MGH Team Identifies New Immune Activity That May Control HIV Levels

The discovery may explain why a tiny group of those infected with HIV have remained healthy for many years and indicates the possibility of duplicating that protective response in other individuals. The report, which appears in the November 21 issue of Science, shows that the immune systems of these long-term nonprogressors 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 based at the MGH and senior author of the report. "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 orchestrators of the entire immune system. Individual helper cells are targeted to 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 — reproducing in great quantity. 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 MGH-led study, however, 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 nonprogressor 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 chronically infected people, some with high levels of virus and some with low viral loads, whose infections had been recently diagnosed. The tests, done 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, the paper's first author. "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 soon had an opportunity to test this hypothesis when Rosenberg met a patient with symptoms of acute HIV infection — fever, severe sore throat, rash and swollen lymph nodes. Discovering that this individual had a possible HIV exposure only two weeks previously, Rosenberg ran blood tests that revealed high levels of virus but no antibody in the patient's blood, indicating a very recent infection. The patient was started on 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 indivi duals 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.

Along with Walker and Rosenberg, the study's coauthors are James Billingsley, Angela Caliendo, MD, PhD, and Spyros Kalams, MD, of the MGH; Steven Boswell, MD, of the Fenway Community Health Center; and Paul Sax, MD, of Brigham and Women's Hospital. The research was supported by grants from the National Institutes of Health and by private donations.