The study, published in the December 9 issue of Nature, also describes how HIV infection is driving human evolution, since individuals with protective versions of the identified genes are more likely to survive and pass those genes along to children.

The investigation is a result of a program established by the Partners AIDS Research Center at Massachusetts General Hospital (MGH) with participants that include researchers from the University of Oxford and the University of KwaZulu-Natal in South Africa.

Genetic Battleground

"This study identifies the genetic battleground where the struggle between HIV and the human immune response occurs," says Philip Goulder, MD, PhD, of the Partners AIDS Research Center at MGH, the study's principal investigator. "The findings will help in understanding precisely how the immune system can succeed or fail against HIV, a prerequisite for a rational approach towards design of an HIV vaccine." Goulder also has an appointment at the Peter Medawar Building for Pathogen Research at Oxford.

The human immune system learns to recognize and attack virus-infected cells through the activity of human leukocyte antigen (HLA) Class 1 molecules, which sit on the surface of cells. When new viruses are being produced within an infected cell, Class 1 molecules grab fragments of viral proteins from within the cell and display them at the cell surface, thereby alerting the body's "killer" T cells that something foreign is within the cell and it should be destroyed.

Three genes called HLA-A, HLA-B, and HLA-C encode Class 1 molecules, and it is known that the HLA-B genes are extremely diverse, with more than 560 versions or "alleles" having been identified. The current study was designed to test the theory that the diversity of HLA Class 1 molecules could reflect differences in the killer T cell activity controlled by those molecules.

HLA-B Genes May Be Key

The researchers analyzed blood samples from 375 HIV-infected patients at the Doris Duke Medical Research Institute at the University of KwaZulu-Natal to determine whether particular HLA Class 1 molecules control the killer T cell response against the virus. They found that an individual's version of HLA-B made a significant difference in how well the immune system responds against HIV, whereas the version of HLA-A or HLA-C inherited did not matter.

To examine the impact of Class 1 molecules on blood viral levels, the team studied more than 700 chronically infected African patients and again found that particular versions of HLA-B were associated with high or low plasma virus levels.

Additional tests that looked at levels of the helper T cells that are destroyed by HIV and that analyzed samples from Australian patients infected with a different strain of virus all supported the conclusion that the form of the HLA-B molecule patients inherit makes a significant difference in how well their immune systems cope with HIV infection.

Evolutionary Fight Happening Now

Evidence of the virus's impact on human evolution was found in an analysis of HLA-B alleles in HIV-infected mothers and their infants. Not only are HIV-infected women who have a protective version of HLA-B more likely to survive, they are also less likely to pass the virus along to their children. From an evolutionary standpoint, that finding suggests a trend towards greater frequency of the protective alleles in a population over time.

"We have known for some time that HLA-B molecules are evolving more rapidly than other types, but it has been unclear why this is happening," says Goulder. "These data suggest an explanation for the more rapid evolution of HLA-B in response to other infectious diseases, not only HIV. This is an exciting time for infectious disease research because we are witnessing the evolutionary fight between the human immune system and the HIV virus happening right now, rather than over a period of thousands of years." Goulder is an assistant professor of Medicine at Harvard Medical School.

"The AIDS crisis will only be solved with the development of an effective vaccine," says Bruce Walker, MD, director of the Partners AIDS Reseach Center at MGH and a co-author of the current study. "This study's results help to focus this effort by telling us what the most effective immune responses are."