Abortive infection theory of ME/CFS

Dr A Martin Lerner developed a remarkable theory regarding the cause of myalgic encephalomyelitis / chronic fatigue syndrome: Dr Lerner posited that herpesvirus-associated ME/CFS is caused not by normal productive infections with herpesviruses, but is caused by herpesviruses in an unusual mode of infection called an abortive infection. An abortive infection is one in which a virus enters a cell, but is unable to replicate fully within that cell, and so does not produce any new viral particles (virions) inside the cell.

Abortive infections are typically created when a virus enters a cell which does not possess an internal environment that facilitates the virus to replicate itself and create new virions — such cells are called non-permissive (their internal environment does not permit the virus to reproduce).

In abortive infections, although the virus cannot fully reproduce itself with non-permissive cells, the virus is constantly trying to do so, and in its persistent attempts to replicate, it synthesises many viral proteins inside the cell; these proteins may then lead to cellular dysfunction or have other adverse effects.

Dr Lerner hypothesized that herpesvirus-associated ME/CFS is caused when herpesviruses inadvertently enter non-permissive cells, and thereby create chronic abortive herpesvirus infections.

Definition of an Abortive Infection

Definition of terms:

Permissive cell — this is a cell that a virus can break into, circumvent any cellular defenses, and fully replicate itself. In permissive cells, a virus will enter the cell, reproduce itself many thousands of times, and these new virions will then burst out of the cell by lysis usually, killing the cell in the process, with the virions escaping and going off to infect more cells.

Non-permissive cell — this is a cell that does not support replication of a virus. This may because the cell does not possess the internal factors or environment 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 and assemble 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. This is the normal viral replication cycle 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.

Abortive Infections Are Not Latent Infections

Abortive infections are not to be confused with latent infections, which are a different phenomenon. Productive infections and abortive infections are both active ongoing infections, whereas a latent viral infection is usually dormant and inactive. But note that while productive infections produce lots of new viral particles, abortive infections do not create any new viral particles, but nevertheless are ongoing infections within the infected cells.

Latent infections are where the virus has stopped replicating for a period of time, and 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). Latency is the viral strategy of "running away in order to live to fight another day". An example of latency is the cold sore virus (herpes simplex virus), which stays in a latent state for months or years in the cells around the 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.

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 A Martin Lerner's Abortive Infection Theory of ME/CFS

Dr Lerner explains his abortive infection theory of ME/CFS in his 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 "non-permissive 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 are producing antibodies to nonstructural proteins made by viruses. 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).

Dr Lerner says that the diffuse and restricted component of Epstein-Barr virus (EBV) early antigen (EA) indicates abortive EBV viral infection. In his 2012 paper, Dr Lerner finds that in 106 ME/CFS patients with herpesvirus infections, 81% had elevated early antibodies, to EBV early antigen (diffuse).

Dr Lerner also found antibodies to deoxyuridine triphosphatase (dUTPase) from EBV and EBV DNA polymerase. 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).

In his 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

A team at Ohio State University have also discovered that antibodies to herpesvirus dUTPase are more common in ME/CFS patients: they found 31% to 53% of ME/CFS patients have high levels of antibodies to the dUTPase protein produced by EBV, HHV-6 and VZV. Ohio State believe dUTPase may be a biomarker in a subset of ME/CFS patients.

Treatment of Abortive Infections in Non-Permissive Cells

In terms of antiviral treatment for abortive infections in ME/CFS, Dr Lerner points out that:

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.

In other words, Dr Lerner says existing commercial anti-herpesvirus antiviral drugs are not effective against abortive infections in non-permissive cells. But he suggests that low-level productive herpesvirus infections elsewhere in the body may be supplying more herpesvirus virions that re-seed the abortive infections, to keep the abortive infection going. Therefore, antivirals that target the productive infections may eventually indirectly reduce abortive infection levels as well.

Learn more

• 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.
• Ohio State researchers isolate biomarker to test for chronic fatigue syndrome
• List of Dr A Martin Lerner's published ME/CFS studies

See also

• Herpesviruses
• List of herpesvirus infection studies
• Epstein-Barr virus
• Cytomegalovirus
• Dr A Martin Lerner
• Non-cytolytic enterovirus

T cell A type of white blood cell which is mostly produced or matured in the thymus gland (hence T-cell) and is involved in the adaptive immune response on a cellular level. Also known as a T lymphocyte. (Learn more: www.youtube.com)

etiology The cause of origin, especially of a disease.

apoptosis a type of cell death in which a cell, in response to a threat, initiates a series of molecular steps that lead to its orderly death. This is one method the body uses to get rid of unneeded or abnormal cells. This form of cell suicide is also called programmed cell death.

serum The clear yellowish fluid that remains from blood plasma after clotting factors have been removed by clot formation. (Blood plasma is simply blood that has had its blood cells removed.)

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

enzyme a substance produced by a living organism which acts as a catalyst to bring about a specific biochemical reaction.

cytomegalovirus (CMV) - A common herpesvirus found in humans. Like other herpesviruses, it is a life-long infection that remains in a latent state inside the human body, until it is 'reactivated' by appropriate conditions. CMV infects between 60% to 70% of adults in industrialized countries and close to 100% in emerging countries. Much is unknown about this virus, although it has been found in salivary glands and myeloid blood cells such as monocytes. It has also been linked to the development of certain cancers. Congenital CMV is a leading infectious cause of deafness, learning disabilities, and intellectual disability. A common treatment for CMV is valganciclovir, commonly known as Valcyte.

assay 1. (verb) analysis (as of an ore or drug) to determine the presence, absence, or quantity of one or more components. 2. (noun) In biochemistry, any laboratory protocol used to test a sample for one or more qualities.

B cell B lymphocyte, or a type of white blood cell, which is involved in the immune response by secreting antibodies to ward off infections. In mammals, they are mostly matured in the bone marrow.