substack directly... to spread it, since he has a lot of followers? Just a shot in the dark from me... sorry if it's not useful.
Interesting, but do we know these anecdotal results are real?
- PCR tests should not be used unless in controlled ways where we know the PCR rounds. They are known to detect old infections for weeks after infection. Also they can simply signal re-exposure (as opposed to re-infection), which is likely in the omicron era.
- Symptoms alone are useless too, as we have countless respiratory illnesses giving the exact same symptoms. We also know co-infection of 2 or more of such 'bugs' is common (~5% according to two recent studies).
My point you can hence test PCR positive and have symptoms and not actually have COVID (again).
So I would only trust a [antigen+ plus symptoms+] to [antigen- plus symptoms-] to [antigen+ plus symptoms+] transition, especially in such a short interval. And even then antigen tests are also notoriously easy to mess up.
And even more so, since we do not know the baseline re-infection rates of COVID-19, let alone the "I have Delta and now Omiron" or "BA.1 vs BA.2", we won't even know if these are then just re-infections within the normal bounds.
Social media is a horrible way to conduct measurements...
Right, which is why I do not endorse taking the anecdotes to confirm the theory or vice versa! Particularly with the antigen test re-positives, I'm suspicious of contamination from environmental exposure in absence of actual ongoing/resumed infection. So it's more that the anecdotes inspired a new proposal for something Paxlovid plausibly could be causing to occur, so I propose keeping a "watch this space" label on the issue.
The "anecdotes" are a signal to pay attention. You could literally take 100 paxlovid recipients, follow them for a month and see how they are doing wrt symptoms and viral clearance.
If they do not achieve viral clearance, to me, it is a failure of paxlovid and further impulse to the pandemic and infectious people walking around like Typhoid Mary.
To me, "symptoms plus a low Ct PCR test" are a good enough evidence of ongoing and infectious Covid illness.
Any Covid that is "asymptomatic", but genuinely infectious and with high viral counts, but is not accompanied by signs of immune response such as fever, is frankly a bad sign to me and a sign of a non-working immune response.
It's very interesting. In some regards I suppose we are entering into new waters with just the administration of a protease inhibitor. Usually these drugs are used in conjunction with a nucleoside analogue to bump of the antiviral effects. For some reason I did not take into account the effects of cellular proteases when examining SARS-COV2 but it does require an initial proteolysis by host proteases unless some intact nsp5 comes along for the ride during assembly and escape.
It is actually quite interesting that we never take into account the factor of tropism as it applies to viruses and to therapeutics. We ingest these drugs, we take blood samples for antibodies, and we swab noses for the presence of virus. All different sites that take into account different scenarios, and yet we treat each of them all the same.
Also, I may be remiss in stating that your speculations are a hypothesis rather than a theory. I think that term gets misused a lot but who am I to talk about misusing terms? I guess I'll blame Game Theory on YouTube for misappropriating the term!
To stick to the lay definition of “theory” - any set of ideas that proposes to explain an observation - was one of the original design choices I made for Unglossed. I may scrap the rule at some point but for now, still try to adhere to it along with my refusal to use titles (“Dr”...) and other bits of scientific court decor. *edit: the word I wanted was "etiquette"
It definitely was a comment made in jest, so no worries about changing terms. It more comes from those who may use theory as something that is both substantiated and unsubstantiated based on criticisms, which would really relegate the idea to a hypothesis like the YouTuber I mentioned.
The nsp5 protease is what cuts Orf1 polyproteins into functional parts. Paxlovid binds to the nsp5 protease, so to any extent that Paxlovid "works," there must be still-whole Orf1 polyproteins waiting to be cut - these proteins include fresh copies of nsp5.
"Chesterton's Fence" refers to some element within a complex system that is torn down before its function is understood, resulting in calamity. By disabling "present" nsp5, Paxlovid ensures that "future" nsp5's will be able to start the viral replication process where it left off, unless the innate immune system has successfully seek-and-destroyed all the cells where replication was paused.
Right, and this is where a vaxx effect on innate immunity or an Omicron effect on memory immunity might be putting a thumb on the scale. If the infected cells aren't taken out before the virus unpauses, then some percentage of infected cells just get right back to work (whichever ones still have viable virus RNA). So the virus is sitting there with its hands tied behind the back but no innate immune system is showing up to take any punches at it.
Thank you. So nsp5 is broken apart, but not destroyed. Do the actual parts hang around and then reassemble or do they just remake themselves as a whole new pieces? It seems paxlovid and nsp5 together make for a Terminator scenario.
Currently-active nsp5 are wheel-locked, so they can't keep slicing open the poly-protein "package." But the polyproteins that don't get sliced open contain more nsp5's - these are freed when our good-enough human Cysteine proteinases get around to opening some of the leftover polyproteins, per the theory. These freed nsp5s go on to open even more leftover polyproteins and viral replication gets right back into the swing of things.
I think I get it. Because not all were not completely destroyed, our bodies try to destroy the foreign locked up nsp5 s and so the nsp5 s are loose. Then your body has to start fighting the infection all over again.
RE trying to destroy the locked up bits, it's more that biology likes to make proteins bigger than they need to be, and put "tags" on the big versions that will prompt other little proteins to chop up the big one - like perforating a piece of cardboard so that a worker who picks up the cardboard later knows where to cut it. It's true that this is part of the process of breaking proteins down, but it's a part that has been flipped into a useful function: For insulin, the final product is made like two model airplane parts that have a plastic bridge between them, and after the parts are folded together and glued, the plastic bridge is cut away. Biology thinks like humans in this respect: Packaging is "wasteful" but it helps control where things go, and so it is a huge benefit.
Different life-forms create different kinds of workers, and different amounts, but often the changes aren't that big. A regular wrench can still take apart a bike, even if a bike wrench will do the job a lot better. And viruses generally always benefit from blending in with and being compatible with their host biology. So eventually, our own C protease "workers" get around to breaking apart the polyprotein at all the right tags. This releases fresh versions of the viruses protease (I'm assuming the drug doesn't bind to them when they are in the polyprotein, because this is a proof-of-concept type theory and I'm not asserting any specific rate of recovery of replication, it could be really rare or really common).
Feigl-Ding is apparently a cancer survivor. In my opinion the socially responsible reaction to cancer is to become a drug lord and leave a trail of dead bodies in your wake and then die after one year, not devote your life to pro-intervention propaganda because you don't think human biology can handle a virus.
Dr Fauci confirmed what you and I were saying about Paxlovid being a PAUSE button, not a STOP button.
https://twitter.com/ichudov/status/1535425707693813765
Et tu, Biden https://www.medpagetoday.com/infectiousdisease/covid19/99987
Yeah - that was the same speculation I offered at some point in the series, that real life dosage is earlier post-onset-of-symptoms than the trial and it doesn’t work well when gun = jumped
Just read this and your subsequent articles on Paxlovid. I can't thank you enough for these. I'm a physicist, not a biologist. I actually loathe molecular biology and find something chilling about it. But God bless you for going there. And then putting together your lockpicker sequences for those of us who can't bear to break life down into molecular steps!
A friend had been told by her doctor that this drug would protect her from hospitalization and death. I've offered her ivermectin; her doctor has told her it's elephant tranquilizer or something. She said she'd heard of the fails of Paxlovid but still ...says it's still better than hospitalization and death. Not sure if she'd appreciate your commentaries here but I sure do. Thank you, and thanks to Igor too.
What does this proposed mechanism tell us about the much-touted efficacy of ivermectin therapy for Covid-19? I thought one of Ivermectin's therapeutic pathways was supposed to be interference with nsp5.
I offered a hot take in the comment thread of the original "snake oil" post - https://igorchudov.substack.com/p/paxlovid-snake-oil-of-the-21st-century/comment/6049690 - ivm isn't necessarily implicated since it has other putative mechanisms, but also, maybe this is related to the FLCCC downgrading for Omicron treatment. Time will tell. I'm more ambivalent about the evidence for ivermectin as a magic bullet in the first place, as opposed to one element within a protocol that doctors should use if they believe in (https://unglossed.substack.com/p/ivermectins-the-dress-moment)
Wanted to offer my experience this past week with my getting covid for the 3rd time in a year and treating with ivermectin per FLCCC protocol.
Had Delta Sept 21, nasty but bearable. Had very mild Omicron Jan 22, only knew I had it because niece with similar symptom tested positive and I'd just been with her. Just got what may be ba5 but who knows, Wednesday July 13, 22. This go round like a nasty cold, came on with scratchy throat, then sniffles and post nasal drip. Fever less than 2F, gone within 4-5 days.
On the second day of symptoms tested positive. Then started ivm 36 mg/day, along with D, zinc and C.
I can't prove the ivm made this end quickly but it sure feels like it turned out around fast.
I no longer think I won't catch this crap again. 68 yo, athletic, good diet, no comorbidities. But I'm paying the old fart tax and glad the ivm tabs were good to go.
Glad to hear of your recovery! So that's an anecdote affirming the "BA.5 = reinfection" meme. It's a very interesting question, actually, whether BA.1 is going to turn out to confer any sort of protection against the rest of the Omicron family due to its super-different spike structure, and general lack of immunogenicity per research I haven't had time to make a post about.
So the question may come down a lot more to T Cells. In this case the old fart tax is probably magnified, since T Cells are typically a lot less plastic as we age.
I just sat down with a cup of turmeric tea, just to see if there is anything new on Substack, and...
... drumroll...
OMG: THE MOST AMAZING POST showed up! Incredible.
I linked your post to mine and the interplay between them is most interesting and worthy of anyone's close attention.
Just FYI: I did NOT, in any way, selectively choose those reddit paxlovid posts. There is not that many on that subreddit. I always read all paxlovid posts on /r/COVID19Positive because I thought I would find something worth reporting, given Pfizer's reputation, and two things jumped to my attention
1) Horrible taste in mouth, which did not seem newsworthy enough
and
2) The story of Paxlovid NOT helping end the infection, which seemed extremely newsworthy to me, even if it seemed anecdotal and premature.
I am glad this got your interest and there is a cellular mechanism for this sort of turn of events.
I hope that someone very important, besides the two of us of course :-) notices this and tests the Paxlovid recipients more closely.
Ah - if these posts are just a snapshot of the most recent entries matching Paxlovid/Positive, then that definitely adds to the weight of the trend.
All the same, the most I'm comfortable with for now is offering a theory for what *might* be in reality's "hand" - not actually calling a bet, just yet!
Hey Brian. More of the same. Another reddit post where the poster did not even realize Paxlovid was the culprit.
My highlights:
https://twitter.com/ichudov/status/1515330356089610245
Reddit
https://www.reddit.com/r/COVID19positive/comments/u4ipvc/reinfection_within_seven_days_of_recovery_so/
I finally hunted down what I believe is the documentation for the assay used to quantify viral load (translate swab PCR Ct to load), and it looks sturdy. The official trial methods text is still a bit vague RE RNA quantification but overall I think the viral load figure should be accurate and translate to normal expectations about infection thresholds. I've added an annotated graph showing that threshold to footnote 2 of this post.
What's notable is 1) there are two Day 10 resurgers as well, though their immune systems seem to bring the virus back in check on Day 14. This only adds to what a robust signal the chart provides for "pausing" normal infection! 2) Some of the Day 14 resurgers went from undetectable to under 10 Ct on PCR. 3)Actually the n seems to be 97, so the overall percent of resurgers isn't crazy high and might be in line with false negatives on earlier time points, except that the Cts are so low so I don't think so
Actually just matching "paxlovid" on Reddit.
This -- that all or at least MOST paxlovid reddit posts providing more than 5 days of history, spoke about continued infection, is what made me write my article in the first place.
I obviously cannot guarantee total completeness of what I read and what am reporting, but it was so prevailing in reddit posts -- which are people asking for advice and help -- that made me almost jump when I saw the connection between them.
It is not "5 anecdotes out of 120", it is more like "5 out of not very many more than 5".
Brian, to be honest we need to make a lot of noise about it, this could be a story of the month, "how to turn a Covid patient into a Covid Mary using paxlovid". And how two substackers "Igor and Brian" discovered it. that kind of thing
Sorry, missed the alert for this one - Right, ~5 for ~5 is what I understood. Without personally having a feel for what's normal over in Reddit-space, I can't form a guess for whether this is still a reflection of some "unusual things tend to be posted more" bias.
Thank you very much for the flattering citation back on your post! I am happy to have my theory cited in any further reporting on the subject. I am not sure what kind of noise can be made until more reports of resurgence emerge, the evidence is still just theoretical / anecdotal for now - the real next step would be experimentation, esp. sequencing of samples from patients on Paxlovid who experience re-positive, which is one tool "our side" doesn't really have access to.
Check out a comment in that latest reddit post
"Read the last last sentence on page 22 of this FDA report about paxlovid https://www.fda.gov/media/155194/download"
Re: your last paragraph, that's why we need to make noise
So, the conditions for being on Figure 2 are what's taking the most time to carefully parse. Best guess is: 1) Received treatment (~1039) + 2) RNA sequencing on Day 0 and Day 5 (97 of 1039) + 3) qPCR on Day 0 and 5 (428 of 1039, ? of 97), but it might just be 1 and 2 (97), even though the results are for qPCR, but I think it's all 3. So the n of subjects seems to be something lower than 97, maybe around ~60, but it's very hard to count the lines.
Either way, most of the condition-meeters continued to be qPCR'd up to Day 14 (few lines appear to end at Day 5 or 10), and so there doesn't seem to be any built in bias toward "still had something going on after day 5" here. Day 14 should be representative of whatever bias was built in to day 5 which should have nothing to do with resurgence susceptibility.
With no apparent bias, it seems like ~10-20% of this sample had a resurgence, depending on the total n. And since these are log values, these are often huge upswings (8 is 1,000,000X of 2, etc.). It's crazy that all the FDA has to say about this huge red flag is "not associated with mutations."
But viral kinetics in absence of Pax. are also important. I'm going through https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8908851/pdf/NEJMoa2118542.pdf now to see if there's any corresponding info for placebo (doesn't seem like it), as well as checking some other recent studies with longitudinal viral load plots.
Well, that's a pretty robust experimental demo, haha. I'm sorting though it now.
Yes please make some noise! Tell Steve Kirsch on Substack directly... to spread it, since he has a lot of followers? Just a shot in the dark from me... sorry if it's not useful.
Interesting, but do we know these anecdotal results are real?
- PCR tests should not be used unless in controlled ways where we know the PCR rounds. They are known to detect old infections for weeks after infection. Also they can simply signal re-exposure (as opposed to re-infection), which is likely in the omicron era.
- Symptoms alone are useless too, as we have countless respiratory illnesses giving the exact same symptoms. We also know co-infection of 2 or more of such 'bugs' is common (~5% according to two recent studies).
My point you can hence test PCR positive and have symptoms and not actually have COVID (again).
So I would only trust a [antigen+ plus symptoms+] to [antigen- plus symptoms-] to [antigen+ plus symptoms+] transition, especially in such a short interval. And even then antigen tests are also notoriously easy to mess up.
And even more so, since we do not know the baseline re-infection rates of COVID-19, let alone the "I have Delta and now Omiron" or "BA.1 vs BA.2", we won't even know if these are then just re-infections within the normal bounds.
Social media is a horrible way to conduct measurements...
Right, which is why I do not endorse taking the anecdotes to confirm the theory or vice versa! Particularly with the antigen test re-positives, I'm suspicious of contamination from environmental exposure in absence of actual ongoing/resumed infection. So it's more that the anecdotes inspired a new proposal for something Paxlovid plausibly could be causing to occur, so I propose keeping a "watch this space" label on the issue.
The "anecdotes" are a signal to pay attention. You could literally take 100 paxlovid recipients, follow them for a month and see how they are doing wrt symptoms and viral clearance.
If they do not achieve viral clearance, to me, it is a failure of paxlovid and further impulse to the pandemic and infectious people walking around like Typhoid Mary.
To me, "symptoms plus a low Ct PCR test" are a good enough evidence of ongoing and infectious Covid illness.
Any Covid that is "asymptomatic", but genuinely infectious and with high viral counts, but is not accompanied by signs of immune response such as fever, is frankly a bad sign to me and a sign of a non-working immune response.
It's very interesting. In some regards I suppose we are entering into new waters with just the administration of a protease inhibitor. Usually these drugs are used in conjunction with a nucleoside analogue to bump of the antiviral effects. For some reason I did not take into account the effects of cellular proteases when examining SARS-COV2 but it does require an initial proteolysis by host proteases unless some intact nsp5 comes along for the ride during assembly and escape.
It is actually quite interesting that we never take into account the factor of tropism as it applies to viruses and to therapeutics. We ingest these drugs, we take blood samples for antibodies, and we swab noses for the presence of virus. All different sites that take into account different scenarios, and yet we treat each of them all the same.
Also, I may be remiss in stating that your speculations are a hypothesis rather than a theory. I think that term gets misused a lot but who am I to talk about misusing terms? I guess I'll blame Game Theory on YouTube for misappropriating the term!
To stick to the lay definition of “theory” - any set of ideas that proposes to explain an observation - was one of the original design choices I made for Unglossed. I may scrap the rule at some point but for now, still try to adhere to it along with my refusal to use titles (“Dr”...) and other bits of scientific court decor. *edit: the word I wanted was "etiquette"
It definitely was a comment made in jest, so no worries about changing terms. It more comes from those who may use theory as something that is both substantiated and unsubstantiated based on criticisms, which would really relegate the idea to a hypothesis like the YouTuber I mentioned.
Well, I don't mind nitpicking, whether in jest or not, haha. Either way keeps on toes.
Last week's Walgreens COVID-19 test data from the USA: https://www.walgreens.com/businesssolutions/covid-19-index.jsp
https://i.redd.it/0h26yrziljt81.png
https://i.redd.it/baa8pwscint81.png
I love the subtitle, the totally reckless theory. 😄👍🏽
The *official* totally reckless theory.
😄 yes, sorry, official!
I understood till you got to Chesteron’s Fence and then I was overwhelmed.
The nsp5 protease is what cuts Orf1 polyproteins into functional parts. Paxlovid binds to the nsp5 protease, so to any extent that Paxlovid "works," there must be still-whole Orf1 polyproteins waiting to be cut - these proteins include fresh copies of nsp5.
"Chesterton's Fence" refers to some element within a complex system that is torn down before its function is understood, resulting in calamity. By disabling "present" nsp5, Paxlovid ensures that "future" nsp5's will be able to start the viral replication process where it left off, unless the innate immune system has successfully seek-and-destroyed all the cells where replication was paused.
Basically what you are saying is that Paxlovid is a five-day PAUSE button.
This is my "popular science version"
Right, and this is where a vaxx effect on innate immunity or an Omicron effect on memory immunity might be putting a thumb on the scale. If the infected cells aren't taken out before the virus unpauses, then some percentage of infected cells just get right back to work (whichever ones still have viable virus RNA). So the virus is sitting there with its hands tied behind the back but no innate immune system is showing up to take any punches at it.
Thank you. So nsp5 is broken apart, but not destroyed. Do the actual parts hang around and then reassemble or do they just remake themselves as a whole new pieces? It seems paxlovid and nsp5 together make for a Terminator scenario.
Currently-active nsp5 are wheel-locked, so they can't keep slicing open the poly-protein "package." But the polyproteins that don't get sliced open contain more nsp5's - these are freed when our good-enough human Cysteine proteinases get around to opening some of the leftover polyproteins, per the theory. These freed nsp5s go on to open even more leftover polyproteins and viral replication gets right back into the swing of things.
I think I get it. Because not all were not completely destroyed, our bodies try to destroy the foreign locked up nsp5 s and so the nsp5 s are loose. Then your body has to start fighting the infection all over again.
RE trying to destroy the locked up bits, it's more that biology likes to make proteins bigger than they need to be, and put "tags" on the big versions that will prompt other little proteins to chop up the big one - like perforating a piece of cardboard so that a worker who picks up the cardboard later knows where to cut it. It's true that this is part of the process of breaking proteins down, but it's a part that has been flipped into a useful function: For insulin, the final product is made like two model airplane parts that have a plastic bridge between them, and after the parts are folded together and glued, the plastic bridge is cut away. Biology thinks like humans in this respect: Packaging is "wasteful" but it helps control where things go, and so it is a huge benefit.
Different life-forms create different kinds of workers, and different amounts, but often the changes aren't that big. A regular wrench can still take apart a bike, even if a bike wrench will do the job a lot better. And viruses generally always benefit from blending in with and being compatible with their host biology. So eventually, our own C protease "workers" get around to breaking apart the polyprotein at all the right tags. This releases fresh versions of the viruses protease (I'm assuming the drug doesn't bind to them when they are in the polyprotein, because this is a proof-of-concept type theory and I'm not asserting any specific rate of recovery of replication, it could be really rare or really common).
Thank you. I’ll keep working on my understanding of it. I appreciate the explanation.
Yes, I've been going through it for the last several hours after Igor's comment below - I just posted my current read on it in reply!
Feigl-Ding is apparently a cancer survivor. In my opinion the socially responsible reaction to cancer is to become a drug lord and leave a trail of dead bodies in your wake and then die after one year, not devote your life to pro-intervention propaganda because you don't think human biology can handle a virus.