Scientists are beginning to change their thinking about why the immune systems of most people infected with HIV cannot control the spread of the virus while the immune systems of a rare group of individuals, called long-term nonprogressors, can. For some time, scientists thought that people who could not control HIV had too few HIV-fighting white blood cells called CD8+ T cells. However, a new study suggests the difference is not the number but the quality of these cells: both nonprogressors and others have about the same number of HIV-fighting CD8+ T cells, but the cells of nonprogressors function better.
"Understanding the mechanisms by which the immune systems of long-term nonprogressors control HIV is important to our development of effective vaccines," says Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). "Studies like this one, which reveal basic knowledge about how the immune system interacts with HIV, form the foundation of our effort to fight this disease." Details of the study, conducted by NIAID scientists, will appear on October 7 in the advanced online issue of Nature Immunology.
Instead of attacking HIV directly, CD8+ cells inhibit virus spread by killing off other immune system cells infected with HIV. "For some time we have known that even patients who cannot control HIV maintain high numbers of HIV-specific CD8+ T cells," says senior author Mark Connors, M.D., of NIAID's Laboratory of Immunoregulation. However, this study represents the first time scientists have observed a difference in the HIV-specific CD8+ T-cell response of nonprogressors, he says. This study also suggests a mechanism whereby the CD8+ T cells of nonprogressors control HIV and those of most individuals do not.
Dr. Connors and colleagues closely examined the immune systems of 40 people infected with HIV, including a group of about 15 nonprogressors - people who have controlled HIV for up to 20 years without antiretroviral therapy. The researchers found no significant difference in the number of HIV-fighting CD8+ cells between nonprogressors and the others. Instead, the scientists found that the nonprogressors' cells were better able to divide and proliferate when called on to go into action; they also produced higher levels of a molecule called perforin, which helps them to kill off cells infected with HIV.
"Some of the newer techniques used in this study enabled us to see the functional differences in the CD8+ T cells of the two groups," says lead author Stephen Migueles, M.D., also at NIAID's Laboratory of Immunoregulation. "The CD8+ T cells of people in the study who did not control HIV had retained only a limited ability to divide and produce perforin."
This finding is especially important to HIV vaccine research efforts, says Dr. Connors, because many candidate HIV vaccines attempt to induce a strong CD8+ T cell response. New knowledge about CD8+ T-cell function opened up by this line of research might lead to preventive vaccines that avoid the development of poorly functioning CD8+ T cells. In addition, this research might lead to therapeutic vaccines for HIV-infected people that improve the function of their CD8+ T cells and control HIV infection.
Next, Dr. Connors and colleagues plan to analyze an even broader array of differences between the CD8+ T cells of nonprogressors and others infected with HIV, seeking to understand what causes the poor function of most HIV-infected people's CD8+ T cells.
NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
SA Migueles et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and maintained in nonprogressors. Nature Immunology, advanced online publication at http://dx.doi.org/10.1038/Ni845.
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