The normal immune system's ability to mount a fight against intruders is essentially unlimited. But exactly which parts of the intruders it picks a fight with is limited by host genetics.
"Which bits of virus we see is really governed, at a first level, by which HLA genes we have," researcher Bette Korber told BioWorld Today.
When a cell is infected by a virus, human leukocyte antigens, or HLAs, are proteins that grab parts of virus - which then are called epitopes - and present them to T cells at the cell surface. The group of HLA genes is extremely diverse, but any given person has six of them, which can in turn recognize and bind a large but still finite number of amino acid sequences.
HIV mutates extremely rapidly, which is one of the challenges in both drug and vaccine development. Since HIV infections are long-term, patients usually end up infected with what are for practical purposes several strains of virus, and a drug or vaccine that works against one strain may not work against another.
Conventional wisdom holds that the main factor in determining which strains a patient comes to harbor over the course of an infection is the phenomenon of T-cell escape. As HIV mutates, strains with mutations that make the virus less visible to its host HLA genes cannot be served up to T cells for lunch, giving them a selective advantage.
But according to research published by Korber, a laboratory fellow at Los Alamos National Laboratory and a visiting professor at the Santa Fe Institute, both in New Mexico, and her colleagues in the March 16, 2007, Science, HLA genes contribute less to HIV strains people are infected with than current theory holds.
That's not to say that there is no such thing as T-cell escape. "Human immunity is very important for the evolution of the virus," Korber said. But viral evolution "is not as predictable [from the host immune system] as one would have hoped," she added. "If you don't factor in the evolutionary history of the virus, you'll be misled."
In other words, viral strains that are related to each other are likely to develop some of the same escape mutations independently of which HLA genes they encounter.
When Korber and her team did factor in evolutionary history, the results were striking. Out of 80 associations between a viral strain and an escape mutation they found in their sample, three-quarters could "most likely be explained by the demographic and geographical structure of the HIV epidemic rather than immune pressure," the authors wrote in their paper.
Of course, one possibility is that even if a given viral strain did not evolve under pressure from its current host, the reason that a certain strain is frequent in a population is that HLA alleles that can recognize that strain are infrequent - in other words, T-cell escape once removed.
Korber said that two results argue against that interpretation. For one, though they saw at least one escape mutation that fit well with a common HLA variant in their data, "the relative frequency of that escape mutation wasn't changing over time," suggesting it was not being selected for. Also, one supposed escape mutation had the same frequency in different populations, while the HLA it was supposedly escaping from had varying frequencies.
Her team's results, Korber said, have little practical application to drug development - but a lot of information for vaccine development.
"These results argue in favor of a polyvalent approach," Korber said - that is, using several different epitopes in a vaccine cocktail to maximize the number of strains that a vaccine will protect against.
"It's more expensive, but these results suggest it may be worth it in the end," she noted.