What kind of virus should we expect to cause chronic infectious diseases? Will it resemble the virus that causes measles? If not, how will it differ? Perhaps we can get a better idea by viewing things from the perspective of a virus.
While we often believe pathogens are out to kill us, the truth is that the death of the host may often mean not only the death of the pathogen, but the end of the infection. The only way a classic infectious disease like cholera makes sense is if the pathogens, in that case bacteria (vibrio cholerae), replicate rapidly and the victim sheds these bacteria in a way that spreads them to others. (If you don't know what cholera is like, trust me, it does a magnificent job of spreading itself quickly.) This evolutionary 'strategy' works by using up one host in a burst of reproduction that spreads pathogens to others.
We generally think of measles as a non-lethal disease. This is certainly not true for a population never previously exposed. (Some island populations were virtually wiped out by measles.) What has happened is that our ancestors, and the ancestors of current measles virus, coevolved to a state that did not result in the extinction of either humans or the virus. From a human standpoint the virus may not be good for much, (unless you want to exterminate natives occupying islands.) From the virus' standpoint the survival of human hosts is essential because it has evolved to the point it can't easily survive in other hosts. At a minimum there aren't billions of alternative hosts where the virus can reach them.
For a really long-term infection, even the measles 'strategy' seems problematic. Acquired immunity may mean all nearby hosts are immune when the current host dies. In that case the infection dies with the host.
This leads to the idea that the pathogen to look for, if such is the cause of a disease like prostate cancer, will be very slow to replicate, and will keep an unusually low profile with regard to immune defenses. If it can slightly weaken the immune response to itself, without killing the host, that is all to the good (from an imagined rational viral standpoint.)
The other viral long-term goal must be to infect another host before the current one dies or eliminates the infection. Infecting sex organs sounds promising (for an ambitious virus.) In the case of a retrovirus, the inserted provirus will remain there as long as the cell survives. The ideas of looking for a retrovirus with a very low-replication rate, a tropism for sex organs, and a tendency to slightly weaken immune response to viruses all fit together.
We now know that changes leading to prostate cancer take place over 20 or more years. (This is also true of changes leading to Alzheimer's disease, and likely Parkinson's and others.) This brings up a useful tip which either tells us something fundamental about the Universe or about the way humans perceive things: quantitative changes by orders of magnitude are typically seen as qualitatively different. A viral infection lasting decades will be viewed as if it is in an entirely different category from one lasting days or weeks. It will not be considered the same kind of thing at all.
In a discussion about the statistics of infectious diseases I brought up the point that some assumptions are fundamentally flawed. (Both Poisson and Gaussian distributions contain hidden assumptions of statistical independence. Infection of one individual or cell is scarcely independent of infection of cells or individuals nearby.) How could they have been used for so long, if that were the case? Part of the answer is that the exponential increase in numbers of pathogens will pass any reasonable detection limit, and/or kill the patient, if you wait long enough. (For common events, there is little difference between the above distributions and those with 'fat tails'. The differences only become apparent in rare events.) Either way, through testing or autopsy, doctors gain an understanding of what is going on without needing to predict precise loads of pathogens. Far more medical discoveries have taken place via morbid pathology during/after autopsy than patients are comfortable knowing. The pathogens we are looking for can be expected to violate assumptions convenient for medical research.
While the human race is sui generis at present, our pathogens are likely to originate in other species. Pathogens tend to evolve faster in short-lived species. This presents a new hurdle for an ambitious pathogen. When a pathogen jumps species it will need to adapt. What are the big differences between mice and humans of interest to a virus?
As said before, in mice, and other small mammals, the corresponding leukemia virus is commonly transmitted vertically (mother to offspring) via milk. Horizontal transmission generally takes place by mating or wounds in fights about mating. (Spread via wounds is from saliva to blood.) The infection must persist between these times without killing the host or being eliminated by immune response.
For mice the delay between weaning and sexual maturity is only two months. For cattle it is around two years. The only species of mammals which come close to the human delay are elephants, which are admittedly inconvenient for laboratory work. We have no good animal model for adaptive changes required to move from mice to men/women.
What we can predict is that a well-adapted virus will have a very low replication rate during the time between weaning and puberty. It will increase this rate in response to hormones indicating maturity. While it is lying low it will need a strategy to avoid attracting the attentions of human immune systems. What's more, all this has to come about without conscious planning. For the virus this handicap would seem terribly unfair. They make up for it by blindly trying huge numbers of possibilities.
My current view of ME/CFS is that it probably has a retrovirus causing specific immune suppression. XMRV has an immunosuppressive domain already investigated in experiments on mice. The other piece of the puzzle seems to be a cofactor involving an immune challenge. This could be one of any number of pathogens which have been examined and rejected as sole causes in the past.
Koch's model of a single pathogen per infectious disease was not handed down engraved in stone tablets. It was the simplest, and most defensible, hypothesis available. He needed this because he was fighting a medical profession which was still resisting the germ theory of infectious disease -- even in the case of TB and cholera! One opponent actually drank a culture of vibrio cholerae in front of his class -- without obvious effect.
After the single pathogen model, a model with dual infection is the next simplest. This is a great deal more parsimonious an assumption than "many mysterious factors" routinely invoked for genetic, autoimmune or psychological causes.
My own experience was that I was exposed to a known outbreak about two months before I had the classic "worst flu in my life". This flu really existed and the virus is well documented. The problem is the single pathogen model. I got over that infection, but have had other problems ever since. I didn't know about the outbreak at the time, and did not connect it with the flu because of the two month delay. When I learned about a possible connection, my first (theoretical) problem was accounting for the delay. Was this incubation? Other cases don't necessarily show a fixed incubation period. What could cause an infection to sit there for months, with minimal symptoms, until another infection took place? We really don't know much about the circumstances near onset of ME/CFS. Hypotheses are unavoidable.
My current model is a retrovirus which infects cells in the immune system and inserts its provirus, but does not activate the genes immediately. Then it simply waits passively until another pathogen comes along to activate the immune cells to fight a disease via clonal expansion. The virus is copied by host cellular machinery in a context where foreign molecules are 'blamed' on another pathogen. If true, this would be ingenious. It is using the host immune system to propagate only in a context where it can avoid detection.
As above, I begin considering how this interaction could evolve in a virus which jumps from mice to humans, where the life cycle is much longer between weaning and sexual maturity. High variability, and defects in parts of the genome needed for rapid replication could do the trick without any foresight. Variability makes immunity, whether innate or acquired, a less effective defense, as flu viruses demonstrate regularly.
The immune challenge could also be a vaccination, but this need not mean the virus is transmitted by vaccine. The vaccine would only be activating a latent infection. This would result in the statistical confusion we see. Patients would see a correlation in time with the vaccination. Public health officials working with aggregate statistical samples and longer time scales would not see a correlation. Unless you can distinguish the subpopulation with the latent infection (less than 10%) you can't find the linkage, particularly since those who skip vaccination are likely to encounter the wild-type of the pathogen for which they are being vaccinated within a few years. (This is particularly true for something easily communicable like measles.) Untangling such a statistical mess without other information would be a nightmare.
Diagnostic confusion may have lumped together a number of distinct diseases because they share signs and symptoms, as do measles and rubella. This is always a problem in research on diseases without sharp diagnostic categories. The dual infection model proposed here offers a different alternative. The underlying pathogen may not have been detected in most cases. The one detected may not be unique.
This differs from some traditional views of opportunistic infection. Epstein-Barr virus (EBV) already infects over 90% of humans. For HHV-6 the percentage is even higher. A slight weakening of immune response to viral disease caused by immunosuppression is all it would take for a viral disease being held latent to turn active. The number of confounding factors would be innumerable.
Both viruses above are herpes viruses. (EBV is HHV-4) Herpes simplex virus (HSV or HHV-1) is also endemic in humans. Varicella Zoster Virus (VZV or HHV-3) is widespread, and known for causing chickenpox and shingles. Cytomegalovirus (CMV or HHV-5) is also widespread. The herpes family looks like a good candidate for coinfections. Diseases caused by dual infections involving the herpes family are known in animal models. In humans dual infection by HIV-1 and HHV-8 appears to be behind Kaposi's sarcoma.
There is one other curious anomaly. HHV-6 is sometimes found integrated into human chromosomes, even passed via germ line cells to offspring. A model of random recombination does not explain some aspects of this. Might an undetected retrovirus play a role? This explanation is used for fragments of RNA viruses occasionally found in the human genome, under the assumption that this happened long ago, when human ancestors had endemic retroviral infections. Why doesn't this happen today? Because we "know" there are no such retroviruses.
Herpes viruses have double-stranded DNA. They do not need reverse transcription. They likely need some kind of integrase to insert genes in chromosomes. So do retroviruses.
Dr. A. Martin Lerner and Dr. Jose Montoya have had some success in treating ME/CFS where tests show active infection by herpes viruses. This may not mean a complete cure, but it is showing a striking ability for therapy to "move" the disease. In cases where the medication had to be stopped because of potential toxicity the demonstrated gains were reversed.
Other classes of virus could play similar roles. Enteroviruses are either endemic or widespread, and some have been considered as possible causes. Dr. John Chia has had some success in treating ME/CFS in patients with significant enterovirus infections. Even this doesn't exhaust possibilities.
This model has considerable explanatory power, testable predictions and therapeutic implications. While this model is unlikely to be original, it deserves serious consideration.
As this post is getting long, I'll write about implications for detection in a separate post.
While we often believe pathogens are out to kill us, the truth is that the death of the host may often mean not only the death of the pathogen, but the end of the infection. The only way a classic infectious disease like cholera makes sense is if the pathogens, in that case bacteria (vibrio cholerae), replicate rapidly and the victim sheds these bacteria in a way that spreads them to others. (If you don't know what cholera is like, trust me, it does a magnificent job of spreading itself quickly.) This evolutionary 'strategy' works by using up one host in a burst of reproduction that spreads pathogens to others.
We generally think of measles as a non-lethal disease. This is certainly not true for a population never previously exposed. (Some island populations were virtually wiped out by measles.) What has happened is that our ancestors, and the ancestors of current measles virus, coevolved to a state that did not result in the extinction of either humans or the virus. From a human standpoint the virus may not be good for much, (unless you want to exterminate natives occupying islands.) From the virus' standpoint the survival of human hosts is essential because it has evolved to the point it can't easily survive in other hosts. At a minimum there aren't billions of alternative hosts where the virus can reach them.
For a really long-term infection, even the measles 'strategy' seems problematic. Acquired immunity may mean all nearby hosts are immune when the current host dies. In that case the infection dies with the host.
This leads to the idea that the pathogen to look for, if such is the cause of a disease like prostate cancer, will be very slow to replicate, and will keep an unusually low profile with regard to immune defenses. If it can slightly weaken the immune response to itself, without killing the host, that is all to the good (from an imagined rational viral standpoint.)
The other viral long-term goal must be to infect another host before the current one dies or eliminates the infection. Infecting sex organs sounds promising (for an ambitious virus.) In the case of a retrovirus, the inserted provirus will remain there as long as the cell survives. The ideas of looking for a retrovirus with a very low-replication rate, a tropism for sex organs, and a tendency to slightly weaken immune response to viruses all fit together.
We now know that changes leading to prostate cancer take place over 20 or more years. (This is also true of changes leading to Alzheimer's disease, and likely Parkinson's and others.) This brings up a useful tip which either tells us something fundamental about the Universe or about the way humans perceive things: quantitative changes by orders of magnitude are typically seen as qualitatively different. A viral infection lasting decades will be viewed as if it is in an entirely different category from one lasting days or weeks. It will not be considered the same kind of thing at all.
In a discussion about the statistics of infectious diseases I brought up the point that some assumptions are fundamentally flawed. (Both Poisson and Gaussian distributions contain hidden assumptions of statistical independence. Infection of one individual or cell is scarcely independent of infection of cells or individuals nearby.) How could they have been used for so long, if that were the case? Part of the answer is that the exponential increase in numbers of pathogens will pass any reasonable detection limit, and/or kill the patient, if you wait long enough. (For common events, there is little difference between the above distributions and those with 'fat tails'. The differences only become apparent in rare events.) Either way, through testing or autopsy, doctors gain an understanding of what is going on without needing to predict precise loads of pathogens. Far more medical discoveries have taken place via morbid pathology during/after autopsy than patients are comfortable knowing. The pathogens we are looking for can be expected to violate assumptions convenient for medical research.
While the human race is sui generis at present, our pathogens are likely to originate in other species. Pathogens tend to evolve faster in short-lived species. This presents a new hurdle for an ambitious pathogen. When a pathogen jumps species it will need to adapt. What are the big differences between mice and humans of interest to a virus?
As said before, in mice, and other small mammals, the corresponding leukemia virus is commonly transmitted vertically (mother to offspring) via milk. Horizontal transmission generally takes place by mating or wounds in fights about mating. (Spread via wounds is from saliva to blood.) The infection must persist between these times without killing the host or being eliminated by immune response.
For mice the delay between weaning and sexual maturity is only two months. For cattle it is around two years. The only species of mammals which come close to the human delay are elephants, which are admittedly inconvenient for laboratory work. We have no good animal model for adaptive changes required to move from mice to men/women.
What we can predict is that a well-adapted virus will have a very low replication rate during the time between weaning and puberty. It will increase this rate in response to hormones indicating maturity. While it is lying low it will need a strategy to avoid attracting the attentions of human immune systems. What's more, all this has to come about without conscious planning. For the virus this handicap would seem terribly unfair. They make up for it by blindly trying huge numbers of possibilities.
My current view of ME/CFS is that it probably has a retrovirus causing specific immune suppression. XMRV has an immunosuppressive domain already investigated in experiments on mice. The other piece of the puzzle seems to be a cofactor involving an immune challenge. This could be one of any number of pathogens which have been examined and rejected as sole causes in the past.
Koch's model of a single pathogen per infectious disease was not handed down engraved in stone tablets. It was the simplest, and most defensible, hypothesis available. He needed this because he was fighting a medical profession which was still resisting the germ theory of infectious disease -- even in the case of TB and cholera! One opponent actually drank a culture of vibrio cholerae in front of his class -- without obvious effect.
After the single pathogen model, a model with dual infection is the next simplest. This is a great deal more parsimonious an assumption than "many mysterious factors" routinely invoked for genetic, autoimmune or psychological causes.
My own experience was that I was exposed to a known outbreak about two months before I had the classic "worst flu in my life". This flu really existed and the virus is well documented. The problem is the single pathogen model. I got over that infection, but have had other problems ever since. I didn't know about the outbreak at the time, and did not connect it with the flu because of the two month delay. When I learned about a possible connection, my first (theoretical) problem was accounting for the delay. Was this incubation? Other cases don't necessarily show a fixed incubation period. What could cause an infection to sit there for months, with minimal symptoms, until another infection took place? We really don't know much about the circumstances near onset of ME/CFS. Hypotheses are unavoidable.
My current model is a retrovirus which infects cells in the immune system and inserts its provirus, but does not activate the genes immediately. Then it simply waits passively until another pathogen comes along to activate the immune cells to fight a disease via clonal expansion. The virus is copied by host cellular machinery in a context where foreign molecules are 'blamed' on another pathogen. If true, this would be ingenious. It is using the host immune system to propagate only in a context where it can avoid detection.
As above, I begin considering how this interaction could evolve in a virus which jumps from mice to humans, where the life cycle is much longer between weaning and sexual maturity. High variability, and defects in parts of the genome needed for rapid replication could do the trick without any foresight. Variability makes immunity, whether innate or acquired, a less effective defense, as flu viruses demonstrate regularly.
The immune challenge could also be a vaccination, but this need not mean the virus is transmitted by vaccine. The vaccine would only be activating a latent infection. This would result in the statistical confusion we see. Patients would see a correlation in time with the vaccination. Public health officials working with aggregate statistical samples and longer time scales would not see a correlation. Unless you can distinguish the subpopulation with the latent infection (less than 10%) you can't find the linkage, particularly since those who skip vaccination are likely to encounter the wild-type of the pathogen for which they are being vaccinated within a few years. (This is particularly true for something easily communicable like measles.) Untangling such a statistical mess without other information would be a nightmare.
Diagnostic confusion may have lumped together a number of distinct diseases because they share signs and symptoms, as do measles and rubella. This is always a problem in research on diseases without sharp diagnostic categories. The dual infection model proposed here offers a different alternative. The underlying pathogen may not have been detected in most cases. The one detected may not be unique.
This differs from some traditional views of opportunistic infection. Epstein-Barr virus (EBV) already infects over 90% of humans. For HHV-6 the percentage is even higher. A slight weakening of immune response to viral disease caused by immunosuppression is all it would take for a viral disease being held latent to turn active. The number of confounding factors would be innumerable.
Both viruses above are herpes viruses. (EBV is HHV-4) Herpes simplex virus (HSV or HHV-1) is also endemic in humans. Varicella Zoster Virus (VZV or HHV-3) is widespread, and known for causing chickenpox and shingles. Cytomegalovirus (CMV or HHV-5) is also widespread. The herpes family looks like a good candidate for coinfections. Diseases caused by dual infections involving the herpes family are known in animal models. In humans dual infection by HIV-1 and HHV-8 appears to be behind Kaposi's sarcoma.
There is one other curious anomaly. HHV-6 is sometimes found integrated into human chromosomes, even passed via germ line cells to offspring. A model of random recombination does not explain some aspects of this. Might an undetected retrovirus play a role? This explanation is used for fragments of RNA viruses occasionally found in the human genome, under the assumption that this happened long ago, when human ancestors had endemic retroviral infections. Why doesn't this happen today? Because we "know" there are no such retroviruses.
Herpes viruses have double-stranded DNA. They do not need reverse transcription. They likely need some kind of integrase to insert genes in chromosomes. So do retroviruses.
Dr. A. Martin Lerner and Dr. Jose Montoya have had some success in treating ME/CFS where tests show active infection by herpes viruses. This may not mean a complete cure, but it is showing a striking ability for therapy to "move" the disease. In cases where the medication had to be stopped because of potential toxicity the demonstrated gains were reversed.
Other classes of virus could play similar roles. Enteroviruses are either endemic or widespread, and some have been considered as possible causes. Dr. John Chia has had some success in treating ME/CFS in patients with significant enterovirus infections. Even this doesn't exhaust possibilities.
This model has considerable explanatory power, testable predictions and therapeutic implications. While this model is unlikely to be original, it deserves serious consideration.
As this post is getting long, I'll write about implications for detection in a separate post.
