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.
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Footprints in the Sand
Blog entry posted by anciendaze, Mar 10, 2012.
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