Interview with Dr. Diane Griffin: Mechanisms of viral RNA persistence: Amy Proal interviews Diane Griffin

[Shanti1]

Dr. Diane Griffin is the Alfred and Jill Sommer Professor and Chair in the Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health. She is also a professor of infectious diseases and of neurology at the Johns Hopkins University School of Medicine. Her team studies RNA viruses such as alphaviruses and measles virus to clarify the mechanisms by which they interact with the host immune system. Importantly her lab also studies the persistence of these RNA viruses. In other words, they study the mechanisms by which a range of RNA viruses or their genetic material (their RNA backbones) can persist in host tissue or body fluids for long periods of time after the resolution of acute infection. This knowledge is incredibly important for the study of LongCovid - since a growing number of studies have found that SARS-CoV-2 RNA and protein can persist in patient samples for months after initial illness.

 

[Shanti1]

Dr Diane Griffin's most recent paper:

Griffin DE. Why does viral RNA sometimes persist after recovery from acute infections? PLoS Biol. 2022 Jun 1;20(6):e3001687
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9191737/

Abstract:
DNA viruses often persist in the body of their host, becoming latent and recurring many months or years later. By contrast, most RNA viruses cause acute infections that are cleared from the host as they lack the mechanisms to persist. However, it is becoming clear that viral RNA can persist after clinical recovery and elimination of detectable infectious virus. This persistence can either be asymptomatic or associated with late progressive disease or nonspecific lingering symptoms, such as may be the case following infection with Ebola or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Why does viral RNA sometimes persist after recovery from an acute infection? Where does the RNA come from? And what are the consequences?

 

[Shanti1]

One important theme of the interview is that RNA persistence indicates viral persistence

Here are my notes from the interview:

Background:

• People understand that DNA viruses, like the herpes virus family can persist in the body and come in and out of latency
• Dr. Griffin was not expecting to find persistence with the RNA alphavirus and measles
  • Her team first observed it with alphaviruses, which infect neurons and cause encephalitis.
    • They discovered that long after “recovery” from these viruses, in mice, you could still find the RNA in the CNS
    • The RNA deceased a bit over time, but could still be detected in most mice for a year or two, basically the life-span of the mouse
    • This RNA persistence resulted in an ongoing immune response in the brain
  • Next this was observed with measles
    • Measles typically infects lymph nodes and other areas, but not the brain. The cells that measles infect have high turnover, so it didn’t occur to them that it may have RNA persistence, but they could have RNA persistence in the lymph nodes and CNS.

RNA Persistence and Infection

• RNA persistence does not typically correlate with an infectious state, the contagion is cleared within 2 weeks or so of acute infection, but viral RNA can persist for months to years.
• This causes some research and medical professionals to discount the RNA persistence as not having significance with the belief that it is just “chewed up RNA that is not doing anything”.
  • To the contrary, there is evidence for persistent immune activation and antibodies in the same regions of the brain where there is RNA persistence.
  • Antibodies are not produced against RNA, the RNA is being translated into proteins, eliciting an immune response, both innate and specific (she mentions that the innate immune system could also react to the RNA in the absence of a protein).
  • There are some viruses that do fragment. Sometimes people will say that RNA persistence is just “RNA fragments”. Viral production RNA fragments is actually a viral survival strategy in which the end of the viral genome is trimmed (unfortunately they didn’t go into more detail).
• The Question: How do you have RNA persistence without viral replication?
  • Dr. Griffin observes that, in animal models, in the face of immune suppression, the virus can come back. So the whole genome is in there. In this context, RNA persistence is not inert RNA, but partial transcription of a whole genome.
  • Amy Proal comments here that the RNA persistence is still creating proteins, immune response, and potential symptoms for people
  • Dr. Griffin comments that in RNA persistence, it is possible that the immune system is neutralizing whole virus just before or just after release
  • We still don’t know what state the viral genetic material is in inside the cell, but it is in some sort of a protected or encapsulated state because the immune system does have mechanisms that should clear it.
  • The cell should have mechanisms to detect and degrade the viral genetic material. In RNA persistence, it does happen, but slowly. In animals, we see viral RNA persistence load decrease over time, but sometimes it hits a plateau.

RNA in the Brain

• Amy mentions an ME/CFS autopsy in which enterovirus RNA was found in the brainstem of a patient
  • Some people have said that this isn’t possible, the patient would have died sooner. This is because they are thinking of the virus as doing what it does in an acute infection. What people don’t understand is that viral RNA persistence is a different state.
  • Neurons are a long lived cell, so may be a good "choice" for viral persistence as the virus can hide from the immune system quite well in these cells
  • Dr. Griffin- If the virus doesn’t kill the neuron and the immune system can suppress the virus without eliminating it, we get RNA persistence.
  • Under-researched area because people aren’t typically looking for a virus in the brain unless they are acutely ill

SARS Cov2

• Patients on immune suppression have been shown to harbor SARS-COV2 complete virus for many, many months
• Where could viral / RNA persistence be most likely to occur in COVID? Amy mentions intestine epithelial tissue and maybe lung. CNS is hard to test in live subjects but has been seen on autopsy, in fact autopsy has shown viral persistence in multiple tissue
• Amy- we are starting a study with the team at Mt. Sinai to biopsy intestinal tissue to check for viral/RNA persistence in Long-COVID patients and how the immune system is acting in that location.

Anti-viral therapy for Long-COVID

• Amy asks, “Is Paxlovid” worth trying in long-COVID, will it be effective against viruses in the “RNA state”?
• Dr. Griffin, “I don’t know!” but she goes on to say that measles infected Monkeys treated early with remdesivir have more rapid clearance of post infection RNA persistence. When they gave remdesivir once the virus was established, at the time when the measles rash developed, it did not make a difference in post infectious RNA clearance.
• Amy-“It might require cocktails of drugs, and some that modulate the immune system, to get clearance.”

 

[BrightCandle]

One of the reasons we don't know much about which viruses could be the cause of ME/CFS is because no researchers are not interested in doing autopsies of dead patients. I tried to see if there was anyone looking to do this sort of testing with the OMF, NHS and the NIH and the best answer I got was to register to get my brain added to a brain bank in the UK. But there is no one interested in ME/CFS brains and we know that if you donate them to science they are just unused. It seems like we could have had a definitive answer decades ago if there was someone interested in looking for this, instead the theoretical possibility continues to be discussed on the rare instances where a limited autopsy was done. It just bothers me there is no interest in answering this question at all.

 

[Pyrrhus]

For anyone interested in this subject, here is a related discussion that also discusses many of the points raised in this interview:

Persistence of RNA viruses is deadly real
https://forums.phoenixrising.me/threads/persistence-of-rna-viruses-is-deadly-real.83408/

 

[Hip]

Here are my notes from the interview:

Great summary!

But there is no one interested in ME/CFS brains and we know that if you donate them to science they are just unused.

Dr Chia, who performed one of the 3 ME/CFS brain autopsies looking for enterovirus in brain tissues, has stated that it is extremely difficult to come by brains. I think he would like to do more brain autopsies, but there are hardly any brains donated.

 

[CSMLSM]

Dr. Diane Griffin is the Alfred and Jill Sommer Professor and Chair in the Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health. She is also a professor of infectious diseases and of neurology at the Johns Hopkins University School of Medicine. Her team studies RNA viruses such as alphaviruses and measles virus to clarify the mechanisms by which they interact with the host immune system. Importantly her lab also studies the persistence of these RNA viruses. In other words, they study the mechanisms by which a range of RNA viruses or their genetic material (their RNA backbones) can persist in host tissue or body fluids for long periods of time after the resolution of acute infection. This knowledge is incredibly important for the study of LongCovid - since a growing number of studies have found that SARS-CoV-2 RNA and protein can persist in patient samples for months after initial illness.

Thanks for posting. I will be taking a look when I get the chance.

 

[Lovalab]

I’ll donate mine, I don’t seem to be using it anyways!

 

[CSMLSM]

One important theme of the interview is that RNA persistence indicates viral persistence

Here are my notes from the interview:

Background:

• People understand that DNA viruses, like the herpes virus family can persist in the body and come in and out of latency
• Dr. Griffin was not expecting to find persistence with the RNA alphavirus and measles
  • Her team first observed it with alphaviruses, which infect neurons and cause encephalitis.
    • They discovered that long after “recovery” from these viruses, in mice, you could still find the RNA in the CNS
    • The RNA deceased a bit over time, but could still be detected in most mice for a year or two, basically the life-span of the mouse
    • This RNA persistence resulted in an ongoing immune response in the brain
  • Next this was observed with measles
    • Measles typically infects lymph nodes and other areas, but not the brain. The cells that measles infect have high turnover, so it didn’t occur to them that it may have RNA persistence, but they did have RNA persistence in the lymph nodes (maybe brain too? Wasn’t clear from the interview).

RNA Persistence and Infection

• RNA persistence does not typically correlate with an infectious state, the contagion is cleared within 2 weeks or so of acute infection, but viral RNA can persist for months to years.
• This causes some research and medical professionals to discount the RNA persistence as not having significance with the belief that it is just “chewed up RNA that is not doing anything”.
  • To the contrary, there is evidence for persistent immune activation and antibodies in the same regions of the brain where there is RNA persistence.
  • Antibodies are not produced against RNA, the RNA is being translated into proteins, eliciting an immune response, both innate and specific (she mentions that the innate immune system could also react to the RNA in the absence of a protein).
  • There are some viruses that do fragment. Sometimes people will say that RNA persistence is just “RNA fragments”. Viral production RNA fragments is actually a viral survival strategy in which the end of the viral genome is trimmed (unfortunately they didn’t go into more detail).
• The Question: How do you have RNA persistence without viral replication?
  • Dr. Griffin observes that, in animal models, in the face of immune suppression, the virus can come back. So the whole genome is in there. In this context, RNA persistence is not inert RNA, but partial transcription of a whole genome.
  • Amy Proal comments here that the RNA persistence is still creating proteins, immune response, and potential symptoms for people
  • Dr. Griffin comments that in RNA persistence, it is possible that the immune system is neutralizing whole virus just before or just after release
  • We still don’t know what state the viral genetic material is in inside the cell, but it is in some sort of a protected or encapsulated state because the immune system does have mechanisms that should clear it.
  • The cell should have mechanisms to detect and degrade the viral genetic material. In RNA persistence, it does happen, but slowly. In animals, we see viral RNA persistence load decrease over time, but sometimes it hits a plateau.

RNA in the Brain

• Amy mentions an ME/CFS autopsy in which enterovirus RNA was found in the brainstem of a patient
  • Some people have said that this isn’t possible, the patient would have died sooner. This is because they are thinking of the virus as doing what it does in an acute infection. What people don’t understand is that viral RNA persistence is a different state.
  • Neurons are a long lived cell, so may be a good "choice" for viral persistence as the virus can hide from the immune system quite well in these cells
  • Dr. Griffin- If the virus doesn’t kill the neuron and the immune system can suppress the virus without eliminating it, we get RNA persistence.
  • Under-researched area because people aren’t typically looking for a virus in the brain unless they are acutely ill

SARS Cov2

• Patients on immune suppression have been shown to harbor SARS-COV2 complete virus for many, many months
• Where could viral / RNA persistence be most likely to occur in COVID? Amy mentions intestine epithelial tissue and maybe lung. CNS is hard to test in live subjects but has been seen on autopsy, in fact autopsy has shown viral persistence in multiple tissue
• Amy- we are starting a study with the team at Mt. Sinai to biopsy intestinal tissue to check for viral/RNA persistence in Long-COVID patients and how the immune system is acting in that location.

Anti-viral therapy for Long-COVID

• Amy asks, “Is Paxlovid” worth trying in long-COVID, will it be effective against viruses in the “RNA state”?
• Dr. Griffin, “I don’t know!” but she goes on to say that measles infected Monkeys treated early with remdesivir have more rapid clearance of post infection RNA persistence. When they gave remdesivir once the virus was established, at the time when the measles rash developed, it did not make a difference in post infectious RNA clearance.
• Amy-“It might require cocktails of drugs, and some that modulate the immune system, to get clearance.”

Thank you for the excellent notes you have shared with us. I hope to be this organised in the future, I hope at least!

It might require cocktails of drugs, and some that modulate the immune system, to get clearance.

Yes, immune modulation to break the persistence of these persistent viral components.
I believe this is what I have been doing for some time with great success and much more so in the last 5 months after finding a good source of Caryophyllene which is the molecule I am using for this complicated biological task by using the bodies own mechanism to achieve this. It is through the Endogenous Cannabinoid system and more specifically the CB2 receptor expressed across many immune types that this can be achieved guiding the immune system towards the homeostatic startpoint of health or the resolution point of an infection. So to use a computer term, reboot the immune system. Keep restarting the system so it recognises invaders/microbes and with a strong dominant innate immune system to direct an effective and correct immune response instead of a dysfunctional one.

I look forward to watching the video you have presented to us.

 

[Shanti1]

Dr Chia, who performed one of the 3 ME/CFS brain autopsies looking for enterovirus in brain tissues, has stated that it is extremely difficult to come by brains. I think he would like to do more brain autopsies, but there are hardly any brains donated.

Thank you for adding that info.

Amy also mentioned that one of her concerns is that if a Paxlovid trial fails for Long-Covid that people will think viral persistence is not an issue when what is more likely is that RNA viruses are super sneaky.

The persistent RNA state of RNA viruses seems akin to the abortive lytic state of EBV.

Even so, I'm still hopeful that Paxlovid may have an impact in Long covid.

 

[Hip]

Amy also mentioned that one of her concerns is that if a Paxlovid trial fails for Long-Covid that people will think viral persistence is not an issue when what is more likely is that RNA viruses are super sneaky.

Yes, people may be fooled into thinking that there is no virus left if antivirals fail. But persisting viral RNA is typically just naked viral RNA living within the cell. It is self-replicating viral RNA. This is not the same as a viral particle, and antivirals which work for viral particles may not work for pure viral RNA.

You find persistent RNA viruses in type 1 diabetes: coxsackievirus B4 is known to infect the insulin producing cells of the pancreas. But we cannot cure T1D with enterovirus antivirals like ribavirin, presumably because these antivirals are not able to clear the viral RNA from the pancreas.

The persistent RNA state of RNA viruses seems akin to the abortive lytic state of EBV.

It is very similar. This persistent RNA state is called a non-cytolytic infection or a non-cytopathic infection.

The enterovirus non-cytolytic infections that exist in the tissues of ME/CFS patients are now quite well understood. We know how they arise. What is not yet clear, however, is why the immune system is not able to clear this enteroviral RNA, though there are some theories.

 

[Pyrrhus]

The persistent RNA state of RNA viruses seems akin to the abortive lytic state of EBV.

In the sense that they are both not replicating quickly, then yes. But otherwise, the two scenarios have very little in common.

Herpesviruses have many different infection states programmed into their DNA. These states include active replication, latency, abortive surveillance, etc. Since the genomes of herpesviruses are huge, they can afford to have multiple states programmed into their DNA.

RNA viruses, on the other hand, have very small genomes and therefore are limited in the types of infection states that they can support:

First, here's a brief review of the virology of RNA viruses:

• RNA viruses generally exist as single-stranded RNA (ssRNA) encased inside a protective shell.
• When an RNA virus infects a cell, it proceeds through certain pre-defined stages in its "lifecycle".
• The stages in the lifecycle include a replication stage, where the single strand of RNA (ssRNA) is used as a template to construct a complementary copy of the viral RNA on top of the original ssRNA. The result of this replication stage is a double-stranded RNA (dsRNA) that contains the original ssRNA bound to a complementary copy of the original ssRNA.
• Then, the dsRNA separates into two strands: the original ssRNA and the complementary ssRNA.
• The original ssRNA is usually then used to make viral proteins while the complementary ssRNA strand is then used as a template to make new copies of the original ssRNA. This is how an RNA virus makes viral proteins as well as new copies of itself.

Now, a human cell contains many enzymes that can degrade ssRNA, so the virus must act quickly to replicate itself before the cell degrades the viral ssRNA.

But a human cell has no enzyme that can degrade viral dsRNA, so if the virus gets "stuck" in the dsRNA stage of its lifecycle, the infected cell will have a hard time getting rid of the viral dsRNA.

There is evidence that some RNA viruses, such as flaviviruses and enteroviruses (and possibly coronaviruses), may exploit this loophole to persist inside cells by getting themselves "stuck" in the dsRNA stage of their lifecycle.

So how does an RNA virus infection get "stuck" in this dsRNA intermediate state as the infection progresses from acute to persistent? Taking enteroviruses as an example, there are multiple mechanisms:

1. The virus encodes a viroporin to raise the intracellular Ca2+ levels to a point where the dsRNA state is thermodynamically stable. (It is normally thermodynamically unstable intracellularly.)
2. Due to the inexact binding of the RdRp polymerase to the 5' end of the viral genome, nucleotides at the 5' end of the viral genome are gradually lost over many replication cycles. Up to about 40 nucleotides are lost in this fashion. (If more than 40 nucleotides are lost, then the genome will lose its IRES, which is the only remaining way that a ribosome can bind to the genome to make viral proteins. And a viral genome that can not make proteins can not survive.)
3. Now, these first ~40 nucleotides at the 5' end of the viral genome contains secondary ssRNA structures, with one major structure called the "cloverleaf". These ssRNA structures normally prevent the formation of dsRNA at this 5' end of the genome, thermodynamically destabilizing the dsRNA intermediate state. Therefore, the loss over time of the first ~40 nucleotides of the viral genome eliminates these secondary ssRNA structures, further stabilizing the dsRNA intermediate state thermodynamically.
4. The viruses also use convoluted membrane structures as part of its replication machinery. These membrane structures can encircle and enclose the dsRNA and associated viral proteins inside "intracellular vesicles", where intracellular enzymes can not attack or degrade them. These "intracellular vesicles" can then be exported out of the cell as "extracellular vesicles", for transport to other cells. (For more information on this process, see Viral Extracellular Vesicles known as ‘Stealth Spheres’)

For more information, see:

https://twitter.com/i/web/status/1385045007996907523

 

[CSMLSM]

In the sense that they are both not replicating quickly, then yes. But otherwise, the two scenarios have very little in common.

Herpesviruses have many different infection states programmed into their DNA. These states include active replication, latency, abortive surveillance, etc. Since the genomes of herpesviruses are huge, they can afford to have multiple states programmed into their DNA.

RNA viruses, on the other hand, have very small genomes and therefore are limited in the types of infection states that they can support:




So how does an RNA virus infection get "stuck" in this dsRNA intermediate state as the infection progresses from acute to persistent? Taking enteroviruses as an example, there are multiple mechanisms:

1. The virus encodes a viroporin to raise the intracellular Ca2+ levels to a point where the dsRNA state is thermodynamically stable. (It is normally thermodynamically unstable intracellularly.)
2. Due to the inexact binding of the RdRp polymerase to the 5' end of the viral genome, nucleotides at the 5' end of the viral genome are gradually lost over many replication cycles. Up to about 40 nucleotides are lost in this fashion. (If more than 40 nucleotides are lost, then the genome will lose its IRES, which is the only remaining way that a ribosome can bind to the genome to make viral proteins. And a viral genome that can not make proteins can not survive.)
3. Now, these first ~40 nucleotides at the 5' end of the viral genome contains secondary ssRNA structures, with one major structure called the "cloverleaf". These ssRNA structures normally prevent the formation of dsRNA at the 5' end of the genome, thermodynamically destabilizing the dsRNA intermediate state. Therefore, the loss over time of the first ~40 nucleotides of the viral genome eliminates these secondary ssRNA structures, further stabilizing the dsRNA intermediate state thermodynamically.
4. The viruses also use convoluted membrane structures as part of its replication machinery. These membrane structures can encircle and enclose the dsRNA and associated viral proteins inside "intracellular vesicles", where intracellular enzymes can not attack or degrade them. These "intracellular vesicles" can then be exported out of the cell as "extracellular vesicles", for transport to other cells. (For more information on this process, see Viral Extracellular Vesicles known as ‘Stealth Spheres’)

For more information, see:

https://twitter.com/i/web/status/1385045007996907523

Maybe on the evolutionary tree these persistent viral RNAs of viruses are the start of a what we call a true latent virus like EBV. EBV on the evolutionary tree started without latency one would assume at some point and evolved step by step to where it is now. Maybe this is how viruses begin on the evolutionary trajectory towards a more complex and thus more persistent infection program like EBV. Building on each step as it goes refining. What works lives on and replicates better, bit by bit.

 

[Pyrrhus]

One additional point regarding the immune system:

Many people mistakenly assume that if a virus persists, then it must be a failure of the immune system somehow.

In this sense, we put far too much faith in our immune system instead of recognizing the immune system as an excellent, but not perfect, defense system. The immune system provides our body with a diverse array of armies to fight invaders, but these invaders have had millenia to evolve ways to outwit our immune armies.

With that said, many RNA viruses have evolved strategies to evade detection by the immune system:

1. Many RNA viruses, such as flaviviruses, enteroviruses, and coronaviruses develop neurotropism. This means that the viruses evolve ways to infect the brain. Once inside the brain, they are largely protected from the blood-borne immune system, since the blood-brain-barrier makes the brain an "immune-privileged organ". As long as the blood-brain-barrier remains intact, the virus will be protected from the blood-borne immune system.
2. But the virus in the brain is still susceptible to the tissue-resident immune system of the brain. The immune cells of the brain can destroy viruses floating around in the extracellular space, and can also kill some infected cells where the virus is hiding. There is one notable exception however: viruses hiding inside infected neurons. The immune system of the brain can identify and surround infected neurons, but they can not kill infected neurons, with very few exceptions. (This is probably an evolutionary adaptation to avoid massive brain damage from otherwise harmless neurotropic infections. Even if the brain were capable of rapidly regenerating the lost neurons, any cognitive memory associated with the lost neurons will also be lost.)
3. Furthermore, viruses have developed multiple ways to disable the intracellular immune system of the cell that it infects. (You may have learned about two branches of the immune system in your immunology course: the cellular branch of the immune system and the extracellular (humoral) branch of the immune system. But there is a third branch of the immune system: the intracellular branch, which is composed of PAMPs/DAMPs, the interferon pathway, the TNF-alpha pathway, and many many other intracellular defenses.)

 

[Rufous McKinney]

It just bothers me there is no interest in answering this question at all.

Dr. Proal brings this type of thing up all the time...I think we will get there eventually.

 

[Shanti1]

@Hip @Pyrrhus Thank you both for adding your knowledge!

Persistence of RNA viruses is deadly real
https://forums.phoenixrising.me/threads/persistence-of-rna-viruses-is-deadly-real.83408/

The thread above was fascinating. It really filled in and complemented Amy's interview because she alluded to much of the research you curated, but she didn't go into detail.

Now, these first ~40 nucleotides at the 5' end of the viral genome contains secondary ssRNA structures, with one major structure called the "cloverleaf". These ssRNA structures normally prevent the formation of dsRNA at this 5' end of the genome, thermodynamically destabilizing the dsRNA intermediate state. Therefore, the loss over time of the first ~40 nucleotides of the viral genome eliminates these secondary ssRNA structures, further stabilizing the dsRNA intermediate state thermodynamically.

Amy mentioned that some RNA viruses fragment from the 5' end as a survival strategy, and I think she wanted to cover that in the interview, but Dr. Griffin didn't bite. What you write above must have been where she was headed.

@Pyrrhus Great summary of the DNA vs RNA viral genome and the mechanism of obtaining the dsRNA state and how it is resistant to degradation. The info on viral vesicles and your additional points on why neurons are ideal for immune evasion were also fascinating. Most of this was new for me, so I love that I got to learn so much! The more I learn about viruses the more I feel I am reading a stranger-than-fiction sci-fi novel!

 

[Pyrrhus]

@Pyrrhus Great summary of the DNA vs RNA viral genome and the mechanism of obtaining the dsRNA state and how it is resistant to degradation. The info on viral vesicles and your additional points on why neurons are ideal for immune evasion were also fascinating. Most of this was new for me, so I love that I got to learn so much! The more I learn about viruses the more I feel I am reading a stranger-than-fiction sci-fi novel!

Yeah, virology is a truly fascinating subject - just as you say "stranger-than-fiction sci-fi"! I really tried to simplify the science in the above posts so that people could understand, but the naturally strange nature of viruses themselves can still make it hard to understand...

I got interested in virology as an HIV advocate back in the early 1990s, and after 30 years I am still blown away by the wild and crazy stuff that different viruses come up with to survive!

But I am also deeply saddened that the fascinating field of virology has been woefully neglected since 1972:

But there's a more historical aspect as well:

1. In the early 1970's the U.S. CDC effectively declared victory over infectious disease, saying that the success of the public vaccination programs begun in the 1950's had effectively wiped out infectious disease. (Yes, they actually said that!)
2. Any remaining disease, then, the CDC declared to be "chronic diseases" due to "lifestyle choices", such as smoking, diet, and exercise.
3. As a result, U.S. government funding agencies declared that they were going to be shifting their research funding from infectious disease to "chronic diseases" due to "lifestyle choices".
4. In just a few years, hundreds of virologists lost their jobs and there began a surge of epidemiologists looking at "lifestyle choices".
5. Although this happened almost 50 years ago, we are still suffering from the entrenched biases that were created back then. To see this, simply take a brief look at the current CDC webpage for "Chronic Disease": https://www.cdc.gov/chronicdisease/about/index.htm
6. For more information on this whole history, see the attached paper by the great epidemiologist Arthur Reingold. (Who, coincidentally, is also a PACE trial critic.)

 

[CSMLSM]

Furthermore, viruses have developed multiple ways to disable the intracellular immune system of the cell that it infects. (You may have learned about two branches of the immune system in your immunology course: the cellular branch of the immune system and the extracellular (humoral) branch of the immune system. But there is a third branch of the immune system: the intracellular branch, which is composed of PAMPs/DAMPs, the interferon pathway, the TNF-alpha pathway, and many many other intracellular defenses.)

Yes I have some awareness of the intracellular immune system from vitamin D research to do with the immune system (autoimmune and dysregulation) and how certain infections actually down regulate the vitamin D receptor (VDR), which helps to surpress intracelluar anti microbials.

I do not have nowhere near the level of knowledge you do. I have been focused on figuring out why cannabis helped me and worked from there. I focused on understanding what was involved in that like the ECS, immune system and HPA axis.
Only recently have I looked for a causal factor but unfortunately started while going through my current recovery during a period on immune activation caused by my treatment and had some memory affects which made me make some statements that are wrong due to this unrealised confusion.
I misremembered a bunch of stuff I was looking up that I thought I may be fighting during the immune activation. So I looked up about Croup (2 to 5 years old, recuring bark cough till teens), Tonsillitis (12-14 years approx really bad removed missed large chunk of school) and bowel infection (leading upto and while I had accident that lead to ME/CFS diagnosis eventually).
What I actually found I think was a link to Croup having a possible cause from another herpies family virus that is also persistant in humans so unfortunately I unknowingly remembered wrong.
Herpes simplex virus infection. A rare cause of prolonged croup - PubMed (nih.gov)

But now I realise that I could have had EBV then at the age of five which is as far back as I remember having symptoms related to my ME/CFS and that the viruses that cause croup may have played a part in starting all this along with a possible enterovirus at point of accident that triggered major disability with ME/CFS at work.

I should have waited until I was much more better like I am now, it seems I am through the immune activation that has been happening and I feel great almost completely symptom free and have reduced (Copaiba/caryophyllene the amount I use to control the condition.

I only want to share the benefit I am having with you all and regret that you will likely not trust or read anything I post now.

 

[Shanti1]

Yeah, virology is a truly fascinating subject - just as you say "stranger-than-fiction sci-fi"! I really tried to simplify the science in the above posts so that people could understand, but the naturally strange nature of viruses themselves can still make it hard to understand...

I got interested in virology as an HIV advocate back in the early 1990s, and after 30 years I am still blown-away by the wild and crazy stuff that different viruses come up with to survive!

I often wish I could become a "mini-me" and actually see it all happening inside the cell, but imagination will have to do!

But I am also deeply saddened that the fascinating field of virology has been woefully neglected since 1972:

This is quite a shame. We thought we had it all figured out, nature conquered and under our control! The history of medicine is peppered with both travesties and triumphs. It makes me wonder what else we hold today as medical absolute truth that will cause us to one day look back on and shake our heads! I can think of a few.... but I digress!

 

[Pyrrhus]

Now, these first ~40 nucleotides at the 5' end of the viral genome contains secondary ssRNA structures, with one major structure called the "cloverleaf". These ssRNA structures normally prevent the formation of dsRNA at this 5' end of the genome, thermodynamically destabilizing the dsRNA intermediate state. Therefore, the loss over time of the first ~40 nucleotides of the viral genome eliminates these secondary ssRNA structures, further stabilizing the dsRNA intermediate state thermodynamically.

Amy mentioned that some RNA viruses fragment from the 5' end as a survival strategy, and I think she wanted to cover that in the interview, but Dr. Griffin didn't bite. What you write above must have been where she was headed.

Here's what Dr. Diane Griffin wrote on the topic in her paper:

Avoiding virus-induced cell death usually requires limiting virus replication [87,128]. A variety of mechanisms are employed by viruses to restrict replication. For example, several RNA viruses (e.g., Borna disease virus, LCMV, coxsackievirus, and hantavirus) undergo 5′-terminal trimming of the genome that both suppresses replication and prevents the activation of innate immune responses [129–132].