Interleukin-2 (IL-2), an immune-boosting drug used experimentally in HIV therapy, greatly increases the lifespan of certain subsets of immune system T cells in some HIV-positive people who respond to this therapy, discovered researchers from the National Institutes of Health (NIH) Clinical Center and the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH. A report describing the study, led by the Clinical Center's Joseph A. Kovacs, M.D., appears online today in The Journal of Clinical Investigation.
A hallmark of HIV infection is the progressive loss of CD4+ T cells (a key type of white blood cell) and the subsequent decline in the infected person's ability to fend off disease. NIH clinical investigators pioneered the experimental use of IL-2 in HIV therapy to help boost the immune systems of people with HIV infection. Produced naturally by T cells, IL-2 is a powerful immune system regulator. While its use in HIV therapy is experimental and can be associated with various side effects, IL-2 is licensed to treat certain cancers.
NIH researchers have long observed that in responsive patients, intermittent cycles of IL-2 therapy lead to substantial increases in the number of circulating CD4+ cells. The mechanisms driving this increase as well as its potential clinical significance, however, have remained unclear, note the scientists.
Using two relatively new techniques for labeling cells, the team demonstrated that IL-2 therapy can lead to greatly increased numbers of new CD4+ cells. "More remarkable than the proliferation of these cells was how long they lived," says Dr. Kovacs. The average lifespan of CD4+ cells in healthy individuals as measured with this technique is about four weeks, according to Dr. Kovacs. In contrast, the average lifespan of CD4+ cells in 15 HIV-positive volunteers who had received three or more courses of IL-2 was 37.6 weeks, about nine times longer.
In the first set of experiments, investigators infused 32 volunteers with a sugar solution containing a harmless chemical label, deuterium (a non-radioactive, stable isotope), for five days. Nine volunteers were HIV-positive but had never received IL-2; 15 volunteers were HIV-positive and had received between three and 28 courses of IL-2; and eight volunteers were HIV-negative.
Deuterium is incorporated into the DNA of actively dividing cells. By taking blood samples in weeks and months following the deuterium infusion and measuring the amount of deuterium remaining in the CD4+ T cell DNA at each time point, the researchers could count how many new cells were made and how long they lived.
The scientists found a marked increase in the numbers of newly made CD4+ cells in all the HIV-positive, IL-2 responsive volunteers. In two HIV-positive volunteers - each of whom had received multiple five-day courses of IL-2 over several years - the researchers detected CD4+ cells that lived for about three years, a result Dr. Kovacs calls "quite surprising."
Using another labeling technique, the researchers determined that IL-2 boosts the numbers of two subsets of CD4+ cells: naïve cells, those that have never encountered an infectious agent; and central memory cells, those that have encountered an infectious agent before and are primed to respond quickly if they encounter the same agent again.
The new data complement clinical observations suggesting that IL-2's effects on HIV disease progression may become apparent only in long-term follow-up, says Dr. Kovacs. Two large, long-term efficacy trials currently underway should provide a clearer picture of the clinical impact of IL-2 on the course of HIV disease and its potential role in the management of HIV-infected patients, he adds. Information on these and other HIV clinical trials is available at www.aidsinfo.nih.gov.
Other authors on the paper include researchers from the NIH's National Cancer Institute and the Science Applications International Corporation of Frederick, MD.
The Clinical Center is the clinical research hospital for the NIH. Through clinical research, physicians and scientists translate laboratory discoveries into better treatments, therapies and interventions to improve the nation's health.
The National Institutes of Health (NIH) - The Nation's Medical Research Agency - is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
Reference: JA Kovacs et al. Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients. The Journal of Clinical Investigation doi: 10.1172/JCI23196 (2005).
Two authors on this paper (Drs. Joseph A. Kovacs and H. Clifford Lane) are named as inventors on a use patent for intermittent IL-2 therapy granted to the United States government.