A more succinct and easier-to-understand intro to abortive infections here:
The reason why antivirals like Valtrex and Valcyte take such a long time to work in ME/CFS.
Dr Martin Lerner developed a groundbreaking theory regarding the cause of myalgic encephalomyelitis: that ME/CFS is caused not by regular productive herpesvirus infections, but by abortive herpesvirus infections.
An abortive infection is one where a virus enters a cell, but is unable to replicate properly, and so does not produce any new viral particles (virions) in that cell.
In abortive infections, although the virus cannot reproduce itself, it nevertheless makes some viral proteins inside the cell, and these may lead to cellular dysfunction.The virus may remain inside the cell as a chronic abortive infection.
Abortive infections are typically created when a virus enters a cell which does not possess the factors needed for the virus to replicate and create new virions — such cells are called non-permissive (they do not permit the virus to replicate).
Dr Lerner hypothesized that ME/CFS is caused when herpesviruses inadvertently enter such non-permissive cells, thereby setting up chronic abortive infections, which he posits are driving the herpesvirus-subset of ME/CFS.
Dr Lerner's very intriguing abortive infection hypothesis of ME/CFS did not get the attention it deserves, because it seems to me that this theory could explain several observations about ME/CFS, and in addition, this theory could neatly tie together herpesvirus ME/CFS with enterovirus ME/CFS into a single framework of understanding (because as we shall see later, the non-cytolytic enterovirus infections found in enterovirus ME/CFS patients can also be considered a sort of abortive infection).
Definition of an Abortive Infection
Before we start, let's properly define some terms:
Permissive cell — this is a cell that a virus can break into, circumvent any cellular defenses, and fully replicate itself. In such cells, a virus will enter, multiply itself many thousands of times typically, and then these thousands of new virions will usually burst out of the cell by lysis, killing the cell and allowing these virions to escape.
Non-permissive cell — this is a cell that does not support replication of a virus. This can because the cell does not possess the internal factors that the virus requires for full replication, and in which case, once in the non-permissive cell, the virus may start producing some of its proteins, but is not able to produce all the proteins necessary to manufacture duplicate virions. So no new virions are created.
Semi-permissive cell — this similar to a non-permissive cell, except that a small yield of new virions may be produced.
Productive infection — this is where a virus enters a permissive cell and successfully completes its replication cycle, reproducing itself typically thousands of times, and then usually bursting out of the cell by lysis. That's the normal viral replication in a cell.
Abortive infection — this is where a virus enters cell but cannot successfully complete its replication cycle. Abortive infections can occur when a virus enters a non-permissive host cell, or when the virus itself is defective, and so cannot replicate properly.
Sources: Microbiology: Virology, Multiplication - Medical Microbiology
Abortive Infections Are Not the Same as Latent Infections
Note that abortive infections are not to be confused with latent infections, which are a different thing.
Productive and abortive infections are both active ongoing infections; whereas latent viral infections are (mostly) dormant and inactive. But note that while productive infections produce lots of new viral particles, abortive infections do not make any new viral particles.
Latent infection is where the virus has stopped replicating for to time being, and instead hides inside a cell, waiting for the right opportunity to reawaken from latency and start replicating again (usually at a moment of immune weakness, to maximize its success).
A well-known example of latency is the cold sore virus (herpes simplex), which stays in a latent state for months or years in the cells around your lips, but every now and then springs back to life, creating a cold sore.
Latent infections only exist in permissive cells (since in a non-permissive cell, a virus can never replicate and thus a latent virus could never later spring back to life, which would defeat the purpose of latency).
So a latent infection is where a virus in a permissive cell has itself switched off its replication for the time being. Whereas in an abortive infection in a non-permissive cell, the virus can never fully replicate itself.
One example of an abortive infections is in HIV: more than 95% of CD4 T-cells dying after infection with HIV are not productively infected; instead, these cells harbor an abortive infection, which leads to cell death. Ref: 1
Abortive infections however are not well studied, because they are normally considered to be of little biological importance. But Dr Lerner thought otherwise, and postulated that abortive infections were the etiological basis of ME/CFS.
Dr Martin Lerner's Abortive Infection Theory of ME/CFS
This section is slightly more technical, and you may want to skip it and go on to the next section.
Dr Martin Lerner explains his abortive infection theory of ME/CFS in this 2011 paper:
By "non-permissive herpesvirus replication," Dr Lerner means an abortive herpesvirus infection in non-permissive cells. Note that Dr Lerner often refers to abortive infections as "nonpermissive infections", although strictly speaking, the term non-permissive refers to cells, not to infections (cells in which abortive infections can arise).We propose that ME/CFS patients have nonpermissive herpesvirus (EBV, HCMV, HHV6) replication, expressing immediate-early (IE) gene products, which induce host cell dysregulation and host cell apoptosis
Dr Lerner says in the same paper that:
EBV ME/CFS subset patients also have uniquely elevated serum antibody titers to the nonstructural gene products EBV-specific DNase and DNA polymerase. These elevated EBV-specific serum antibody titers are also present in patients with EBV-related malignancies, Burkitt’s lymphoma, and nasopharyngeal carcinoma, but are not present in patients with infectious mononucleosis or in healthy individuals.
So ME/CFS patients seem to be producing antibodies to nonstructural proteins made by viruses. I wonder if this might be because in abortive infections, there may be higher levels of nonstructural proteins, and a lack of structural viral capsid proteins (since in abortive infections, full virions are not constructed).
In this press release, Dr Lerner says that the diffuse and restricted component of EBV early antigen (EA) indicates abortive viral infection. In this 2012 paper, Lerner finds that in 106 ME/CFS patients with herpesvirus infections, 81% had elevated early antibodies, to EBV early antigen (diffuse). He also found antibodies to EBV dUTPase and EBV DNA polymerase.
Lerner also talks about abortive infection in ME/CFS in this 2010 paper.
In this 2008 paper on cytomegalovirus in ME/CFS, Dr Lerner says that:
The p52, CM2 recombinant IgM assay to early human cytomegalovirus (HCMV) antigens is diagnostic of abortive HCMV infection.
These results confirm our previous findings that p52 and CM2 serum antibodies are specific in diagnosis of HCMV abortive infection in CFS patients similar to those infected with EBV.
In that study, p52 and CM2 HCMV IgM serum antibody titres were present in this HCMV subset of CFS patients, but not in control non-CFS patients. In turn, the presence of p52 and CM2 antibodies to p52 and CM2 non-structural antigens may account for difficulties in detecting HCMV DNA in blood or cardiac biopsies in these CFS patients, consistent with the paradigm of incomplete or abortive viral multiplication.
Abortive viral multiplication in immunocompetent CFS patients may be unique
This study also found antibodies to herpesvirus dUTPase more commonly in ME/CFS patients. dUTPase is a viral enzyme produced in both productive and abortive infections. EBV-encoded dUTPase has been shown to induce sickness behavior symptoms (which are similar to ME/CFS symptoms). Refs: 1 2
A good paper on viral dUTPase and their link to ME/CFS and autoimmune disease is found here.
Dr Lerner thinks these abortive herpesvirus infections occur in the heart; although I can't see why it should be only the heart, and not also in other areas of the body.
In some of the early British research on enteroviruses is ME/CFS, they found enterovirus RNA in the muscle biopsy tissue samples of ME/CFS patients, but they also found EBV DNA in these muscle tissues. See this 1991 study. So perhaps that EBV DNA was due to an EBV abortive infection in the muscles.
Unifying the Herpesvirus and Enterovirus Etiology of ME/CFS
What's interesting about Dr Lerner's abortive infection theory of ME/CFS is that it is congruent with what we know about enterovirus in ME/CFS. In the chronic enterovirus infections found in ME/CFS patients, very few enteroviral particles (virions) are to be found, and much of the infection exists as non-cytolytic enteroviruses (which live inside cells on a long-term basis, but do not produce any new virions).
These non-cytolytic enterovirus infections are in some ways similar to herpesvirus abortive infections. Non-cytolytic infections are produced when an enterovirus enters a non-dividing (quiescent) cell. Non-dividing cells lack a certain factor which is essential for enterovirus to complete its full replication cycle, so a non-dividing cell is a non-permissive cell as far as enterovirus is concerned. As in abortive infections, in non-cytolytic infections some viral proteins get produced in the cells, but without a full virion being constructed.
The slight difference between non-cytolytic enteroviruses and abortive herpesviruses is that the non-cytolytic enteroviruses are able to reproduce to a degree, and may even be able to infect adjacent cells. But this non-cytolytic enterovirus just consists of a strand of naked viral RNA, so non-cytolytic virus replication does not involve the creation of any new virions, just replication of this viral RNA. Enterovirus non-cytolytic infection infections are described in this post.
However apart from that difference, non-cytolytic and abortive infections are similar in some ways.
So the beauty of Dr Lerner's theory is that may unify the herpesvirus etiology and the enterovirus etiology of ME/CFS into one simple theory: that of ME/CFS occurring when either of these viruses is able to set up a chronic abortive / non-cytolytic infection in the tissues. (Dr Lerner does not actually mention enteroviruses in his theory; his clinical and research interests were always focused on herpesviruses; but it seems to me that the broad principles of his theory could encompass both herpesviruses and enteroviruses).
Does Immune Weakness During Acute Infection Lead to Abortive Infection, Thereby Giving Rise to ME/CFS?
When I was thinking about this abortive / non-cytolytic infection theory of ME/CFS, it suddenly occurred to me that this could explain why people are at higher risk of developing ME/CFS when they are hit with a viral infection during period of immune suppression: Dr John Chia found that giving people immunosuppressive corticosteroids during an acute viral infection is almost a recipe for creating ME/CFS. So temporary immunosuppression during acute viral infection seems to create the conditions in which ME/CFS can appear.
And along these lines, ME/CFS has been associated with a prologued period of stress just before the (presumed viral) onset of this disease — prologued stress may itself cause immunosuppression, so that again the immune system is weak at the time of contracting a virus.
My speculative idea is that if the immune system is suppressed when a person is hit with an acute viral infection, this may give the virus more scope to infect non-permissive cells — cells which perhaps the virus would not normally infect. Once it has infected these non-permissive cells, then ME/CFS may ensue.
Why might immunosuppression allow non-permissive cells to be infected? Well if you think about it, infections in permissive cells lead to lots more viral particles being produced, which in turn can infect more cells in the surrounding tissues. So it's easy to infect tissues comprising permissive cells.
However, infections in non-permissive cells do not create viral particles, so I am guessing it would be a lot more difficult to set up an infection in tissues comprising non-permissive cells. But if the immune system is weak, this may give the virus the time and opportunity to spread to even non-permissive cells, where it may set up a chronic abortive or non-cytolytic infection.
So in this way, the abortive / non-cytolytic infection theory of ME/CFS could explain why some people develop ME/CFS after an acute herpesvirus or enterovirus infection, whereas most people do not get ME/CFS from these same infections. It may simply be that temporarily weakened immunity during the time of acute infection — whether this weakening is from corticosteroids, psychological stress, or other immune-affecting factors like mold, biotoxin or pesticide exposure — allows an acute viral infection to spread into non-permissive cells, and once that tragedy happens, ME/CFS may then arise.
Abortive Infections and Viral Testing
Dr Lerner's abortive infection theory of ME/CFS would also explain the sometimes paradoxical results obtained during viral testing of ME/CFS patients. Generally speaking, I believe PCR blood tests for viruses often come out negative in ME/CFS patients, whereas antibody tests usually show positive results.
This study for example found no difference between ME/CFS patients and healthy controls when peripheral blood mononuclear cells were analyzed by PCR for the presence of Epstein-Barr virus, HHV-6, HHV-7 and cytomegalovirus. And the Enterovirus Foundation says that PCR is not sensitive for chronic enterovirus infections.
In the light of the abortive infection theory of ME/CFS, these paradoxical testing results start to make sense, because if ME/CFS is driven by an abortive / non-cytolytic infection in non-permissive cells, any viral test that relies on productive infections in permissive cells, or latent infections in permissive cells, is going to miss these abortive infections. Indeed, this paper says that:
PCR and culturing approaches will not demonstrate abortive lytic replication, which is reported to occur with several herpesviruses
Whereas antibody tests do not detect the viral infection directly, but measure the immune antibody response to the infection. So antibody tests will be able to detect abortive / non-cytolytic infections in non-permissive cells, because these infections are expressing a subset of viral proteins, so you can still get an antibody response.
Treatment of Abortive Infections in Non-Permissive Cells
So if ME/CFS is due to an abortive herpesvirus or non-cytolytic enterovirus infection, what can be done to treat this infection? Well, Dr Lerner points out that:
To be sure, no antiviral drug is active in vitro vs. any latent, nonpermissive persistent herpesvirus infection.
However, implicit in this unified hypothesis is the assumption that low-level, continuing, infectious herpesvirus multiplication is occurring in susceptible B cells (EBV) and epithelial cells (EBV), and/or in tissue macrophages (HCMV) and cardiac myocytes (EBV and HCMV).
Infectious EBV or HCMV might, we presume, intermittently be carried to the heart by the blood within productively infected B cells (EBV) or monocytes macrophages (HCMV). Eradication of productive virus infection by an effective antiviral drug might inhibit the slowly active, persisting pathologic process we hypothesize.
Source: Hypothesis: a unified theory of the cause of chronic fatigue syndrome
So Dr Lerner is saying that anti-herpesvirus antiviral are not directly effective against abortive infections in non-permissive cells; but he suggests that low-level productive infections elsewhere in the body may be supplying more virions that re-seed these abortive infections, and keep them going. Therefore, antivirals that target the low-level productive infections may indirectly eventually reduce abortive infection levels as well.
This may be why antiviral treatment for herpesviruses in ME/CFS is so slow to produce results (it takes around 6 months for the benefits of antivirals like Valtrex and Valcyte to appear in ME/CFS): because herpesviruses antivirals do not directly target the abortive infections, they only target them indirectly.
In this presentation (see page 16) Dr Lerner proposes that inhibitors of herpesvirus intermediate or early gene products would rapidly improve ME/CFS. Thus if new antivirals were developed to treat these intermediate or early viral proteins, that would produce an effective treatment of ME/CFS, according to Lerner's theory.
Good Phoenix Rising article by Cort on Dr Martin Lerner and his abortive infection theory of ME/CFS here.
A list of Dr Lerner's ME/CFS studies here.
Dr Lerner's patent describing abortive infections in ME/CFS and their treatment here.
A team at Ohio State University, led by Dr Maria Ariza and Dr Marshall Williams, are currently researching the hypothesis that chronic abortive herpesvirus infections may be causing ME/CFS and other diseases. See: Could Crippled Herpesviruses Be Contributing to Chronic Fatigue Syndrome (ME/CFS) and Other Diseases?