Helper T-Cells vs. HIV

In most cases, the HIV virus dismantles the very immune cells that should be stopping it. However, since the dawn of the AIDS epidemic in the early 1980's, researchers have noticed that a very small percentage of patients who become infected with HIV do not go on to develop AIDS. These patients, called long-term non-progressors, have long been considered a hopeful sign that there is some potential for the human immune system to control HIV infection.

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Researchers from the Massachusetts General Hospital have now identified a mechanism of immune activity in long-term non-progressors that appears to suppress replication of HIV.  Their research shows that the immune systems of these patients produce large numbers of  helper T cells specifically targeted to HIV. Previous studies of individuals infected with HIV have found very few or none of these virus-specific helper cells, which animal studies have suggested are important in controlling many types of viral infections.

"One of the biggest mysteries in our understanding of AIDS and HIV has been why the immune responses that usually control viral infections don't work," says Bruce Walker, MD, director of the Partners AIDS Research Center. "Our work now suggests a simple explanation for how HIV escapes the normal immune response, why the immune system slowly but inexorably breaks down, and why a very small group of people have been able to avoid getting sick from this virus."

Helper T cells are the central organizers of the entire immune system. Individual helper cells target specific antigens- the protein signatures of viruses, bacteria, tumors or other disease-causing entities. All helper cells are vulnerable to infection by HIV, and AIDS develops when so many helper cells have been infected and destroyed that the entire immune system breaks down.

Usually when a virus invades the body, helper T cells that recognize that virus's antigens become activated and reproduce in great numbers. Not only does this proliferation of helper cells direct the immune response to suppress the original infection, but the immune system keeps making virus-specific cells to deal with any recurrence of the same infection. Since proliferation of HIV-specific helper T cells had never been previously observed, some scientists thought the virus somehow avoided all recognition by helper cells. The new research shows that, in rare instances, HIV-specific helper cells are generated and may be able to keep viral levels under control.

The initial clues came from studies of a long-term non-progressor who has been infected with HIV for more than 18 years with no evidence of illness. Although the presence of HIV antibodies proves he is infected with the virus, the amount of virus in his blood has remained so low as to be undetectable, even though he has never been treated with antiviral drugs. When the researchers exposed samples of his blood to several HIV-specific antigens, they observed something totally new. "Not only did this individual have HIV-specific helper cells, but he had a huge helper-cell response, the first such response we had ever seen to HIV," Walker says.

The researchers then looked for helper-cell responses in samples from ten patients with new and active HIV infections. Tests conducted before the patients started antiviral therapy showed a strong correlation between levels of virus and helper-cell response: those with the strongest HIV-specific T-cell response had the lowest viral loads, while those with higher viral levels showed weaker T-cell responses.

"We began to develop a theory about why these virus-specific cells usually don't appear in HIV-infected people," says Eric Rosenberg, MD. "Perhaps the very helper cells capable of recognizing HIV were being destroyed in the earliest stage of infection. We wondered if antiviral treatment at that time might keep these helper cells from being eliminated."

The research team were soon able to test this hypothesis. Rosenberg saw a patient with symptoms of acute HIV infection -- fever, severe sore throat, rash and swollen lymph nodes who had been exposed to HIV only a few days before. Rosenberg ran blood tests that revealed high levels of virus but no antibody in the patient's blood, confirming a very recent infection. The patient was given powerful antiviral drugs, and his viral loads dropped dramatically to virtually undetectable levels 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 did reduce viral levels but did not produce the helper T-cell response seen in those treated immediately after infection.

"This suggests that there is a window of time -- and we don't know yet how large it is -- during which we might be able to salvage the helper T-cell response through vigorous antiviral treatment," Walker says. "So 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." Walker stresses that preservation of the helper T-cell response probably requires beginning treatment immediately after infection, and he emphasizes that his team has not yet proven that this response is solely responsible for controlling virus levels. Except for the known long-term nonprogressors, all of the individuals participating in this study continue to receive antiviral therapy. It also will be important, he adds, to determine whether induction of this helper cell response in persons who lack it would lead to more effective immune control of the virus. Recent studies have shown that the virus persists in the body in spite of potent antiviral therapy. Whether the immune response to the virus can be augmented to provide additional benefit remains an open question.

The research appeared in the November 21, 1997 issue of Science