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When treating herpesvirus-associated ME/CFS with antivirals such as Valtrex and Valcyte, Dr Lerner's studies showed it takes a long time for benefits to appear, usually 3 or 4 months for the very first signs of improvements to materialize, and a year or more for the full benefits to manifest. And for many ME/CFS patients, improvements from antivirals may not appear at all (you have to be lucky for antivirals to work for you).
Dr Martin Lerner, who pioneered antiviral treatment for herpesvirus ME/CFS, had a theory to explain why antivirals work so slowly in ME/CFS, or may not work at all:
Dr Lerner theorized that ME/CFS is caused not by regular herpesvirus infections, but is caused by abortive herpesvirus infections (to be defined in a moment).
Lerner says that all current herpesvirus antiviral drugs (including Valtrex, Famvir, Valcyte, cidofovir and foscarnet) have no direct effect against abortive infections. So these drugs cannot directly tackle the infections that Dr Lerner thinks are the cause of herpesvirus-associated ME/CFS.
These antiviral drugs work fine for regular herpesvirus infections, but not for abortive infections.
How does an abortive infection differ from a regular infection? A regular viral infection is technically known as a productive infection. It's called productive because when the virus infects cells, it replicates inside those cells and produces thousands of copies of itself, thousands of new viral particles. A productive infection is the sort you get when you catch a cold or flu.
An abortive infection by contrast does not produce any new viral particles.
An abortive infection arises when a virus (like EBV, CMV or HHV-6) enters into a type of cell in which it is not able to reproduce, because the conditions in the cell are not right.
Viruses are not able to reproduce inside certain types of cell, because those cells do not possess the necessary cellular machinery to allow the virus to make new copies of itself. The body has many types of cell: inside some cell types a virus can reproduce, but inside other cell types, the conditions are not right for viral reproduction.
Cells which a virus can enter, and then reproduce, are called permissive cells. Cells which a virus can enter, but once inside cannot reproduce, are known as non-permissive cells.
When a virus enters a non-permissive cell, it produces an abortive infection, which does not create new viral particles. In abortive infections, the virus may remain inside the cell for a long time, constantly trying to reproduce, but always failing to do so.
Dr Lerner believed that ME/CFS was due to such abortive infections (he explains his theory is this paper). In ME/CFS patients, herpesviruses like EBV, CMV or HHV-6 would start of as a regular productive infection, but some of these viruses would go off and infect non-permissive cells, and in those cells create an abortive infection.
So in the body of herpesvirus ME/CFS patients, according to Lerner, there are two parallel infections going on at the same time: the productive herpesvirus infection, and the abortive herpesvirus infection.
Lerner says the productive infection constantly makes a small amount of new viral particles, and these new viral particles then re-seed and sustain the abortive infection, by infecting more non-permissive cells. So the abortive does not die out, because it is constantly being re-seeded by the productive infection.
The way to tackle abortive infections is not to address them directly, according to Lerner, because we don't have the drugs to do so. So instead we fight abortive infections indirectly, by targeting the productive side of the infection with antivirals.
Dr Lerner posits that by using antivirals, you can inhibit the productive infection, and that stops it from creating new viral particles which re-seed the abortive infection. So the abortive infection is starved of its reinforcements. Then you just have to wait for the immune system to slowly kill off the abortive infection over many, many months.
So this was Dr Lerner's explanation for why antivirals take such a long time to work in ME/CFS. It's a slow process to kill off the abortive infection in this indirect manner.
According to Lerner, if we developed some new antiviral drugs which would directly target abortive herpesvirus infections, you could cure herpesvirus ME/CFS in a matter of weeks.
How might abortive infections cause ME/CFS? In abortive infections, no new viral particles are produced in the cell; but nevertheless the infected cells are littered with the viral genes and viral proteins created by the virus during its attempts to reproduce.
The virus may remain inside a cell for a long time in abortive infections, constantly trying to reproduce, but always failing to do so. And always synthesizing viral genes and proteins in the infected cells.
These viral genes and proteins may cause cellular dysfunction, and they may also be packaged up into tiny exosomes (little spheres made of lipids) which are ejected into the bloodstream and travel to reach other cells. The purpose of exosomes is to transport and deliver their contents into other cells.
One protein made in herpesvirus abortive viral infections is deoxyuridine triphosphatase (dUTPase), and this can be transmitted cell to cell via exosome transport. This particular protein is known to induce ME/CFS-like symptoms.
And this protein was found in ME/CFS patients: Ohio State University found around 31% to 53% of ME/CFS patients have high levels of antibodies to the dUTPase protein produced by EBV, HHV-6 and VZV. Ref: here, here and here.
Ohio State believe dUTPase may be a biomarker in a subset of ME/CFS patients (presumably the herpesvirus subset).
So herpesvirus ME/CFS may in part be caused by this dUTPase protein, which is constantly being produced by abortive herpesvirus infections, and may travel in exosomes to reach other cells.
One new dUTPase inhibitor drug in the pipeline is TAS-114, and perhaps potentially this might be beneficial for herpesvirus ME/CFS.
More info on Dr Lerner's abortive herpesvirus theory of ME/CFS can be found in this thread:
Dr Martin Lerner's abortive infection theory of ME/CFS.
Although Dr Lerner passed away in 2015, work on the abortive infection theory of ME/CFS (and other diseases) has been taken up by a research group in Ohio State University — see Cort's excellent article here.
Dr Martin Lerner, who pioneered antiviral treatment for herpesvirus ME/CFS, had a theory to explain why antivirals work so slowly in ME/CFS, or may not work at all:
Dr Lerner theorized that ME/CFS is caused not by regular herpesvirus infections, but is caused by abortive herpesvirus infections (to be defined in a moment).
Lerner says that all current herpesvirus antiviral drugs (including Valtrex, Famvir, Valcyte, cidofovir and foscarnet) have no direct effect against abortive infections. So these drugs cannot directly tackle the infections that Dr Lerner thinks are the cause of herpesvirus-associated ME/CFS.
These antiviral drugs work fine for regular herpesvirus infections, but not for abortive infections.
How does an abortive infection differ from a regular infection? A regular viral infection is technically known as a productive infection. It's called productive because when the virus infects cells, it replicates inside those cells and produces thousands of copies of itself, thousands of new viral particles. A productive infection is the sort you get when you catch a cold or flu.
An abortive infection by contrast does not produce any new viral particles.
An abortive infection arises when a virus (like EBV, CMV or HHV-6) enters into a type of cell in which it is not able to reproduce, because the conditions in the cell are not right.
Viruses are not able to reproduce inside certain types of cell, because those cells do not possess the necessary cellular machinery to allow the virus to make new copies of itself. The body has many types of cell: inside some cell types a virus can reproduce, but inside other cell types, the conditions are not right for viral reproduction.
Cells which a virus can enter, and then reproduce, are called permissive cells. Cells which a virus can enter, but once inside cannot reproduce, are known as non-permissive cells.
When a virus enters a non-permissive cell, it produces an abortive infection, which does not create new viral particles. In abortive infections, the virus may remain inside the cell for a long time, constantly trying to reproduce, but always failing to do so.
Dr Lerner believed that ME/CFS was due to such abortive infections (he explains his theory is this paper). In ME/CFS patients, herpesviruses like EBV, CMV or HHV-6 would start of as a regular productive infection, but some of these viruses would go off and infect non-permissive cells, and in those cells create an abortive infection.
So in the body of herpesvirus ME/CFS patients, according to Lerner, there are two parallel infections going on at the same time: the productive herpesvirus infection, and the abortive herpesvirus infection.
Lerner says the productive infection constantly makes a small amount of new viral particles, and these new viral particles then re-seed and sustain the abortive infection, by infecting more non-permissive cells. So the abortive does not die out, because it is constantly being re-seeded by the productive infection.
The way to tackle abortive infections is not to address them directly, according to Lerner, because we don't have the drugs to do so. So instead we fight abortive infections indirectly, by targeting the productive side of the infection with antivirals.
Dr Lerner posits that by using antivirals, you can inhibit the productive infection, and that stops it from creating new viral particles which re-seed the abortive infection. So the abortive infection is starved of its reinforcements. Then you just have to wait for the immune system to slowly kill off the abortive infection over many, many months.
So this was Dr Lerner's explanation for why antivirals take such a long time to work in ME/CFS. It's a slow process to kill off the abortive infection in this indirect manner.
According to Lerner, if we developed some new antiviral drugs which would directly target abortive herpesvirus infections, you could cure herpesvirus ME/CFS in a matter of weeks.
How might abortive infections cause ME/CFS? In abortive infections, no new viral particles are produced in the cell; but nevertheless the infected cells are littered with the viral genes and viral proteins created by the virus during its attempts to reproduce.
The virus may remain inside a cell for a long time in abortive infections, constantly trying to reproduce, but always failing to do so. And always synthesizing viral genes and proteins in the infected cells.
These viral genes and proteins may cause cellular dysfunction, and they may also be packaged up into tiny exosomes (little spheres made of lipids) which are ejected into the bloodstream and travel to reach other cells. The purpose of exosomes is to transport and deliver their contents into other cells.
One protein made in herpesvirus abortive viral infections is deoxyuridine triphosphatase (dUTPase), and this can be transmitted cell to cell via exosome transport. This particular protein is known to induce ME/CFS-like symptoms.
And this protein was found in ME/CFS patients: Ohio State University found around 31% to 53% of ME/CFS patients have high levels of antibodies to the dUTPase protein produced by EBV, HHV-6 and VZV. Ref: here, here and here.
Ohio State believe dUTPase may be a biomarker in a subset of ME/CFS patients (presumably the herpesvirus subset).
So herpesvirus ME/CFS may in part be caused by this dUTPase protein, which is constantly being produced by abortive herpesvirus infections, and may travel in exosomes to reach other cells.
One new dUTPase inhibitor drug in the pipeline is TAS-114, and perhaps potentially this might be beneficial for herpesvirus ME/CFS.
More info on Dr Lerner's abortive herpesvirus theory of ME/CFS can be found in this thread:
Dr Martin Lerner's abortive infection theory of ME/CFS.
Although Dr Lerner passed away in 2015, work on the abortive infection theory of ME/CFS (and other diseases) has been taken up by a research group in Ohio State University — see Cort's excellent article here.
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