By David N. Leff

In sub-Saharan Africa, AIDS hits hardest at young, sexually active people in their teens and 20s. The interval between HIV infection and full-blown, high-mortality AIDS averages 7.8 years.

¿The lifetime risk of dying of AIDS for a boy who was 15 years old in 1999,¿ observed mathematical biologist Montgomery Slatkin, ¿is over 65 percent in South Africa and almost 90 percent in Botswana.¿

Slatkin is professor of integrative biology at the University of California/Berkeley. He is senior author of a paper in Nature dated May 31, 2001, titled: ¿Natural selection and resistance to HIV.¿

A cytokine receptor called CCR5 is the skeleton key that allows that virus to break and enter the T cells, which are its target for immune-system destruction. Back in 1997, an Australian man with a flagrantly anti-safe-sex lifestyle ¿ homosexual intercourse with multiple male partners ¿ made headlines. This risk-defying individual became HIV-positive in 1992, but remained on parole ever since as far as AIDS itself was concerned.

His guilty secret was receiving a genetic gift from each of his parents ¿ mutations in the CCR5 genes they bequeathed him at birth.

¿This defect,¿ Slatkin told BioWorld Today, ¿makes it harder for the virus to enter the T cell and replicate. It causes a two- to four-year delay to the onset of AIDS, eventually resulting in death.¿

The CCR5 receptor perches on the surface of T lymphocytes, where it flags the immune system that its cell is not foreign. This self/not-self feature of the immune defenses is what the purposeful HIV aims to up-end.

¿What led us to publish this paper,¿ Slatkin said, ¿was a United Nations report on the occurrence of AIDS in Africa, which was much much higher than we had realized. It cited prevalence of the disease as approaching 40 percent in some African countries. Pathologies serious enough to affect this proportion of the population can, by natural selection, affect genetic variation in that population.

¿Our interest,¿ Slatkin said, ¿lies in the effect of natural selection on human populations, and the particular role that disease plays in affecting human evolution. Charles Darwin coined the term, natural selection,¿ and focused on it as the driving force of evolution ¿ where slight variations that increase the number of offspring tend to become more common in successive generations.¿

How Vaccines, Drugs May Tilt African Evolution

¿Over several generations,¿ Slatkin foresees, ¿AIDS could alter the frequency of specific genetic mutations in African populations, delaying the average time between HIV infection and onset of disease. Though this genetic evolution probably won¿t impact health management in Africa, public health experts pray that drugs or vaccines will soon cut the high mortality and infection rates on the continent. AIDS there provides a rare example of how epidemic infectious diseases can exert selective pressure on the human genome.¿

Another segment of African humanity affords a significant example of disease-driven evolution. ¿The natural selection of genes,¿ Slatkin said, ¿such as are found in the CCR5 receptor, is very strong on sickle-cell genes in regions of Africa where malaria is endemic.

¿Malarial parasites,¿ he explained, ¿in the course of blood-sucking, invade the hemoglobin molecule. Sickle-cell disease genes distort that molecule, which makes it harder for the parasite to survive. So, there¿s a significantly lower death rate from malaria for individuals who carry one copy of the sickling genes. It provides a 15 to 20 percent advantage in regions of very high, endemic malaria.

¿CCR5 has been on the human genome forever,¿ he pointed out. ¿Its most common mutation is actually at very high frequency in Europeans, in whom it has appeared for the past thousand years. These have a greater than 10 percent frequency of CCR5¿s so-called delta-32 mutation. With two copies of delta-32, HIV cannot enter the cell.

¿Why is the delta-32 mutation so common in Europeans?¿ Slatkin asked. ¿Since it is obviously a part of the immune system, one idea was that there was some other plague in Europe¿s history during the last 1,000 years that created natural selection of the type that HIV has created in Africa.

¿One suggestion ¿ not ours ¿ was that this was bubonic plague ¿ the Black Death, which ravaged Europe between 1346 and 1352. Some calculations I¿ve done,¿ Slatkin said, ¿show that this was possibly not true. Plague was a very severe cause of mortality but for a relatively short period of time. We speculate that it could also have been measles or smallpox. All of these diseases led historically to very high infant mortality.

¿Natural selection in the case of AIDS in Africa,¿ he said, ¿is as strong as the selection malaria had on the gene that causes sickle-cell anemia. We showed that over the course of 100 years, the gene conferring greater resistance to AIDS would increase in frequency from 40 percent of the population to 53 percent. The mutation that makes people more susceptible would decrease from 20 percent of the population to only 10 percent.

¿The shift in frequency of these genes would lengthen the average latency from HIV infection to AIDS by one year ¿ from 7.8 to 8.8 years,¿ Slatkin said. ¿The frequency shift is due primarily to the opportunity for continued reproduction during the extra two to four years, allowing those carrying the resistant gene to produce 10 [percent] to 20 percent more children than those with the susceptible allele.¿

How Epidemics Influence Survival of Fittest

Slatkin observed: ¿Assuming no change ¿ no new vaccines or novel, highly effective drugs ¿ how rapidly will the human population respond to natural selection? I figure it will, after 100 years, result in about a one-year increase in the time to onset of AIDS.

¿What this illustrates,¿ he said, ¿is that even though there¿s a tremendous mortality associated with AIDS, and the gene that results in substantial effects in response to AIDS, evolution doesn¿t happen very fast in human populations. There still won¿t be a one-year increase in survival after 100 years.

¿Roughly speaking,¿ Slatkin calculated, ¿for every three years longer that a partially resistant person survives, they would live long enough to have one more child because people are infected at the peak of their reproductive behavior.¿

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