Gene research finds clues to AIDS survival

Boston-led study is part of vaccine search

By Stephen Smith
Globe Staff / November 5, 2010

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For decades, they lived a mystery: Why were they able to survive with the AIDS virus, free of symptoms and the need for potent drugs, while so many others with the same germ turned deathly ill?

Their innate ability to keep HIV infections in check intrigued researchers, who suspected these people, known as “controllers,’’ might carry clues to designing effective vaccines after nearly 30 years of frustration.

Now, an international team of researchers, led by specialists in Boston, has cracked these HIV survivors’ genetic code, sifting through almost 1.4 million pieces of DNA to discover five amino acids that separate the small cadre of controllers from the vast majority who must take medication or face death.

Although authors of the study released yesterday cautioned that a vaccine remains years away, the discovery is testament to genetic tools that did not exist even a few years ago and to intellectual cross-pollination among hospitals, universities, and research institutes in Boston and Cambridge.

It also reflects the tenacity of scientists who were once dismissed with skepticism and of patients who were part of the AIDS epidemic but were not touched in the same way as friends and relatives dying all around them.

The discovery was reported on the website of the journal Science. The researchers said the differences they found cause small changes on the surface of HIV-infected cells, which could alter the immune system’s response to the virus.

“HIV is slowly revealing its secrets,’’ said Dr. Bruce Walker, one of the leaders of the international consortium and director of the Ragon Institute, an AIDS-vaccine research center affiliated with Massachusetts General Hospital, Harvard University, and MIT.

“We’ve now been able to go from a haystack down to a needle and see that this is really the key place where we need to focus our effort,’’ he said.

Doctors not involved with the research said they hoped the findings would hasten development of an AIDS vaccine at a time when the world struggles to provide drugs to the 33 million people already infected.

Dr. Calvin Cohen, research director for Community Research Initiative of New England, which conducts AIDS-treatment trials, said that while the discovery “doesn’t mean we should start opening the champagne tomorrow, it does seem to me there are reasons to pursue this observation and see if we can mimic this in some therapeutic manner.’’

This medical detective story traces its roots to San Francisco. In the early days of the epidemic in the 1980s, it seemed virtually everyone infected with HIV was dying within months or a few years of diagnosis.

Then, researchers who had collected blood from gay men years earlier for a hepatitis B study reanalyzed the stored blood and recognized that some of the men had already been infected with HIV. But medical exams done years later found that those men had none of the classic signs of the disease: no fever, no pneumonia, no opportunistic infections.

Doctors were seeing the same thing in their clinics. “When I was interacting with individuals on a one-to-one basis, they didn’t know what was going on; they didn’t know how long it would last,’’ said Dr. Steven Deeks, an HIV specialist at the University of California, San Francisco. “There was this survivor guilt — they were surviving and their friends had not.’’

Walker was enlisted in the early 1990s to perform analyses of controllers’ blood and found that their ability to control the virus almost certainly had nothing to do with the virus itself — they weren’t infected with a feeble form of HIV, for example. Instead, researchers began to suspect the answer must be sewn into genes, especially those involved with letting the virus enter cells or those governing the body’s immune response.

But it would take the genetics revolution — and a dinner at the home of Lawrence H. Summers, then Harvard’s president — to translate a finding in the clinic to a major discovery in the laboratory. At that soiree, Walker encountered Eric Lander, a genetics pioneer and founding director of the Broad Institute, a leading genomics research center in Cambridge. They discussed harnessing the growing might of genetics to explore the mysteries of AIDS.

Walker carried his idea back to Mass. General and shared it with Dr. Florencia Pereyra, then training to become an infectious disease specialist. She was enthusiastic about the project but saw soon enough that not everyone shared that zeal.

“There were a lot of skeptics along the way,’’ Pereyra said. Initially, the Boston researchers could not gin up grants from the usual sources, such as the National Institutes of Health. Instead, an investment banker named Mark Schwartz provided early support four years ago, and the NIH provided money later.

It’s estimated that only one of every 300 people infected with HIV is a controller, but such patients provided copious blood samples by the hundreds for Pereyra’s and Walker’s study.

“They could say, ‘What the hell, why do I care? I’m controlling the virus,’ ’’ Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said of controllers in the study. “But instead, they’re willing to participate in this kind of research.’’

The study involved genetic analyses of 974 controllers and 2,648 patients whose HIV infections had progressed.

Earlier research had identified the genetic neighborhoods in which most of the variation among humans dwells. So it was those areas of DNA where researchers hunted for differences among the HIV-infected.

When viruses invade the body, they hijack healthy cells to produce multiple copies of themselves. The body’s natural response is to take a sliver of that virus to the surface of the cell and expose it to immune-system warrior cells.

“It basically acts as a fire alarm and says, ‘Hey, look at me guys. I’m infected with a foreign material, do something about it,’ ’’ said Paul de Bakker, a geneticist at the Broad.

The genetic testing found something distinctive about that warning system in controllers — differences in five amino acids, which are the building blocks of proteins. In those people, a tiny groove in a molecule that is part of the warning system has a particular shape, affecting how the warning flag sits atop cells.

“A handful of amino acids doesn’t sound like a huge change,’’ de Bakker said. “But the impact of those protein changes may make a huge difference in an individual’s ability to naturally control HIV.’’

Barry Greenfield figures he caught the virus in the 1970s. He tested positive in the ’80s. He watched friend after friend die, but he has never had a single symptom associated with HIV. Not one.

Now 64 years old, he has traveled to Boston from his home near Los Angeles three times to have blood drawn and biopsies performed for the study.

“My community was decimated, and I got to live and am in a very special place in history where my body has some of the answers,’’ Greenfield said. “I owe it.’’

Stephen Smith can be reached at

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