A controversial vaccine against HIV, the virus that causes AIDS, has been shown to stimulate a critical part of the HIV-specific immune response in chronically infected patients. The small study conducted by researchers at Massachusetts General Hospital (MGH) finds that a vaccine made from an inactivated form of the AIDS virus (Remune) induces the proliferation of CD4 cells – also called T helper cells – that specifically target HIV. Appearing in the June issue of the journal AIDS, the study is the first clear demonstration of the potential reconstitution of the immune response in chronic HIV infection. However, this pilot study was not designed to tell whether or not the vaccine would have any effect on the eventual course of the disease. When the human body is infected by a typical virus, the immune system mounts a response that starts with the production of T helper cells specifically targeted against the particular virus. T helper cells are the immune system's "generals," directing the activity of T killer cells (also called cytotoxic T lymphocytes or CTLs) that attack the invading virus. But when the virus is HIV, the T helper cells themselves are destroyed by the virus.
"A hallmark of HIV infection is the absence of immune cells that recognize the virus and develop an antiviral response," says Gregory Robbins, MD, MPH, of the MGH Infectious Disease Division and the Partners AIDS Research Center, the paper's lead author. "Our carefully controlled study showed that this vaccine was able to induce one aspect of a normal response against HIV in patients who previously did not have such a response."
One of several potential vaccines being tested against HIV, Remune is made from killed, inactivated HIV from which the outer protein envelope has been removed. It is designed to be a therapeutic vaccine that could increase the body's defenses against a pre-existing infection, rather than a preventive vaccine to keep infection from occurring. An earlier study of the vaccine did not find an effect on disease progression. However, that study was stopped prematurely due to the decrease in AIDS-related illness resulting from the introduction of more effective antiviral drug combinations. In addition, the study was not well controlled. Participants differed in terms of the antiviral medications they were taking, and many changed their medications during the course of that study, making interpretation of the findings problematic.
The current study is the first randomized, controlled, prospective investigation of this vaccine's impact on the cellular immune system in persons with chronic HIV infection. The researchers enrolled 10 HIV-positive patients who had been receiving HAART (highly-active antiretroviral therapy) treatment for 6 months or more and had an overall CD4 cell count of more than 250. All patients had low blood levels of HIV at the study's outset, indicating that the antiviral treatment was keeping the virus under control.
The participants were randomly assigned to receive injections of either the vaccine or a placebo, and the injections were administered every 12 weeks for a 48-week period. Neither researchers nor study participants knew who was receiving the active vaccine.
Tests of the immune response to HIV were conducted every four weeks throughout the study period, during which all patients continued to receive their antiviral therapy as well. Early differences in immune responses were apparent in most individuals receiving the vaccine soon after the first or second vaccination. Significant proliferation of HIV-specific T helper cells, which none of the participants demonstrated before the study began, was seen in all five participants receiving the vaccine but in none of the control group.
"This is the first proof of the principal that therapeutic vaccination can help people with chronic HIV infection mount a strong CD4 helper cell response," says Bruce Walker, MD, director of the Partners AIDS Research Center at MGH and a co-author of the study. "But we need to go on and investigate whether this response can help control viral levels, which would require a very different type of study – one in which patients would eventually discontinue antiviral therapy." Walker also is director of the Harvard Medical School Division of AIDS.
In 2000 a study led by Walker and Eric Rosenberg, MD, senior author of the current report, showed that starting antiviral therapy during the earliest stage of HIV infection could eventually allow the immune system to control the virus without drugs for several months. "Since only limited anti-HIV immune activity has been observed in individuals with chronic HIV infection," says Rosenberg, "further studies need to be performed to determine if the findings from this study will translate into a clinical benefit to persons with HIV infection."
Other authors of the study are Marylyn Addo, MD, Hien Troung, Almas Rathod, Kathy Habeeb, Benjamin Davis, MD, Howard Heller, MD, and Nesli Basgoz, MD – all of MGH and the Partners AIDS Research Center. The study was supported by a grant from the Immune Response Corporation, manufacturer of Remune, although the researchers had complete control of the design and reporting of the study. Support also came from the Doris Duke Charitable Foundation, the National Institutes of Health and the Deutsche Forschungsgemeinschaft.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $350 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.
Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.
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