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A plea for broad leukemia virus research

Blog entry posted by anciendaze, Jun 5, 2012.


While I fall far short of the above ideal, I keep trying to look beyond the incredibly narrow perspectives of most researchers in biomedical fields, and the ephemeral subjects of disputes which dominate their working lives. Admittedly, this is moving upstream against a powerful current which drives cautious researchers to end up knowing everything about a subject of no particular interest to anyone else.

Just in case anyone out there buys the argument that research into possible human leukemia viruses is nothing more than wasted effort, and a sop for crazy patients who don't have any real disease, I thought I'd build a case for research on diseases which are both acknowledged and fatal. The reason certain viruses are called leukemia viruses is simple, they have been shown to cause leukemia in a number of species. The causes of most human leukemias remain unknown.

The primary examples are murine leukemia viruses, but this is not a single virus with a straightforward sequence. You need to distinguish between Abelson, Friend, Moloney and Rauscher murine leukemia viruses, for starters. (Did I mention that what we commonly call mice are actually many different species?) Another kind of classification splits this group into ecotropic, polytropic, amphotropic and xenotropic. You also need to worry about the role of helper viruses, which make it possible for another virus to replicate, even though defective, e.g. myeloproliferative leukemogenic virus (MPLV). If similar complexity exists in human pathogens a lack of repeatable initial findings should be expected. It is far easier to experiment on mice than humans, and it took quite an effort to reach our present understanding of mouse viruses.

Mice are not the only species affected by these. Perhaps it is to be expected that there should be a feline leukemia virus (FLV) corresponding to MLVs. The are several similar endogenous retroviruses in cats, with at least one still exogenous. Gibbon Ape leukemia virus (GALV) jumped to that species recently enough so that it is still exogenous. (BTW: a receptor used by this virus is also present in humans.) Another similar exogenous virus shows up in domestic fowl, reticuloendotheliosis virus (REV). This is a rare example of a virus jumping from one class of animal host to a completely different class. (This is beyond species, genus, family and order, but less extreme than jumping to a different phylum or kingdom. Sorry kids, you are probably safe from diseases affecting broccoli, and Mom can be expected to know this.)

Homologous sequences to GALV also show up in a new koala retrovirus (KoRV), a jump to marsupials. This is not ancient history, even on human time scales. Epidemiology shows this infection has invaded new territory after 1900. It is not clear that it even existed in its present form at earlier dates.

These are all gamma retroviruses, and we still have not exhausted their range. What we can show is that recent speciation events reach into historical times, and this group exhibits remarkable versatility in terms of hosts.

Not all leukemia viruses are gamma retroviruses. One of the most widespread in a human environment is bovine leukemia virus, a delta (and complex) retrovirus. Many animals shedding virus are asymptomatic. Tests for antibodies to this virus have now found them in humans. Even if the structural differences are substantial, there is a human leukemia virus in this group, HTLV-1. It is known to cause adult T-cell leukemia/lymphoma (ATL), a fatal disease. I will only mention that HTLV-2 through HTLV-4 exist.

This virus and disease are notable in two respects: this is a human leukemia with a clear viral etiology; the latency between infection and appearance of the progressive and fatal disease is over 20 years, and may be closer to 40 years. What about etiology of other human leukemias? If you read current literature you will find that researchers have damn near emptied the bit bucket in the search for possible explanations. If you compare this with earlier literature on say, cervical cancer, you will see corresponding confusion over etiology prior to proof that a strain of human papilloma virus (HPV) caused most such.

HTLV-1 also causes another fatal disease, HAM/TSP, originally called tropical spastic paraparesis. This is a neurodegenerative disease which typically manifests clear symptoms 20 to 30 years after infection, which often takes place around birth and before weaning. The virus was isolated from cases of ATL and HAM/TSP which showed geographic localization in very different places: the Caribbean and islands near Japan. There was clear epidemiological evidence of transmission from mother to child, and of sexual transmission from male to female. If it had not been localized to island populations, or had not had a distinctive and fatal pathology, it is doubtful it would have been isolated and identified on the basis of symptoms, (at least not until technology has advanced beyond its present state.) We now know about 97% of those infected are asymptomatic carriers. (Has any infected individual ever been cured?)

My point here is that it is not special pleading to insist that a human version of a leukemia virus should be expected to have a very long latency and relatively low short-term lethality. We have clear evidence that the characteristics of well-adapted viruses match host life cycles, and human life cycles from weaning to reproduction are longer than almost any mammal except elephants. A leukemia virus in humans should not be expected to behave exactly like a mouse virus. If it did it would kill human hosts before it could be passed on to the next generation. HIV-1 is an anomaly among human retroviruses with about 99% lethality and only 5 year latency.

This brings me to an important point: a virion is not living, it is not even a complete organism; it has no metabolism. (Virions can even be crystallized and stored like salt or sugar. X-ray crystallography was used to deduce some properties that were not visible.) Essentially all the activities caused by a virus are carried out by the host cell. Expecting a virus to behave exactly the same way in different hosts is foolish. Assuming behavior will be completely unrelated is foolish in a different way, it denies the common ancestry of host animals.

There is another lesson in the story of HTLV-1, it causes two very different diseases: a neurodegenerative disease and a hematological disease. These are ordinarily treated by different medical specializations. But this is not the end of the problem. Below is a quote from the Wikipedia entry:

We have now brought in ophthalmologists, rheumatologists, immunologists, pulmonologists and dermatologists. Since urinary incontinence is common we might throw in a urologist. (Would other malfunctioning sphincters bring in a gastroenterologist? I'm not sure how patient organ systems are currently gerrymandered.) But this is not the end, sensory disturbances are very common. Could a TSP patient end up in the hands of a psychiatrist? And, could this fine fellow, reaching back two decades to recover memories from medical school obscured by a fog of student fatigue, classify this as a somatization disorder? Surely, all these disparate symptoms could not possibly be caused by a single thing, let alone something that happened 30 years ago.

Not to worry, this disease is almost invariably fatal, so any momentary confusion caused by misdiagnosis will be cleared up eventually -- at autopsy.

A better adapted pathogen would not kill the host. What would modern medicine do with the patient in that case?
Little Bluestem, merylg and Merry like this.
anciendaze

About the Author

As the name suggests, I am old and dazed. The avatar illustrates my rule of thumb: "Hang on! This ride isn't over."
  1. anciendaze
    A public response to some private messages: I am not saying I know that viruses A, B, C must cause diseases P, Q, R - quite the contrary. What I am saying is that the potential for totally unexpected discoveries concerning disease etiology is high with this group of viruses. This is precisely the opposite of what funding agencies want to hear. The predictable advances which look good on proposals and progress reports are the least valuable discoveries I can imagine. If we have to explore the entire immune system to solve the mystery of this illness I would describe that as the scientific equivalent of trench warfare in a swamp. To have some chance of benefiting those of us who may not live to see the next transit of Venus we need to think outside the box of the last quarter century. Even if this does not benefit me, it has a real chance to benefit other patients with diseases of unknown etiology.
  2. anciendaze
    Merry, your report is not the first I have heard. Even before I considered the possibility of a virus causing my troubles, I was aware of a cluster of leukemias/lymphomas in a friend's family. My friend was told such clusters do not exist. When I raised the question with another doctor, I was told these were diseases with unrelated causes. After a little library research (remember when we had to go to libraries?) I found there was no clear etiology for any of these. How do you know diseases have different causes if you haven't pinned down causes for any?

    On the subject of HTLV-1, I've had other interactions with doctors. A response from two was that this was extremely rare, because they just don't see a lot of cases. When I asked "How often do you test for HTLV?" I got responses indicating that generally they don't, because the disease is always fatal. Which takes me back to questions about incidence. If you never test for it how do you know? How many cases are never correctly diagnosed? An analysis of many reported causes of death indicates that doctors were aware the patient's heart stopped, or he/she stopped breathing. This is not the basis for any kind of epidemiology.
    Merry likes this.
  3. Merry
    Terrific science writing, anciedaze. Thank you.

    I'm particularly interested in this topic because my mother (who for decades had ME/CFS symptoms but was never diagnosed) late in life developed myelodysplasia syndrome, a pre-leukemia. She was told that the condition is rare. But a couple of years after her death in 1997, the father of one her daughters-in-law was also diagnosed with myelodyspasia syndrome. One of this man's other daughters had been diagnosed with CFS (as I had been some years before after years of symptoms). So here are two families socially connected, rather than genetically connected, with members coming down with the same illnesses.