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06 May 2010Massachusetts Institute of Technology/Nature
New insights into the mystery of natural HIV immunity
When people become infected by HIV, it's usually only a matter of time, barring drug intervention, until they develop full-blown AIDS. However, a small number of people exposed to the virus progress very slowly to AIDS — and some never develop the disease at all.
In the late 1990s, researchers showed that a very high percentage of those naturally HIV-immune people, who represent about one in 200 infected individuals, carry a gene called HLA B57. Now a team of researchers from the Ragon Institute of Massachusetts General Hospital, MIT and Harvard has revealed a new effect that contributes to this gene's ability to confer immunity.
The research team, led by MIT Professor Arup Chakraborty and Harvard Professor Bruce Walker at MGH, found that the HLA B57 gene causes the body to make more potent killer T cells — white blood cells that help defend the body from infectious invaders. Patients with the gene have a larger number of T cells that bind strongly to more pieces of HIV protein than people who do not have the gene. This makes the T cells more likely to recognize cells that express HIV proteins, including mutated versions that arise during infection.
This effect contributes to superior control of HIV infection (and any other virus that evolves rapidly), but it also makes those people more susceptible to autoimmune diseases, in which T cells attack the body's own cells. This new knowledge, published online in Nature on May 5, could help researchers develop vaccines that provoke the same response to HIV that individuals with HLA B57 muster on their own, says Walker, who is director of the Ragon Institute and a professor at Harvard Medical School.
Most killer T cells are genetically unique and recognize different pieces of foreign proteins, known as epitopes, attached to the surface of cells that have been infected by viruses or bacteria. After a killer T cell grabs hold of such a protein, it becomes activated and starts sweeping the body for more cells that express the same protein, so it can kill them. It also clones itself to produce an army of T cells targeting the invader. The new Ragon Institute study shows that individuals with the HLA B57 gene produce larger numbers of killer T cells that are cross-reactive, meaning they can attack more than one epitope associated with HIV, including mutants that arise to escape activated killer T cells.
The finding offers hope that researchers could design a vaccine to help draw out cross-reactive T cells in people who don't have the HLA B57 gene. "It's not that they don't have cross-reactive T cells," says Chakraborty. "They do have them, but they're much rarer, and we think they might be coaxed into action with the right vaccine."
The work is a valuable contribution to scientists' understanding of HIV, says David Baltimore, professor of biology and former president of Caltech. "This is a remarkable paper because it starts from a clinical observation, integrates it with experimental observations, generates a valuable model and derives from the model a deep understanding of the behavior of the human immune system. Rarely does one read a paper that stretches the mind so surprisingly far," says Baltimore, a Nobel laureate in physiology or medicine who now studies HIV and human T cell interactions.
A. Kosmrlj, E. Read, Y. Qi, T. Allen, M. Altfeld, S. Deeks, F. Pereyra, M. Carrington, B. Walker and A. Chakraborty: Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection," Nature, May 6, 2010, doi:10.1038/nature08997.
