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MEDICINE Immune Cells May See Strain of HIV But Be Blind to Viral Cousin Findings Place Hurdle in Path of AIDS Vaccine A study by HMS scientists is putting a new face--or rather faces--on the virus that causes AIDS. Researchers have known for some time that HIV comes in a variety of strains, but what has not been clear is how good the human immune system is at recognizing different variants. Many thought that immune cells trained to recognize one HIV strain should be able to recognize a closely related viral cousin. "It is frustrating to see that the incidence of new HIV infections in the United States is not going down," said Bruce Walker, second from right. He is shown with (from left) Xu Yu, Todd Allen, and Marcus Altfeld. (Photo by Steve Gilbert) It now appears that slight structural differences may provide enough of a mask to keep two strains of HIV from being detected by the same immune cells. In their study, reported in the Nov. 28 Nature, Massachusetts General Hospital researchers Marcus Altfeld, Todd Allen, Bruce Walker, and their colleagues found that a patient whose immune system was able to keep one strain of HIV in check was unable to fend off infection by a second closely related virus. What was surprising is the magnitude of the immune system's failure. The second strain, which the man contracted two and a half years after the first, differed genetically from the first by only 12 percent, and yet half of the immune cells controlling the first virus failed to notice the newcomer. "Safe sex--even among consenting partners who are both infected--that is the public health message." --Bruce Walker "We have always known about the diversity of HIV, but this study shows what we are up against," said Allen. He and Altfeld are HMS instructors in medicine. The discovery that HIV can avoid immune detection through subtle changes in structure carries powerful implications. "Safe sex--even among consenting partners who are both infected--that is the public health message," said Walker, professor of medicine and director of the Division of AIDS at the Medical School. Other cases of superinfection have since been brought to light. Those findings, and the MGH patient's failure to respond, raise a series of troubling questions for AIDS researchers. "The fact that half the cellular immune responses were compromised in this one individual is surprising. Are we really expecting that a vaccine is going to have to induce twice as many responses as we originally thought, or is this a worst-case scenario?" asked Allen. "It is, without a doubt, an obstacle for vaccine design." But the picture is not all bleak. Though their patient was unable to control the second virus with the immune cells he had already produced, the researchers did find three new T cell responses in his bloodstream, each specifically directed against the new invader. "We hope that a vaccine will develop a stronger immunity in someone with an uninfected immune system, which would then allow him to do a better job at fighting new infection," said Walker. "There is no way that we should take these data to say that we cannot develop a vaccine." A Case of Clueless Killers Walker's quest to harness the human immune system against AIDS began in 1987 when he and colleagues noticed populations of largely impotent HIV-specific killer T cells in the bloodstream of infected patients. The reason for the killer cells' impotence was clear. To mount an effective defense, killer T, or CD8, cells must receive orders from helper T, or CD4, cells--the very cells that are infected and ultimately killed by HIV. What Walker did not know was whether or not HIV-specific helper T cells were being induced in the first place. Then in 1994, he encountered an HIV-infected hemophiliac who was in perfect health. Walker suspected that helper T cells might be helping to control the virus. Sure enough, the man exhibited a healthy supply of HIV-specific CD4 cells. Convinced that the immune system could produce helper T cells in the face of HIV infection, Walker wondered, might it be possible to nurture their development? Working with HMS instructor in medicine Eric Rosenberg, he hatched a plan: find a newly infected person and treat him immediately with antiretroviral drugs. "Our thinking was that maybe we could put a protective shield around these helper cells, allowing them to mature," he said. While moonlighting in a medical walk-in clinic, Rosenberg found such a person. Though a bit pokey to start, the patient's helper T cells began to surge several weeks after treatment. Infection by HIV had triggered the production of helper T cells. Might more exposure trigger more T cell production? Walker wondered. To find out, he proposed interrupting antiretroviral treatment. "It was quite unorthodox at the time," he said. "People thought we were nuts." Testing HAART The plan worked in one patient. Walker and his colleagues tried the protocol--highly active antiretroviral therapy (HAART) followed by supervised treatment interruptions (STI)--in 13 other newly infected patients. Twelve were able to at least transiently control their infections. Several were able to stop antiretroviral treatment altogether, though some of them relapsed. One of these patients began to exhibit high levels of virus 290 days after his last treatment. The first inkling that the virus might be an altogether new strain came when Altfeld and Xu Yu, HMS research fellow in medicine, identified three new killer cell responses in the man's blood, each directed to a novel stretch of viral amino acids. Allen sequenced the virus in blood collected in the months before and after the man's loss of immune control. "As we looked at more of the sequenced virus, we saw this dramatic change in sequence," he said. In fact, the new virus had swept through the man's immune system over the course of a single month. The man later revealed that he had had an unprotected sexual encounter during the previous month. "Together it told a convincing story," Allen said. Having solved one mystery, he and Altfeld are now trying to figure out why some of the other members of the original cohort of 14 patients have not been able to maintain control of their virus. None of them appear to have been superinfected. Meanwhile, Walker and his colleagues have received a grant from the National Institutes of Health to conduct a larger trial of the HAART STI protocol. One of their aims will be to see if the protocol has better clinical outcomes than continuous drug treatment. "The jury is still out on that," said Allen. --Misia Landau