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Why are the body's immune defenses so powerless to stop the onslaught of HIV, the virus that causes AIDS? Within the past year, discoveries made at the Partners AIDS Research Center, based at the MGH, may have at least partially answered that question and opened new approaches to therapies. As with many such discoveries, what appears to be a sudden breakthrough is actually the result of years of painstaking investigation. Like pieces of a puzzle, each bit of information about how the immune system functions normally and how it is destroyed by HIV infection helps form an overall picture that may someday reveal ways to slow, control or stop the progression to AIDS.

More than 10 years ago, Bruce Walker, MD, director of the Partners AIDS Research Center, began focusing on the immune system's killer cells, called cytotoxic T lymphocytes.

He and his colleagues discovered that these cells, which are not infected by HIV, mount a defense against the virus soon after an initial infection. For most infected people, levels of killer cells gradually decrease, eventually leaving the body vulnerable to life-threatening infections. But a few individuals who remain infected with HIV for years without becoming ill continue to produce high levels of killer cells specifically targeted to HIV.

Walker and his team set out to solve the mystery of these long-term nonprogressors. They focused on how the killer cells attack the virus but also directed their attention to another immune component, the helper T cells that are the virus's primary target. Normally when a virus invades the body, a group of helper T cells that recognize that virus become activated and reproduce in great quantity. These virus-specific helper cells — the central orchestrators of the immune system — suppress the initial infection and continue directing the immune system to protect the body against any recurrence of the same infection.

In HIV infection, however, it appeared that this proliferation of virus-specific helper cells just did not happen. "The lack of these T helper cells is the most dramatic hole in the immune system of people with AIDS," Walker says. "So we tested one of our long-term nonprogressors for a response to HIV-specific antigens [proteins recognized by the immune system] and were stunned to see a huge helper-cell response."

The researchers then found a similar strong correlation between levels of virus and the helper-cell response in several recently diagnosed individuals: those with the strongest HIV-specific helper T-cell response had the smallest amount of detectable virus in their blood, while those with higher viral levels showed weaker T-cell responses. Eric Rosenberg, MD, a research fellow in Walker's lab, says: "We began to theorize that perhaps these virus-specific cells were being destroyed in the earliest stage of infection. And we wondered if antiviral treatment at that time might preserve these helper cells."

Rosenberg soon had an opportunity to test this hypothesis when a patient with symptoms of acute HIV infection — fever, severe sore throat, rash and swollen lymph nodes — came to the MGH Medical Walk-In Unit. Discovering that this individual had a possible HIV exposure only two weeks previously, Rosenberg ran blood tests that showed high levels of virus but no antibody in the patient's blood, indicating a very recent infection. The patient was started on combination therapy with powerful antiviral drugs, and his viral loads dropped dramatically while his immune system began to generate a strong HIV-specific helper T-cell response. Similar treatment in two other recently infected individuals produced the same responses. In people infected for longer periods — six months or more — treatment reduced viral levels but did not induce production of helper T cells.

"This response suggests that there is a window of time during which we might be able to salvage the helper T-cell response through vigorous antiviral treatment," Walker says. "It could be critically important for physicians to be alert for the symptoms of acute HIV infection and, in those patients who appear at risk, to test for the presence of virus."

Rosenberg adds: "It now looks like when HIV first enters the body it attacks and kills those cells that would be the first line of defense — the virus-specific helper T cells, against any other infection. It's the lack of these crucially important cells that keeps the killer cells and other immune system cells from containing or eliminating the infection."

This apparent duplication of the long-term nonprogression response, is only one more step toward solving the complex challenge of AIDS. Walker and his colleagues hope that what they have learned about the role of helper T cells and continuing studies of killer cells and other aspects of the immune system will lead to the most critical need: a vaccine.

"The combination antiviral therapies that have made such a difference in the health of many people with AIDS — an approach pioneered by Drs. Martin Hirsh and Richard d'Aquila at the MGH — aren't going to be available to the 90 percent of those infected with HIV who live in the world's developing nations," says Walker. "But the more we learn about how this virus works and how we might redirect the immune system around its very insidious attack, the closer we'll be to having practical ways of protecting people around the world from this terrible disease."