Mystery Rays from Outer Space

Meddling with things mankind is not meant to understand. Also, pictures of my kids

November 30th, 2010

HIV evolution: individual vs. population

Worldwide HIV/AIDs Epidemic Statistics
Worldwide HIV/AIDs Epidemic Statistics

(We are in the process of selling one home and buying another, while at work I just finished organizing a course on biosecurity for an international group. In the upcoming week I’m traveling to a conference in Washington. To say nothing of the Thanksgiving holiday. All this means short and scarce updates for a little while.)

We know that the immune response to HIV forces the virus to evolve at great speeds, so that the viral targets of the immune response change and become at least temporarily invisible. We also know that the specific targets are different for almost every infected person. So although you have rapid evolution in each individual, what does this mean to overall evolution of the global population of HIV?

The several dozen CTL epitopes we survey from HIV-1 gag, RT and nef reveal a relatively sedate rate of evolution with average rates of escape measured in years and reversion in decades. For many epitopes in HIV, occasional rapid within-host evolution is not reflected in fast evolution at the population level.1

(My emphasis) This is a modeling study (though it did look at real-life data to some extent), but their conclusion is consistent with larger-scale population studies as well; see my previous post here and links therein.


  1. Fryer, H., Frater, J., Duda, A., Roberts, M., , ., Phillips, R., & McLean, A. (2010). Modelling the Evolution and Spread of HIV Immune Escape Mutants PLoS Pathogens, 6 (11) DOI: 10.1371/journal.ppat.1001196[]
November 10th, 2010

Rinderpeste through the years

Rinderpeste (1880)

RINDERPEST. Lips and gums, showing apthous condition1

1711 (via 1902):

Rinderpest is the most fatal disease affecting cattle. … The first great epizootic of which there seems to be records occurred about 1709 and spread over nearly all of the countries of Europe. It is reported that 1,500,000 cattle died from its effects during the years from 1711 to 1714. 2

1839 (via 1861):

Previously to the present century the only well recognized epizootics that are known to have prevailed extensively among horned cattle in Europe were the Eczema Epizootica, or “mouth and foot disease”, a complaint well known in England since the year 1839, and the terrible Rinderpest or Steppe murrain.

This last named disease, which is described as being of the nature of a highly infections typhus fever, terminating in dysentary, is said to be indigenous to the Steppes of Tartary and Siberia, from whence it has descended, from time to time, upon Russia, Germany, and other European countries.

It has been estimated that during the eighteenth century the Rinderpest destroyed, in Europe, as many as two hundred millions of cattle.3

1865 (via 1880) :

In 1865 the plague appeared in Holland, and was carried thence to England. In both countries the disease carried off one hundred thousand head of cattle in the course of a few months.4

1889 (via 1909):

About the year 1889, or shortly before, a virulent form of rinderpest started among the domestic cattle and wild buffalo almost at the northern border of the buffalo’s range, and within the next few years worked gradually southward to beyond the Zambesi. It wrought dreadful havoc among the cattle and in consequence decimated by starvation many of the cattle-owning tribes; it killed many of the large bovine antelopes, and it wellnigh exterminated the buffalo.5

2010:

14 October 2010, Rome – An ambitious global effort that has brought rinderpest, a deadly cattle plague, to the brink of extinction is ending all field activities, paving the way for official eradication of the disease.6


  1. Contagious Diseases of Domestic Animals. Department of Agriculture. Washington. Government Printing Office. 1880[]
  2. The Pathology and Differential Diagnosis of Contagious Diseases of Animals. Veranus Alva Moore. Taylor and Carpenter. Ithaca, N.Y. 1902[]
  3. REPORT of the COMMISSIONER OF PATENTS for the year 1860: AGRICULTURE.
    Washington. Government Printing Office. 1861[]
  4. Cattle Plague or Rinderpeste. A history of the Disease. in: Report of the C0mmissioner of Agriculture for the year 1879. Washington. Government Printing Office. 1880[]
  5. African Game Trails. Theodore Roosevelt. Charles Scribners’ Sons. 1909[]
  6. FAO Media Office[]
November 4th, 2010

Mutation rates in man and virus

John Hawks1 has a long and very interesting post on the human mutation rate — not just the actual number (which turns out to be less well documented and much more slippery than I had realized), but the techniques used to calculate the rate, and difficulties therein.

So much of the literature in this area is ultimately circular, I’m pulling out my sparse hair reading through it. By the time we get back to the mid-1990′s, the sequence data are even sparser than my hair by today’s standards — only a few hundred base pairs, or a sampling of restriction sites. But the divergence time estimates have propagated forward from that time to today, recycled through the assumptions of papers in the intervening time. It’s like the genetic equivalent of money laundering!

Conceptually, it’s very reminiscent of the questions about viral mutation rates, although the technical barriers are quite different and (especially for RNA viruses!) the mutation rates are vastly different. For example, Hawks’ post talks about which edge of a two-fold range the human mutation rate falls on — between 2.5 x 10-8 and 1.1 x 10-8 mutations per site; in a table I’ve used before we see a ten-thousand-fold range for poliovirus error rate estimates.

Virus polymerase error rates
RNA virus mutation rates 2

I have to get my kids ready for school now, so I don’t have time to talk about the techniques here — it’s notable that sequencing, though much easier on the tiny viral genomes than on the much vaster human scale, hasn’t completely resolved the issue, though the variation gets smaller as sequencing technology gets getter.

Here are some of my previous posts that mention replication error and mutation rates …


  1. Whose blog you should all be reading[]
  2. CASTRO, C., ARNOLD, J., & CAMERON, C. (2005). Incorporation fidelity of the viral RNA-dependent RNA polymerase: a kinetic, thermodynamic and structural perspective Virus Research, 107 (2), 141-149 DOI: 10.1016/j.virusres.2004.11.004[]
November 3rd, 2010

Shield or target? A downside of immune evasion

T cells & herpes simplex
T cells (green) and herpesvirus-infected cells (red)
(from Akiko Iwasaki)

We know that lots of viruses, especially herpesviruses, block antigen presentation. The assumption has been that they are thereby preventing T cells from recognizing infected cells, though long-term readers of this blog1 will know that I’ve been puzzled about the details of this for quite a while.

A recent paper2 raises yet another complication for this pathway: In humans3 there are T cells that specifically recognize cells in which antigen presentation is blocked:

Our data indicate that the human CD8+ T cell pool comprises a diverse reactivity to target cells with impairments in the intracellular processing pathway2

If so, you might wonder why the viruses would bother blocking antigen presentation. They might avoid recognition by T cells specific for the viral proteins, but at the cost of being recognized and eliminated by the T cells that recognize antigen-presentation-defective cells.

As always, I don’t have an answer. I do have the unhelpful observation that viruses are incredibly subtle and efficient, and given that herpesviruses have apparently maintained the ability to block antigen presentation for some 400 million years it’s presumably useful to them. I’ll also add the even more unhelpful observation that immune systems are also incredibly subtle and efficient and have also persisted for 450 million years.

How Not to be Seen

However, there may be a clue in the techniques that Lampen et al used to turn up this subset of T cells: They used multiple rounds of stimulation, which is going to expand these cells massively. We don’t know how abundant they are inside a normal human – perhaps they are so rare that they don’t have a chance to impinge on herpesvirus infection early enough.

The catch with that, though, is that tumors also frequently get rid of antigen presentation via mutation; in fact, eliminating antigen presentation seems to be one of the most common forms of mutations in cancers, suggesting that it’s an important part of their ability to survive and expand in the face of immune attack. Tumors are immunologically present much longer than viruses ((Although herpesviruses set up a lifelong infection, most of that is generally in a non-immunogenic, latent form). So why doesn’t this long-term tumor presence lead to amplification of these antigen-presentation-deficient-specific T cells that would eliminate the tumor?

My guess here is that this is where TRegs come in. As I said in a recent post, TRegs are very commonly, if not universally, associated with tumors, and prevent immune attack on the tumor. I wonder if the tumors mutate to avoid T cell recognition early in their development, before they are able to trigger the TReg response; that allows them to grow large enough and long enough that by the time the presentation-defect-destroyers kick in, the tumors have their TReg defenders set up.  (I admit that this doesn’t account for the correlation between a tumor’s loss of antigen presentation, and poor prognosis, but I leave this as an exercise for the reader.)

And, of course, where either of these defense systems for the proto-tumor fails, we normally would simply not see any tumor at all. Perhaps this is happening all the time inside us — proto-tumors are being eliminated by T cells, some are mutating their antigen presentation pathway and lasting a little longer and are then eliminated by a different subset of T cells, and we never know it.


  1. If any[]
  2. Lampen, M., Verweij, M., Querido, B., van der Burg, S., Wiertz, E., & van Hall, T. (2010). CD8+ T Cell Responses against TAP-Inhibited Cells Are Readily Detected in the Human Population The Journal of Immunology DOI: 10.4049/jimmunol.1001774[][]
  3. As has been previously shown in mice[]
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