Footprints in the Sand

For impressionable antediluvians who grew up prior to television the passage in Robinson Crusoe where the protagonist finds footprints in the sand might raise hair on the back of the neck. It was not necessary for him to meet these visitors to know that he had company. (Probably just as well, since his visitors turned out to be cannibals. I remember being properly horrified by this, somehow overlooking the original purpose of Crusoe's voyage: to make his fortune by buying slaves cheaply at the source. This was one person who might expect to get all his work done by Friday.) Similar reasoning is possible on the disputed subject of retroviral infections.

Multiple sclerosis (MS) presents an interesting parallel to ME/CFS. It was long ago recognized as a neurological disease, though the etiology is still disputed. For those patients without the characteristic large lesions in the central nervous system diagnostic confusion with CFS is quite possible. (I'm still waiting for someone to explain how you can have two diagnoses of exclusion with common symptoms.)

A connection with viral infection has long been postulated, and several putative retroviral causes have been proposed. Until quite recently, this has not led to much of anything except spilled ink. Arguments over contamination and endogenous retroviruses have generated much heat and little light.

A human endogenous retrovirus labeled HERV-Fc1 seems to be changing matters. The HERV-F family might not seem a good candidate, since some members have been around for many millions of years, and most are highly defective. Some years back, however, it became suspected that this family was still active in primates, including humans. This evidence primarily concerned the genes labeled gag and env, which form the capsid and envelope of the virion. The pol gene, which encodes reverse transcriptase, seemed to be thoroughly disabled.

Genetic studies in Scandinavian populations showed surprisingly high correlations between simple changes (SNPs) in locations near the HERV-Fc1 locus, and MS. This was immediately plausible because this locus is on the X-chromosome, and would explain the 2:1 ratio of female to male cases of MS. (Males have only one X chromosome; females have two.)

HERV-F is also highly homologous to HERV-H and somewhat less to HERV-W, both of which have been considered suspect in MS and several mental illnesses. These are all similar to exogenous gamma retroviruses.

A second indication was that changes in the TRIM5 gene correlated with the disease. TRIM5 is important in response to human retroviral infections, and seems to act in an analogous manner to the mouse gene Fv-1. It is responsible for the formation of protein complexes with ubiquitin ligases, an important step in the identification and degradation of misfolded proteins, which also play a prominent role in neurodegenerative diseases. This association has implications for pathology and possible treatments.

Expression of RNA from the gag and env genes of the HERV was detected, but expression of the pol gene was not. This is important because reverse transcription is essential for infective replication of a retrovirus. (Passive replication via host-cell mitosis is still possible without it.) If the active virus were being replicated this would imply the presence of a "helper" virus with its own pol gene.

Now, we come to the least expected aspect, which turned up in sequencing a complete dog genome (Canis Familiaris, hence the prefix Cf for dog ERVs). (Earlier sequencing had concentrated on genes which were transcribed into proteins, overlooking many ERVs.) Dogs have surprisingly similar ERVs to HERV-Fc1, now labeled CfERV-Fc1. With common ancestors very far back, before the first primates, this seems a clear indication of horizontal transmission at a more recent date. Domestication of dogs within the last 50,000 years would be a good reason for transmission between humans and dogs, most likely within the last 10,000 years. By evolutionary standards, this is the day before yesterday.

None of these results depend on satisfying Koch's postulates. An infectious agent has not been isolated, cloned, sequenced, etc. We do have a much better idea of what to look for.

The assumption that a retroviral infection is responsible for the disease already has implications for treatment. If this autoimmune disease is a response to infected immunological memory cells it makes sense that B-cell depletion early in the pathology might allow the immune system to purge itself of replication-competent virus. This would explain limited success in treatment of MS with Rituximab. It would also explain association with other viral infections, like Epstein-Barr virus (EBV). Corresponding infections in other species cause immunological impairment.

ME has the same 2:1 female to male ratio, the same history of disputed retroviral involvement, similar association with infection by EBV, and many common symptoms. Rituximab has also had some success against ME. Scientific research on etiology and treatment of MS should be highly relevant to research on our own illness.

One other impression formed while reading this material may be significant. Genetic studies have focused on finding stable sequences in genomes. The same stability in a laboratory may be evidence of contamination. Stable elements sit at the same site for many generations. Active retrovirus infections typically insert provirus at many locations, though assumptions of purely random behavior are not justified. Studies typically take one view or the other, as if there were no overlap between exogenous and endogenous retroviruses. Evidence discarded in the course of genetic studies might have already settled arguments about the presence of exogenous retroviruses had it been analyzed. Some footprints, like fingerprints, are distinctive enough to convict an unseen perpetrator.
Likes: George


Just wondered if understanding is taking off now anciendaze - I do recall a noted biologist when asked at 2000 what his prediction was for the the next century saying it will be the Virus (and genetics). Very interesting piece - thank you.
My point in that last paragraph was less about understanding taking off than about deliberate neglect ending. At the start of research in a new field the breakthroughs are disproportionately made by those who have a nose for easy problems. This then becomes ossified into social constructs given the spurious status of natural laws. To some extent the response to questions about exceptions is "don't ask those questions", or the erudite mumble of authority in place of a simple "we don't know". It takes time for enough anomalies to be acknowledged to bring about a general reappraisal of the field. We are now in such a period.

My own peculiar personal history included a period when making predictions and catching unsuspected anomalies was literally a matter of personal life or death. The predictions were numerical, and the anomalies showed up as "residuals" in data. I became hypersensitive to anomalies in simple models which might kill people. My motto became "always pay attention to your residuals." It was important to use these to judge not how much your model could predict, but how much remained unexplained. If an exception kills you the fact that it is merely an exception is no comfort at all.

In both human genetics and in virology we have strong indications of huge deficiencies in current knowledge. In both MS and schizophrenia, for example, there has long been the indication of 25% concordance between homozygous twins. This has been taken as evidence these diseases are genetic. The other 75% has been overlooked until we can find the genetic explanation for the 25%. This has remained true for about 50 years, with minimal progress on etiology, prevention and treatment. Those things which indicate genetic cause become ignorable exceptions in relation to virology, and vice versa. The presumed action of genes seems tied to what I call a "player piano model" with little interaction with environment in far too much thinking. That this should persist into an era dominated by much more sophisticated machines in daily life is astonishing.

The virological side of the equation has seen repeated incidents in which fragmentary results have been discredited because they do not accord with methods and theories developed in dealing with progressive diseases where newly introduced viruses replicate rapidly. How anything meeting those standards could result in relapsing/remitting disease lasting decades is beyond me. The idea that the healthy population is completely free from corresponding infections was convenient at the outset of research, but remains an untested hypothesis. Whether viral genes arrive via heredity or infection is far less important than their effect. Because viruses are not complete organisms we cannot even be sure these genes will all arrive together. The onset of symptoms may simply reflect the last piece fitting into a puzzle.

We now see large fractions of the general population facing long-term prospects of dementia, cancer or autoimmune disorders, resulting in major healthcare costs. Mental illness carries enormous social costs and affects all ages. There are distinctive neuropsychiatric problems associated with acknowledged physical illnesses like systemic lupus erythematosus (SLE) and MS, yet the physical causes, even in cases with sudden onset, remain obscure. In mice we can explain 95% of mammary tumors as caused by viruses, in other species lesser but significant percentages. In humans we are still wondering if any percentage is due to viral infection. This is not acceptable. Business as usual must change.
I was given a glossy brochure today by our Uni's psych department, titled something like "Brain Disorders, what do we know ..." Pages and pages on Alzheimers, what is known and how much is unknown, promising areas of research and treatment etc. Not a word on immunological aspects or any of those super interesting HSV-1 studies, or potential for reducing plaques with acyclovir

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