May 12, 1998
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Leslie Franz (619) 543-6163
RESEARCHERS IDENTIFY NEW MECHANISM IN IMMUNE RESPONSE TO HIV INFECTION
In recent years, researchers studying the immune system have identified a signal which acts as a master switch to turn on the body's defenses against infectious disease microbes and tumors.
This master switch, called the "CD40 ligand" (CD40L), triggers cells in the body that play a key role in fighting infection and disease, telling them to go on full alert status and protect healthy cells and tissue against the invaders. This important mechanism has been the focus of studies of the body's response to Human Immunodeficiency Virus (HIV), which devastates the immune system by disabling the cells that normally fight off infection.
In a recent report published in the Proceedings of the National Academy of Sciences (April 1998), scientists from the University of California, San Diego AIDS Research Institute and the Veterans Affairs Medical Center describe for the first time a specific pathway for the launch of a counterattack against HIV, with cells called macrophages stimulated by CD40L to produce proteins which bolster T lymphocytes ("T cells"). T cells are a front-line of the normal immune system, but they are especially vulnerable to HIV infection, leading to the overall breakdown of the body's ability to ward off infectious agents which is the hallmark of AIDS.
The PNAS study shows that CD40L activates macrophages to produce HIV-fighting proteins called beta-chemokines, which in turn protect a form of T cells called CD4+T cells from infection by HIV. Activated CD4+T cells are especially vulnerable to HIV, with the widespread demise of these cells leading to AIDS. Previous studies have identified other mechanisms for stimulating production of beta-chemokines, but this is the first published evidence of a direct link between CD40L and macrophage production of anti-HIV chemokines.
"The discovery of CD40L as a master switch in the immune system was one of the most important recent developments in studies of the human immune system," said Richard
Kornbluth, M.D., Ph.D., of the UCSD School of Medicine's Department of Medicine and the Veterans Affairs Medical Center. "Our findings indicate that when this switch is turned on, specific cells make proteins which appear to prevent HIV from infecting T cells, and which also seem to recruit more immune cells to the site of infection as reinforcements in the developing immunological battlefield. This is potentially important information to incorporate in efforts to design an HIV vaccine, giving us a focus for boosting the body's own natural response system at the earliest possible stage of HIV infection, in order to prevent the destruction of the immune system."
According to principal investigator Kornbluth, these findings might also have implications in studies of other diseases with a strong immunological component, such as cancer, lupus, rheumatoid arthritis and multiple sclerosis. A better understanding of immune response also has important implications for the prevention of tissue and organ rejection in transplant patients.
Co-investigators in the study are Douglas D. Richman, M.D., of the Departments of Pathology and Medicine at UCSD, and Kristin Kee, of the UCSD Department of Medicine. They also are members of the Department of Veterans Affairs Medical Center in San Diego, and members of UCSD's AIDS Research Institute.
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