HARVARD GAZETTE ARCHIVES

Researchers from the Dana-Farber Cancer Institute and Harvard Medical School (HMS) have prompted human immune cells to attack HIV protein fragments, showing that the long-sought vaccine to protect against AIDS is still a possibility.

Researchers using advanced data-analysis programs identified five protein fragments from HIV - the virus that causes AIDS - that promote a strong immune response from the cells of people who have never been exposed to the HIV virus before.

That means, researchers said, that creation of a vaccine to protect unexposed individuals from infection with HIV appears possible. Researchers conducted their study using fragments from HIV-1, the more virulent of the two strains known to cause AIDS.

For 20 years, scientists have fought the disease and sought ways to prevent the AIDS virus from devastating patients' immune systems. It is the virus's destruction of the body's immune response that opens patients to a variety of opportunistic infections that run rampant and, ultimately, cause death.

Researchers had thought that human immune system cells don't fully recognize the HIV-1 virus and so can't eliminate it from the body after infection. The new study shows that isn't the case and suggests shifting efforts toward creating a vaccine aimed at uninfected individuals.

The study, published in the online journal Medical Immunology, was led by Dana-Farber's Pedro Reche, an instructor in medicine at HMS, and by Derin Keskin, a research fellow in medicine at HMS.

"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, 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."

If these findings hold true in follow-up studies, they suggest that exposing healthy people to HIV-1 proteins might train their immune system to attack the virus and prevent them from developing AIDS if exposed to HIV-1 in the future, Reche said.

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.

From 37 preliminary candidates, the team narrowed the field to the five likely to spark an immune response in over 95 percent of people.

The authors grew laboratory cultures of T lymphocytes from both unexposed people and from HIV-1-infected people and exposed the cells to the five protein fragments. Cells from infected donors responded only weakly to the exposure, in contrast to those from uninfected donors: These cells produced large amounts of an infection-fighting substance called interferon gamma. 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 said. "Therapies for infected patients would most likely benefit from other approaches."

Senior author of the study is Professor of Medicine Ellis Reinherz, of Dana-Farber and Harvard Medical School. Other co-authors, all of Dana-Farber and Harvard Medical School, are Rebecca Hussey, research associate in pathology; Petronela Ancuta, research fellow in pathology; and Professor of Neurology Dana Gabuzda.