May 18, 2006
Study offers new hope for preventive vaccine for AIDS
Pedro Reche, PhD, and Derin Keskin, PhD
New research by Dana-Farber Cancer Institute scientists suggests that it may one day be possible to immunize healthy individuals against HIV-1, the virus that causes AIDS.
In a study published in the online journal Medical Immunology, investigators led by Dana-Farber's Pedro Reche, PhD, and Derin Keskin, PhD, upend the long-held view that human immune system cells do not fully recognize HIV-1 following infection, and thus are unable to eliminate it from the body. The researchers found that lab-grown immune system cells from uninfected individuals are able to distinguish and respond to key HIV proteins. Cells taken from infected individuals, by contrast, were much less responsive to the virus.
If these findings hold true in follow-up studies, they suggest that exposing healthy people to HIV-1 proteins might train their immune to attack the virus and prevent them from developing AIDS if exposed to HIV-1 in the future, Reche said.
"It has been unknown for 20 years why HIV-1 becomes persistent and isn't cleared from the bodies of AIDS patients," says Medical Immunology's editor, Kendall Smith, MD, chief of the Division of Immunology at Weill Medical College at Cornell University. "This study suggests that in HIV-positive people, the immune system cells that respond to HIV-1 are either deleted or have lost the ability to recognize and home in on major parts of the virus."
Reche, Keskin, and other collaborators at Dana-Farber and Harvard Medical School, used advanced data-analysis programs to predict which protein fragments, or "epitopes," from HIV-1 were most likely to provoke an attack from immune cells called cytotoxic T lymphocytes. They found 37 preliminary candidates.
The team then analyzed which of these epitopes would spark an immune response in most people, taking into account ethnic differences in immune system genes known as HLA genes. They narrowed down the 37 candidates to five that were predicted to bring on an immune response in over 95 percent of people.
The authors grew laboratory cultures of T lymphocytes from HIV-1-infected people and exposed the cells to these five epitopes. They then repeated the experiment with cultured lymphocytes from uninfected donors. They determined how strongly the cells responded to the epitopes by measuring the levels of interferon gamma (IFN gamma) produced by the lymphocytes. (Lymphocytes produce IFN gamma when activated by proteins on disease-causing viruses. The interferon helps destroy infectious agents.)
"We found that only a small proportion of cells from HIV-1-infected patients recognized the epitopes and mounted a sufficiently strong immune response," Keskin says. Cells from only 31-45 percent of patients produced IFN gamma, and only in small amounts. Cells from all the uninfected donors, by contrast, responded and produced IFN gamma in large amounts. The researchers also found that the lymphocytes from uninfected individuals could kill HIV-infected cells.
"Our findings suggest that research into vaccines for HIV-1 — and for other chronic infectious diseases such as malaria as well as neoplastic disorders — could benefit from a shift in focus from HIV-positive patient populations to uninfected individuals," Reche says. "Therapies for infected patients would most likely benefit from other approaches."
Senior author of the study is Ellis Reinherz, MD, Dana-Farber and Harvard Medical School. Other co-authors are Rebecca Hussey, Petronela Ancuta, PhD, and Dana Gabuzda, MD, all of Dana-Farber and Harvard Medical School.
The research was funded in part by grants from the National Institutes of Health.
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
