Dr Martin Lerner's abortive infection theory of ME/CFS

[Hip]

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:

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

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).

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.



Further Info

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?

 

[Hip]

This article from the HHV-6 Foundation mentions some studies which found evidence of abortive infection in ME/CFS:

Past studies of both CFS patients that have used assays targeted at abortive infection (by measuring antibodies to the p41 early antigen protein) have been positive for an association.

One study found that 77% of CFS patients compared to 12% of controls had antibodies to HHV-6 early antigen antibodies (Patnaik 1995) and another found 57% of CFS patients compared to 16% of controls had IgM antibodies to HHV-6 early antigen (Ablashi 2000).

Studies that have looked for HHV-6 late antibodies, on the other hand, have been mixed: five were negative (Burbelo 2012, Chapenko 2012, Buchwald 1996, Wallace 1999, Levine 1992, and Gupta 1991).

Similarly in MS studies, serological assays that target intermediate early or early antigen antibodies have been positive for an association with HHV-6 (Ablashi 2000, Soldan 1997, Patnaik 1995, Ben-Fredj 2012) while those using late antibodies have been mixed (Nielsen 1997, Gutierrez 2002, Sola 1993).

So it looks like early antigen antibodies are indicative of abortive infection, but late antibodies are not.



On the subject of multiple sclerosis, this article from the HHV-6 Foundation says:

David Mock’s group at University of Rochester reported in 2004 that HHV-6A establishes an abortive infection in oligodedrocyte precursors. This is significant because the abortive infection was associated with a profound reduction in the number of mature oligodendrocytes which are essential for the repair process.

In fact, transplanted oligodendrocyte progenitor cells have recently been shown to remyelinate and restore spinal cord injury in mice.

So HHV-6A abortive infections may be implicated in MS.



This article suggests that TLR-9 inhibitors might mitigate the inflammation produced by abortive infections:

he presence of HHV-6A in the CNS, even if only a latent or abortive infection, can have a strong impact on inflammation through upregulation of CCL5, CCL2, CXCL10 and CCL1.

HHV-6A-induced chemokines in the glial cultures were inhibited when toll-like receptor 9 (TLR9) was blocked. This finding may have important clinical implications, as TLR9 inhibitors may now be useful in therapeutic approaches to decrease the production of pro-inflammatory cytokines

The article then lists some TLR-9 inhibitors, including artesunate, which Dr Cheney found can be beneficial for ME/CFS (he assumed it works as a antiviral, but perhaps its benefits arise from TLR-9 inhibition).

 

[Jesse2233]

Very interesting, thanks @Hip

Any thoughts on how Lerner's theory might tie in with autoantibody production, the microbiome, and cellular metabolism? And do other commonly associated infections such as mycoplasma pneumonia, bartonella, borrelia, cytomegalovirus, etc form similar abortive infections?

 

[rodgergrummidge]

Dr Martin Lerner developed a groundbreaking theory of myalgic encephalomyelitis: that ME/CFS is caused by abortive herpesvirus infections in non-permissive cells.

An abortive infection is not the same as a regular productive infection.

An abortive infection is one where a virus enters a cell, but is unable to fully complete its replication cycle, and so does not produce any new viral particles (virions). It's a dead end infection. In such abortive infections, although the virus is not able to reproduce itself, it may nevertheless produce a subset of its viral proteins, and the virus may remain in the cell as a chronic infection.

Abortive infections can be created when a virus enters a cell which does not have the right cellular factors needed for the virus to complete its replication cycle (such cells are called non-permissive). Dr Lerner hypothesized that ME/CFS is caused by herpesviruses inadvertently entering such non-permissive cells, thereby setting up chronic abortive infections, which he posits are driving ME/CFS.

Dr Lerner's 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-associated ME/CFS with enterovirus-associated ME/CFS into a single framework of understanding (because as we shall see in a moment, the non-cytolytic enterovirus infections found in ME/CFS patients can be considered as a sort of abortive infection).
.

Wow @Hip great work! Although, I'm not sure about so-called 'abortive viral infections'.

A few comments for discussion and debate:

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 is 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.

Its not really true that latent infections only occur in permissive cells. For example, memory B-cells can lie dormant for years. If a dormant memory B-cell is infected with a virus (e.g. EBV, other), the virus cannot replicate because a dormant cell doesnt contain the necessary machinery to allow virus replication. The virus can still express latent genes, but the cell is 'non-permissive for virus replication' and the lytic cycle. According to the Lerner definition, the dormant B-cell would have an abortive infection (ie the cell is non-permissive for viral replication). But its not. Its simply a dormant B-cell that contains a latent infection.

Now, if that same latent B-cell that contains the same virus (EBV, other) becomes activated by the presence of a foreign antigen, it will mobilize, divide and start producing antibodies. Under these conditions, the B-cell now contains all the necessary machinery for viral replication.

Thus, the exact same B-cell depending on its status can harbour either a latent or a replicative virus.

Now it doesnt need to be a B-cell. The same latent versus replicative infections can also occur in any cell infected with a virus. In the case of EBV, it would include B-lymphocytes, squamous epithelial cells, glandular epithelial cells, myoepithelial cells, smooth muscle cells, T cells, NK cells, plasma cells, and follicular dendritic cells. In each case, EBV can cause a latent or a replicative/lytic infection. The precise distinction between latent and abortive infection is not clear to me?

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.

I think the current understanding of why the 95% of CD4 T-cells die is fairly well understood. Its not because they harbour either abortive or non-productive infections of HIV. It is because the death of the 5% of CD4 cells infected with HIV create such a proinflammatory storm within the lymph nodes that the remaining 95% of uninfected CD4 T-cells are killed in what is described as a 'bystander effect'. This video gives a really nice explanation for what kills the 5% of HIV-infected CD4 cells and the 95% of non-infected HIV cells.

Lerner says: 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

Why does it have to be non-permissive virus replication? IE gene products are not specific for abortive infections. They will also be produced in latent infections. Non-productive latent viral infections are measured by measuring IE gene products and have been proposed to cause dyregulation and host cell death. I'm not sure why a model that invokes abortive infection is required to explain the biology?

So ME/CFS patients seem to be producing antibodies to nonstructural proteins made by viruses.

Sure, but this is known. Taking the B-cell example again: A dormant B-cell that contains a latent infection of a virus (ie, it is non-replicative and non-lytic) is known to express non-structural genes. Such gene expression can be monitored by RT-PCR to provide evidence of a latent infection. Thus, gene expression analysis can be used to determine if there are latent and/or replicative infections occurring (an individual can have both). Again, why the need for an abortive infection model?

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).

EBV-EA is not diagnostic for abortive infection. Firstly it is clearly detectable in primary infections as well as reactivated infections (see below). Also, because of the long-life of both antibodies and circulating plasma/B-cells, neither viral serology nor viral antibody titres provide an accurate understanding of current infection status of an individual. They simply indicate whether the individual has had a past infection (exceptions would be the presence of IgM versus IgG Abs, or possibly Abs related to virus resolution such as EBNA-IgG, see below). This issue of why serology doesnt provide an accurate diagnostic picture of latent, abortive, reactivated or chronic viral infection has been discussed elsewhere in PR (I think @Jonathan Edwards has discussed it in some threads?) so I wont detail it here.

Dr Lerner thinks these abortive herpesvirus infections occur in the heart;

what is his evidence?

that of ME/CFS occurring when either of these viruses is able to set up a chronic abortive / non-cytolytic infection in the tissues.

again, I dont really understand the distinction. Remember, latent infections are not silent infections. Viruses can express latent gene products which could be presented by MHC and induce pro-inflammatory responses and ME/CFS.

Dr John Chia found that giving people immunosuppressive corticosteroids during an acute viral infection is almost a recipe for creating ME/CFS

I agree! Immune suppression during a acute viral infection or during ongoing latent infections (such as may be cause CFS) could be a disaster. Unless there is strong evidence to indicate that the CFS is caused by hyper-immune activation, taking corticosteroids could actually make the disease worse.

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.

Sure, but why not just say, "But if the immune system is weak, this may give the virus the time and opportunity to spread to even permissive cells, where it may set up a chronic latent or non-cytolytic infection."?

any viral test that relies on productive infections in permissive cells, or latent infections in permissive cells, is going to miss these abortive infections.

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.

Unless I am missing something, antibody tests and serology will not allow the diagnosis of an 'abortive infection'. The status of an infection/infections (latent and replicative can co-exist in the same patient) requires analysis of the viral expression pattern in the target tissue. For example:
1) active infections that lead to virus replication and lysis can be measured and quantitated by RT-PCR for viral replicative genes. Significant levels of replicative gene expression means that the tissue being analysed has replicative virus.
2) latent infections in any cell can be measured and quantitated by RT-PCR of viral latent genes. Significant levels of latent gene expression means that the tissue being analysed has latent virus.

Unlike serology which only provides an historical picture of viral infections, viral gene expression provides a diagnostic result for the type of infection at time of tissue collection (ie real time)

In the case of 'abortive infections', what do you specifically measure? How do the measurements allow determining the difference between replicative, latent and abortive infections? Even if there was an accepted specific antibody that recognized only an 'abortive infection' antigen, serology only provides an 'historical snapshot'. The 'abortive infection' serology may be due to antibody production years prior. How would the test distinguish between abortive and latent by using serology alone?

However, I do agree @Hip that latent virus infections could be a major player in ME/CFS. I'm trying to read more. For example, long-term latently infected cells could explain many of the symptoms in ME/CFS. 2 possibilities could be:

1) An immune-deficient model: Latent infected cells are able to survive long-term because the immune system is not able to clear them leading to chronic non-resolving immune stimulation, inflammation and CFS symptoms.
2) An immune-competent model: Sporatic rounds of viral replication and lysis in one tissue (eg mucosa) leads to ongoing rounds of latent infections in a different tissue type (lymphocytes). While each new round of viral replication produces infective virus that goes on to produce latent infections that can be cleared by the immune system, the ongoing cycles of replicative and latent infections leads to chronic immune activation, inflammation and CFS symptoms
3) Other immunological possibilities? Thoughts? Ideas?

very interesting

Rodger

 

[heapsreal]

Id be interested to know if the nk dysfunction comes before cfs onset and allows infections to take hold or the chronic infection 'wears' out the nk cells?? It would take testing people before and after cfs onset to have any idea, which would be very difficult to do.

My understanding is that some chronic herpes viruses can avoid stimulating the bodies interferon production which reduces nk function.

I wonder if theres research into antiviral drugs for herpes infections that can treat the virus by different mechanisms similar to haart for hiv?

@Hip does chia have research showing low nk function is a common finding in his EV cfs patients? Its possible EV can lower ones interferon and therefore nk function , is this maybe why interferon treatment can lower EV load.

I know chia says patient feel horrible on interferon but i wonder why he doesnt start with interferon treatments to get on top of EV and try to maintain this with interferon inducers like immunovir or cycloferon. There maybe a negative feedback issue with interferon treatment so that once its stopped ones natural interferon takes awhile to switch back on?? Could explain relapses of EV after interferon treatment??

 

[nandixon]

Id be interested to know if the nk dysfunction comes before cfs onset and allows infections to take hold or the chronic infection 'wears' out the nk cells?? It would take testing people before and after cfs onset to have any idea, which would be very difficult to do.

Can't answer what was going on with natural killer cell function prior to ME/CFS onset, of course, but once in the ME/CFS state it seems likely that ongoing low NK cell function is an effect of elevated TGF-beta. The elevated TGF-beta being, I think, an attempt to down-regulate T cell activation and expansion (viewing this with the recent work of Mark Davis and Maureen Hanson in mind).

 

[heapsreal]

The elevated TGF-beta being, I think, an attempt to down-regulate T cell activation and expansion

For me, attempt is the word. Nk function low but t cell subsets mostly high/activated. Antivirals lowered these t cells but no effect on nk function.

 

[Hip]

Its not really true that latent infections only occur in permissive cells. For example, memory B-cells can lie dormant for years.

I think we can say that latent infections only occur in permissive cells just by definition. Viral latency is a program that viruses use to lay quiet for a while, so that they can come back and infect the host another day. If a virus cannot fully reactivate from latency, then it is not in a latency program, because the object of latency is to come back to life at a later time. No virus can fully reactivate in non-permissive cells, because those cells do not contain the machinery necessary for the virus to replicate.

When it comes to EBV in B-cells, this virus does periodically reactivate from time to time: see this paper:

Ultimately, the virus persists for the lifetime of the host in subsets of memory B cells ...

In this setting the virus maintains a latent state as an episome and expresses no viral genes thereby allowing EBV to remain hidden from the immune system. Periodically, the virus may become reactivated through mechanisms that are unclear, but the host immune response typically is sufficient to maintain control.

So the fact that EBV can and does reactivate from latency in B-cells indicates that B-cells are permissive for EBV infection.

Also, note that latency has very specific mechanisms to protect the virus during its dormant period. In the case of EBV and many herpesviruses, these viruses create episomes in order to store and protect their genetic material while laying low inside a host cell. So latency is a planned action by a virus.

Whereas in abortive infections, there is no such plan, and there are no episomes. In an abortive infection, the virus is not trying to lie low and go in to dormancy; the very opposite, the virus is constantly trying to replicate itself, but because the non-permissive cell does not contain the right machinery to allow full replication, the abortive infection fails to produce any new virions. But nevertheless, the abortive infection is always actively trying to replicate, and always failing to do so. It is never dormant.


What adds further complexity is that fact that some viruses have several latency states: in the deepest latency states the virus is completely dormant, but they also have latency states in which the virus is partially awakened, and starts synthesizing a few proteins. Epstein-Barr virus is know to have three latency states, denoted by latency I, latency II and latency III — see here.

It has also been proposed by Dr Kazuhiro Kondo that HHV-6 may have three latency states, and that the HHV-6 latency II state may be the cause of ME/CFS — see this post.

So viral latency is an interesting phenomenon in its own right, and has also been considered as a theory of ME/CFS, but latency is not that same as an abortive infection.

I think the current understanding of why the 95% of CD4 T-cells die is fairly well understood. Its not because they harbour either abortive or non-productive infections of HIV. It is because the death of the 5% of CD4 cells infected with HIV create such a proinflammatory storm within the lymph nodes that the remaining 95% of uninfected CD4 T-cells are killed in what is described as a 'bystander effect'. This video gives a really nice explanation for what kills the 5% of HIV-infected CD4 cells and the 95% of non-infected HIV cells.

I don't really know much about HIV, but according to the study I cited, it says: "The mechanism by which CD4 T cells are depleted in HIV-infected hosts remains poorly understood." So that nice video you linked to may not be fully reliable, if there is uncertainty in the field. Interestingly, your video mentions pyroptosis as the cause of death of this 95% of CD4 T-cells, and explains that pyroptosis is cell death caused by inflammation.

Well in this paper (which reiterates that "CD4 T-cell death in HIV-infected hosts remains poorly understood"), they state that 95% of CD4 T-cells are killed by pyroptosis — pyroptosis which results from abortive infection.

So your video and the studies I cited both agree that 95% of CD4 T-cells are killed by the inflammatory process of pyroptosis; but what your video does not mention is that this inflammation is thought to be due to abortive infection.

Why does it have to be non-permissive virus replication? IE gene products are not specific for abortive infections. They will also be produced in latent infections.

That's a good question, and I could not find much info from Dr Lerner regarding latent infections versus abortive infections. However, everyone has latent infections, healthy people and ME/CFS patients, so on its own a latent infection could not be the cause of ME/CFS.

But I presume that not everybody has extensive abortive infections. So abortive infections may be the differentiating factor between health and ME/CFS.

(This is not rule out the possibility that latent infections could also play a role in ME/CFS, which is also an interesting idea; but Dr Lerner's theory focuses on abortive infections, not latent ones.)

EBV-EA is not diagnostic for abortive infection. Firstly it is clearly detectable in primary infections as well as reactivated infections (see below).

I agree that EBV-EA also occurs in productive infections, and it's not clear to me either why Dr Lerner says that EBV-EA diffuse is indicative of abortive infections; I guess he may just mean that in the context of his abortive infection theory of ME/CFS, and in the context of the patient being symptomatically diagnosed with ME/CFS, EBV-EA indicates an abortive infection.

I think the important thing here is that if the abortive infection theory of ME/CFS is correct, then you would only expect to see early stage viral proteins, but not the later viral proteins that build viral capsids, because no virions are created in abortive infections.

So any researcher looking to viral etiologies of ME/CFS needs to bear in mind when you look at late stage viral proteins, you may not find any difference between ME/CFS patients and healthy controls.

Also, because of the long-life of both antibodies and circulating plasma/B-cells, neither viral serology nor viral antibody titres provide an accurate understanding of current infection status of an individual.

I think most ME/CFS specialists would disagree with that, because they use antibody titers as a quantitative means to gauge infection levels in ME/CFS patients. Dr John Chia uses sensitive antibody neutralization test to gauge levels of enterovirus infection (which in chronic infection consists of non-cytolytic infection as well as productive infection). Dr Lerner and Prof Montoya use antibody titers to herpesviruses to quantitatively gauge infection levels in ME/CFS patients. These specialists treat ME/CFS patients on the basis of the results of these antibody tests (Dr Chia for example considers a titer of 1:320 or higher in the ARUP Lab micro-neutralization tests as indicative of a chronic active enterovirus infection).

what is his evidence?

I did not look into this, but Dr Lerner has always had a strong focus on heart dysfunction in ME/CFS, so I expect his theory of an abortive heart infection arises from that area of his research. But I don't think we necessarily have to go along with this aspect of his abortive infection theory.

I agree! Immune suppression during a acute viral infection or during ongoing latent infections (such as may be cause CFS) could be a disaster. Unless there is strong evidence to indicate that the CFS is caused by hyper-immune activation, taking corticosteroids could actually make the disease worse.

Long term high dose corticosteroids often provides temporary improvements in ME/CFS, but after some months, the disease can become worse, presumably because the immunosuppression allows further viral proliferation. Low dose hydrocortisone though seems safe and helpful for some patients.

However, I am interested in understanding Dr Chia's observation that acute viral infection + corticosteroids = ME/CFS. How specifically do corticosteroids given during acute infection trigger ME/CFS? My hypothesis is the one I gave above: that the immunosuppression due to corticosteroids gives the virus a chance to infect a lots of non-permissive cells, and once that happens, ME/CFS may then arise.

In the case of 'abortive infections', what do you specifically measure? How do the measurements allow determining the difference between replicative, latent and abortive infections?

I don't know enough to answer this question, regarding whether there may be a unique signature for abortive infections that can be found in a blood test.

However, I would expect that biopsy tests could in principle definitively determine whether an abortive infection was present. If like Dr Lerner we assume that the abortive infection occurs in non-permissive cells in the heart, then a biopsy of those non-permissive heart cells showing the presence of viral proteins or viral genes would be definitive proof of an abortive infection.

 

[Hip]

Any thoughts on how Lerner's theory might tie in with autoantibody production, the microbiome, and cellular metabolism?

The paper mentioned earlier looks into that; it says:

few studies have asked the question of whether a protein that is expressed during abortive or productive virus replication, namely a deoxyuridine triphosphate nucleotidohydrolase (dUTPase), can contribute to the pathophysiological alterations that occur in diseases associated with human herpesviruses infections.

The authors speculate that viral dUTPase may play a role in autoimmunity, though there's not much "meat" in that paper, so it's not really clear how such abortive infections could lead to autoimmunity, or disruptions in cellular energy metabolism. But abortive infections are very under-studied, so we don't know what sort of disruptive effects they are capable of.

And do other commonly associated infections such as mycoplasma pneumonia, bartonella, borrelia, cytomegalovirus, etc form similar abortive infections?

I think only viruses can form abortive infections, so yes to cytomegalovirus, but no to those bacteria that you listed.

 

[Hip]

@Hip does chia have research showing low nk function is a common finding in his EV cfs patients?

Not that I am aware of. There are supplements that can potently increase NK function, like Biobran, yet a study found that Biobran had no benefit for ME/CFS, suggesting that low NK function is likely not the cause of ME/CFS, but rather may be a consequence of it.

 

[heapsreal]

Not that I am aware of. There are supplements that can potently increase NK function, like Biobran, yet a study found that Biobran had no benefit for ME/CFS, suggesting that low NK function is likely not the cause of ME/CFS, but rather may be a consequence of it.

I guess what comes to my mind is the australian nk studies where they measure not only nk function but nk bright cell function. Not sure a drug exist that can increase nk bright cell function.

During one lot of nk testing i used cycloferon and this raised my nk function quite high but had little effect on nk bright cells. Is it possible that past studies at increasing nk function havent been targeted at nk bright cells?

Biobran is their research legit as it appears to be an overpriced supplement?

Id like to see if some of these immunotherapies used in cancer could possibly increase nk and nk bright cell function? I think that in many viral cfsme subsets the reason for relapses once off antiviral therapy including for EV is that ones immune/nk function isnt strong enough to keep these viruses suppressed or that the immune system in combination with the different antivirals are needed to completely eradicate these infections or keep it to a level its easily controlled.

If nk cells are broken, they need fixing even if not the root cause??

 

[pattismith]

I don't really know much about HIV, but according to the study I cited, it says: "The mechanism by which CD4 T cells are depleted in HIV-infected hosts remains poorly understood." So that nice video you linked to may not be fully reliable, if there is uncertainty in the field. Interestingly, your video mentions pyroptosis as the cause of death of this 95% of CD4 T-cells, and explains that pyroptosis is cell death caused by inflammation.

Well in this paper (which reiterates that "CD4 T-cell death in HIV-infected hosts remains poorly understood"), they state that 95% of CD4 T-cells are killed by pyroptosis — pyroptosis which results from abortive infection.

So your video and the studies I cited both agree that 95% of CD4 T-cells are killed by the inflammatory process of pyroptosis; but what your video does not mention is that this inflammation is thought to be due to abortive infection.

Edit bis: interesting finding in wikipedia about Loss of Th17 cells in HIV pathogenesis:

Additionally, the loss of Th17 cells in the intestine leads to a loss of balance between inflammatory Th17 cells and Treg cells, their anti-inflammatory counterparts. Because of their immunosuppressive properties, they are thought to decrease the anti-viral response to HIV, contributing to pathogenesis. There is more Treg activity compared to Th17 activity, and the immune response to the virus is less aggressive and effective.[16]

Revitalizing Th17 cells has been shown to decrease symptoms of chronic infection, including decreased inflammation, and results in improved responses to highly active anti-retroviral treatment (HAART). This is an important finding—microbial translocation general results in unresponsiveness to HAART. Patients continue to exhibit symptoms and do not show as reduced a viral load as expected.[20] In an SIV-rhesus monkey model, it was found that administering IL-21, a cytokine shown to encourage Th17 differentiation and proliferation, decreases microbial translocation by increasing Th17 cell populations.[17] It is hopeful that more immunotherapies targeting Th17 cells could help patients who do not respond well to HAART.

Maybe if we favor CD4 differenciation into Th17, it would allow them to survive and to restore equilibrum between Tregs and Th17?

Further mechanistic studies demonstrated that the combination of CIM and LMS promoted DC activation and blocked anti-inflammatory cytokine IL-10 and TGF-β production in CD4(+) CD25(+) T cells. These findings suggest that CIM and LMS have the synergistic and additive ability to enhance cellular response to HBV DNA vaccine, which may be mediated by DC activation and inhibition of anti-inflammatory cytokine expression. Thus, the combination of cimetidine and levamisole may be useful as an effective adjuvant in DNA vaccinations for chronic hepatitis B virus infection.
Synergistic and Additive Effects of Cimetidine and Levamisole on Cellular Immune Responses to HBV DNA Vaccine in Mice.. Available from: https://www.researchgate.net/public...r_Immune_Responses_to_HBV_DNA_Vaccine_in_Mice [accessed Nov 11 2017].

In a case report:

HIES patients have impaired differentiation of Th17 T cells from mutations in STAT3.5 Experimental models in which Th17 cells or Th17 cell‐dependent cytokines are defective have shown that immunity to several extracellular bacteria, including Staphylococcus aureus, Klebsiella pneumoniae and Candida albicans, is impaired.6
....
Other therapies. Isotretinoin, cyclosporin A, and plasmapheresis have been tested on a few patients but are not generally indicated.[URL='http://www.sciencedirect.com/science/article/pii/S0873215914000038#bib0020']4,11 H2 antagonists like cimetidine seem to improve symptoms.[/URL]

(I found only anecdotal reports that cimetidine may improve the differenciation of Th17 at the expense of Tregs)

I found also a paper about synergia between Praziquantel and Cimetidine... Was Praziquantel tryed by some patient here?

 

[wastwater]

Is it likely that rather than defective infections there’s a defective immune response

 

[Hip]

@pattismith, Dr Lerner's abortive infection theory of ME/CFS is not the same as the abortive infection in CD4 T-cells in HIV; I just gave HIV as an example of a known abortive infection.

 

[pattismith]

@pattismith, Dr Lerner's abortive infection theory of ME/CFS is not related to the abortive infection in CD4 T-cells in HIV; I just gave HIV as an example of a known abortive infection.

I understand, but I thought that in ME/CFS, we could observe an inbalance between Tregs and Th17, so that what would benefit to HIV could benefit to ME in this aspect (although I must be of topic so I apologize)

 

[Hip]

@pattismith, we certainly could do with some new ideas about how to tackle abortive herpesvirus infections if these are indeed the cause of ME/CFS as Dr Lerner suggests.

 

[Wonkmonk]

This thread is fascinating. I knew about Dr Lerner's theory for quite some time, but having it explained so thoroughly made a lot of points much clearer to me. Many thanks to @Hip and also to @rodgergrummidge for interesting discussion.

Perhaps I might add - I think it hasn't come up so far - that there is a group of patients that don't get any common infections since having CFS. I am one of those, I haven't been sick even once since almost four years, which is actually impossible. In my opinion, that's also an indicator that there is permanent immune system overactivation and that would be consistent with the idea that the body is fighting a permanent non-permissive infection. I think Prof. Edwards also had a theory that involved CFS symptoms being caused by the overproduction of an unknown type of broad-spectrum/low affinity antibodies (not necessarily autoantibodies). These antibodies (which our serology does not detect) might be produced in response to non-permissive infection all over the body.

But what I am thinking the most about for some time is how Dr Lerner's theory fits into the Rituximab story.

If the numbers of the initial Fluge/Mella study hold, Rituximab does the following:

(1) Brings a few patients into permanent remission (i.e. possibly cured them)

(2) Brings 1/3 of patients to complete or nearly-complete remission for a limited amount of time (usually a few weeks or months).

(3) Brings another 1/3 of patients into partial remission for a limited amount of time.

(4) Doesn't help the last 1/3 of patients.

(5) Made a few patients considerably worse (some permanent).

My hypothesis is that Rituximab helps:

(a) those patients whose CFS is caused by an autoimmunity problem not directly linked to EBV infection (e.g. possibly patients like @Gingergrrl). In these cases, Rituximab helps in the same way as it helps Rheumatoid Arthritis patients, by killing the B-cells and reducing the autoimmune process --> Depending on how well the patient responds, they fall in bucket (2) or (3), i.e. they experience temporary partial or near-complete remission as long as they take Rituximab and usually relapse if they stop treatment.

(b) those patients whose CFS is caused by EBV non-permissive infection (and only EBV, not other viruses). In those patients, Rituximab kills EBV's main reservoir (memory B-cells). That is a big step towards ending the non-permissive infection as detailed by @Hip above, and that's why some of them make a very pronounced recovery after 3-6 months (which coincidentally is exactly the timeframe Dr Lerner says antivirals need to start working). But in most cases, they don't kill all the B-cells and EBV lytic replication may continue in some permissive cells or semi-permissive cells elsewhere in the body, so new memory B-cells are reinfected and non-permissive replication starts all over again after some time, if Rituximab is discontinued. But in a lucky few, repeated Rituximab treatment clears EBV entirely (I think there is a study in which Rituximab did that in some patients) or puts the body into a position to fight it back into latency, i.e. a few patients are cured. --> So most of the patients in this group also fall in buckets (2) and (3) and some lucky few fall in bucket (1).

On the other hand, Rituximab doesn't help patients, whose CFS is neither caused by autoimmunity or by a virus other than CFS or something else entirely. They fall in bucket (4) and don't benefit or even get much worse, because of either Rituximab side effects or because Rituximab kills their B-cells which they need to fight off another virus which causes their CFS but is not affected by killing B cells - the unlucky few in bucket (5).

So following this line of reasoning, the Rituximab results obtained so far are consistent with Dr Lerner's theory.

The following inferences would follow:

- Those who benefit from antiviral therapy directed at EBV (Valtrex, Famvir) might also benefit from Rituximab
- In those patients, Rituximab and antivirals should work synergistically
- Antivirals should help retain the benefits gained from Rituximab and Rituximab should further improve the response of those who benefitted from antivirals
- Co-administration of high-dose antivirals and Rituximab for several months should lead to an increase of patients in bucket (1), i.e. lead to more people being cured entirely and able to stop all treatment without relapsing
- Drugs like Belimumab should have a similar effect, possibly with lower risk (I started a discussion here, sadly no on replied https://forums.phoenixrising.me/ind...-accelerate-response-to-anti-ebv-drugs.54683/)
- High-dose antivirals over a long period of time might achieve the same as Rituximab, in fact there are many similarities in response patterns:
---time until response is similar
---initial worsening of symptoms occurs in both cases
---relapse usually occurs if treatment is stopped
---Patients recover to varying degrees under both protocols, response patterns appear similar (near-complete remission, partial remission, no effect), although it has to be considered that Dr Lerner made a selection based on EBV titers and the Rituximab study did not.

 

[heapsreal]

@Wonkmonk
What worries me about rituximab is that if one has an ongoing infectiin rtx could make it worse. I recall one woman here a few years back had high titres for the usual herpes suspects in cfs and went on rtx. She crashed quite severe from these infections going into over drive.

Id like to see the theory of dr kogleneck looked into where antivirals or any treatment for other active infections is used while on rtx. The problem i see is medicine cant accurately detect these smouldering infections very well.

It would be interesting to have a pure ebv group and treat one with rtx and another with antivirals and another with both and a control.

As for your earlier comment about some cfsers never getting colds etc , is that many infective symptoms like fevers etc are caused by the immune system fighting the infection, if immune suppressed its possible the symptoms we get from infections wont be present. One example ive seen is that many cfsers run a lower than normal body temp 36c or lower, normal being 37c and if one is at 38c then its probably a fever from an infection. Myself and others have had say a cold type virus where a normal person will get a fever of 38c plus, a cfser will have a fever at 36.5c but drs wont recognize it.

One thing for sure is we aint normal in many aspects.

 

[jstefl]

@rodgergrummidge

In response to your questioning Dr. Lerner's theory that herpes viruses can occur in the heart, I can offer my experience.

I have had CFS/ME since 1991, and things had gotten progressively worse as time went on. By 2008 my blood pressure had dropped to 80/50 and my pulse dropped to 50. I was taking a blood pressure increaser to keep going and I was taking my BP readings on a daily basis and recording the results.

I finally convinced my doctor to put me on Valcyte in 2008 and I stayed on it for 10 months. During that time I was able to slowly reduce the BP meds that I was taking and weaned myself off of them after about 6 months. That has been over 9 years and my BP has stayed at an acceptable level since. I realize that I am a case of 1 and my experience may not apply to others, but I am very thankful for the Valcyte.

I had a chance to meet Dr. Lerner at the HHV-6 conference in Baltimore in 2008 and hear what he had to say about Valcyte. The one thing that has stayed with me was his response to a question about how long he keeps his patients on Valcyte. His response was" until they are cured". He said that he had one patient that had been on Valcyte for 7 years and was still taking it.

I am very thankful for my time on Valcyte. In addition to fixing my blood pressure problems, I had many other improvements. I was suffering from extremely painful headaches on a continuous basis that were alleviated after a few weeks on the drug. I won't list all of the other improvements as they are off topic.

Drs Peckerman and Natelson did research into viral infections of the heart, but that never seemed to reach the average cardiologist, the ones I saw were completely clueless. I had all of the tests by three different cardiologists including two specialists and they had no clue. Their answer was to prescribe a antidepressant.

John

 

[jstefl]

@Hip

How does your theory fit with Dr. Davis's finding that the problem seems to be a large particle in the blood?