Monday, December 11, 2006

Selective Pressures on CCR5-Δ32 in the European Population

I'm Pete Levandoski

Recent research into the HIV pandemic has focused on the presence of individuals who do not become infected by HIV when exposed to the virus. So-called co receptors, which are essential for viral docking and infection, are thought to play a role in this immunity. One such co receptor is the protein CCR5, a chemokine receptor on the surface of T4 cells (Galvani et al.). Individuals who lack functional CCR5 protein do not become infected when exposed to HIV-1. A gene mutation, CCR5-Δ32, which causes a deletion of the allele for making CCR5, is present in about 10% of the European population (Galvani et al.). Homozygous individuals are completely immune to HIV-1 and heterozygotes while still susceptible to viral transmission, show slower progression of infection (Galvani et al.). A study done by Doctors Alison P. Galvani and. Montgomery Slatkin published in the December 9th, 2003 Proceedings of the National Academy of The Sciences in the United States, suggests that the higher rate of CCR5-Δ32 in European populations is the direct result of selection pressure caused by Small Pox epidemics.
Previous studies have tried to correlate the augmented prevalence of CCR5-Δ32 in Europe with the intense selection pressure caused by Bubonic Plague. Galvani et al. propose that a correlation between CCR5-Δ32 and Small Pox is a more likely scenario (Galvani et al.). To back this up, a population genetics model was set up using derivations of Hardy-Weinberg equations. These models assume that the CCR5-Δ32 is at least 700 years old and measure selection pressure caused by both diseases on CCR5-Δ32 since 1300 (Galvani et al.). Derivations of the Hardy-Weinberg equation, which factor in the frequency of outbreaks, percentage of mortality and age of the victims, were used to calculate the selection pressure of each disease on CCR5-Δ32. These models were used to determine whether or not each disease exerted enough selection pressure to cause 10% prevalence of CCR5-Δ32 in the European population over a 700 year period (Galvani et al.). This model shows conclusively that the Bubonic Plague did not exert enough selection pressure over 700 years to cause 10% prevalence of CCR5-Δ32 in the population while Small Pox did (Galvani et al.)..
Small Pox exerted higher selection pressure than Plague for a variety of reasons. Small Pox appeared in the population as early as 1,300 years before the first outbreak of Plague. Small Pox outbreak cycles were more frequent than Plague, correlating to a greater mortality (Galvani et al.). Finally, children, who had the greatest reproductive potential, were most susceptible to death by Small Pox while Bubonic Plague tended to eliminate people indiscriminately (Galvani et al.). All of these factors were included in the mathematical model, which showed that Small Pox was enough of a selecting force in Europe to cause the prevalence of CCR5-Δ32 to increase from 0-10% over 700 years.
There were two other pieces of evidence used by the authors to support their claim. The first came from noting that CCR5-Δ32 was present in a higher percentage of the population (14%) in Scandinavia, where Small Pox epidemics were most severe (Galvani et al.). When examined at the molecular level, the mechanism for infection by Small Pox virus involves the use of chemokine receptors, like CCR5, while Y. pestis infection in Plague is independent of these receptors (Galvani et al.).
The implications of this study on the future the HIV-1 pandemic are alarming. At least 700 years of fairly high selective pressure on a population by Small Pox conferred only 10% immunity (Galvani et al.). Since jumping species, HIV has already evolved into two subtypes, three groups and nine clades. In addition, co-infection with different clades is producing recombinant viruses, which are resistant to drug treatments and have stronger binding affinities for immune cells (Avert). HIV is evolving faster than the human race, which from a Darwinian perspective, does not bode well for our species. An interesting application of this data would be to run the same sort of population models in Africa. The selection pressure there on CCR5-Δ32 and other genes, which confer immunity to HIV, theoretically will be high. A measurement of the evolution of HIV immunity would be a helpful tool in determining the prospects for this embattled continent.

Avert. “Introduction to HIV types, groups and subtypes”. . Avert International Aids Charity: 13 July 2006. (21 October 2006).
Galvani, A.P. et al.. “Evaluating plague and smallpox as historical selectivepressures for the CCR5-Δ32 HIV-resistance allele”. Proceedings of the National Academy of The Sciences in the United States. Vol. 100, no. 25. 9 December 2003. pp. 15276-15279.

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