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About 10 percent of HIV-infected individuals remain symptomless for 10 years or more, says Jay A. Levy, MD, professor of medicine and a research scientist with the Cancer Research Institute at UCSF. In comparison to the immune cells of those who progress to AIDS, immune cells in long-term survivors produce different proportions of common proteins that control immune system responses, according to Levy, Edward Barker, PhD, and Carl Mackewicz, PhD.
This more favorable protein production helps prolong an effective immune response against the AIDS virus, HIV, the UCSF researchers suggest. This anti-HIV response is spearheaded by immune cells called CD8 cells, they say.
The findings indicate that healthy survival despite HIV infection might be promoted through administration of an extra dose of one or more of certain naturally occurring proteins, called cytokines, according to the UCSF researchers. The study by the Levy laboratory group appears in the November 21 issue of the Proceedings of the National Academy of Sciences.
"Loss of responsiveness by CD8 cells is associated with increase in viral replication in the patient and is directly correlated with progression to disease," Levy says. "This new study raises our hopes that we can use naturally occurring cytokines or other immune regulators to boost CD8 cell response. We would be helping the infected person's own immune response to fight HIV."
For this study the researchers obtained blood samples and measured the strength of immune cell responses against HIV in the laboratory.
The major targets of HIV in the body are called CD4 immune cells. HIV takes up residence in CD4 cells, replicates, and eventually kills the host cells. CD8 cells are a main line of defense against the virus, Levy's group has shown. Both cell types make cytokines.
The UCSF researchers tested the ability of CD8 cells to prevent HIV from replicating in laboratory cultures of CD4 cells. They found that CD8 cells from the 21 long-term HIV survivors studied had a three-fold greater ability to suppress HIV replication compared to CD8 cells from patients who had already suffered a significant loss of CD4 cells, but who had not yet progressed to full-blown AIDS.
The researchers found that both CD8 cells and CD4 cells from the blood of long-term survivors naturally produced more of a cytokine called interleukin 2 (IL-2) than corresponding cells from those with AIDS symptoms.
Barker, Mackewicz and Levy found that exposing the CD8 cells of long-term survivors to an extra dose of IL-2 for three days further enhanced the ability of the cells to prevent HIV replication. In a similar test on CD8 cells from six patients who had progressed to disease, prolonged exposure to IL-2 resulted in an improved ability of CD8 cells from two of the patients to prevent HIV replication.
Conditioning CD8 cells from long-term survivors with other immune-regulating cytokines, such as IL-4 or IL-10, downregulated the HIV-inhibiting power of the CD8 cells. However, reconditioning these cells with IL-2 restored the potency of the CD8 anti-HIV response. Some researchers believe progression towards AIDS is associated with a shift toward greater production of IL-4 and IL-10 by immune cells. According to Levy, "Maintaining IL-2 levels early in the course of HIV infection might be necessary to stabilize CD8 cell antiviral activity and thereby provide long-term control of HIV infection."
The lack of responsiveness to IL-2 in CD8 cells from some patients who have already contracted AIDS may occur because the cells have a depleted supply of receptor proteins needed to attach to IL-2 and receive its signal, Barker adds. A National Institutes of Health research team led by Anthony Fauci, MD, previously determined that a loss of these receptors is associated with a decline in CD8 activity. IL-2 already is being tested clinically for its ability to fight HIV in patients whose immune systems are damaged by the infection but who have not yet contracted full-blown AIDS. The new results reported by the UCSF team are the first to demonstrate that the potential benefit of this experimental therapy may stem from the fact that IL-2 can promote the ability of CD8 immune cells to stop HIV from replicating, Levy said.
Researchers in Levy's laboratory are working to isolate in pure form a protein they discovered called CD8 cell antiviral factor (CAF), which also appears to control the ability of CD8 cells to suppress HIV replication.
CONTACT: UCSF Jeffrey Norris, 415/476-2557
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