Pump Up The Volume (of Immune Cells) to Fight HIV

Transfusions of Self-Donated CD4 T Cells Boost Resistance to Infection

(Philadelphia, PA) - For patients suffering from HIV, a virus that specifically targets white blood cells, the best donors of new CD4 T cells just might be themselves. In the January 2002 issue of Nature Medicine, researchers at the University of Pennsylvania Medical Center report the first autologous - or self-donated - transfusions of pure CD4 cells, in eight HIV-positive volunteers. The infused cells were resistant to re-infection with both a laboratory strain of HIV and the volunteer's own HIV strain.

"Basically, we took a volunteer's own T cells, engineered the cells to mimic a genetic lesion that renders some people resistant to HIV infection, grew them in large amounts, and then transferred them back to the volunteer," said Bruce L. Levine, PhD, a researcher in the Leonard & Madlyn Abramson Family Cancer Research Institute at the Penn Cancer Center. As a result, the volunteers showed a sustained resurgence of their active CD4 cells. "The technique not only holds promise for people who are HIV positive, but also for those suffering from the various types of cancers that suppress the immune system."

Although the technique is not yet ready for FDA approval, the article outlines how Levine, Carl June, MD, Professor at the Abramson Institute, and colleagues at Bethesda Naval Hospital and the Walter Reed Army Medical Center demonstrated the safety and feasibility of boosting the immune system through large-scale transfusions of activated immune cells.

The researchers enrolled HIV positive active duty or retired military personnel into the study. Their blood was drawn and CD4 cells were purified and exposed to tiny metal beads coated with antibodies for CD28, a receptor on the surface of T cells. Once 'activated' by these antibodies, the cells were grown in culture for two weeks. The researchers then removed the beads with a magnet and washed the cells, readying up to 30 billion cells to be infused back into the volunteers. The researchers repeated this process up to six more times over an interval of six to eight weeks. Each of the volunteers experienced an increase in CD4 cells and, most interestingly, the ratio of CD4 cells to other T cells rose to near-normal levels.

"Considering that we only gave each volunteer a dose equal to about 10% of the CD4 cells in their body, it indicates that rise is due to cell growth and replication and not just the influx of new cells," said Levine. "Just as importantly, we also see a marked decline in the HIV receptor CCR5 on CD4 cells, which shows that the cells are resistant to infection."

Like most cells, the surface of T cells are covered in receptors, sensor molecules that react when they encounter specific molecules, such as antibodies. Each receptor is like a button that starts a different process in the machinery within the cell. HIV infects CD4 cells by attaching to a number of receptors on the surface of the cell, including a critical receptor called CCR5.

Previously Levine and June have shown that, by activating the CD28 receptor, T cells are stimulated to multiply and become resistant to HIV.

"There is a certain portion of the population that is resistant to HIV infection because they lack a working CCR5 receptor," explained Levine. "Here, we copy that effect by stimulating the CD28 receptor, which apparently acts like a switch, turning off the production of CCR5 receptors within the CD4 cells."

Of course, safety was the primary concern of Levine and his colleagues. Since HIV attacks CD4 cells, the researchers feared that an influx of new CD4 cells would only serve to add fuel to the fire. Although preclinical results had shown that activated CD4 cells were resistant to HIV, volunteers remained on their prescribed therapies. Since the first cohort of volunteers began the study in 1996, before the widespread use of anti-retroviral 'cocktails,' the researchers were able to note that the infusions did not appear to interfere with drug therapy. The researchers observed no severe side effects or significant problems stemming from the infusions.

This technology is being further evaluated in several clinical trials in HIV and various cancers. In cancer, the goal is to use this approach to more quickly reconstitute the immune system of patients who have received chemotherapy and to augment the immune response to any residual cancer cells.

"This report is important to the field because it demonstrates the practicality of augmenting CD4 T cells in HIV infection," said Levine. "Since functioning CD4 T cells are absolutely essential in controlling a number of chronic viral infections and cancers, our results here encourage our confidence in the potential of this technology."

This study was funded through Army contract DAMD17-93-V-3004 and the generosity of the Leonard & Madlyn Abramson Family Cancer Research Institute.

The current HIV trial is for Department of Defense active duty and retired personnel ONLY. Physician contact: COL Naomi Aronson, MD, Walter Reed Army Medical Center, (202) 782-8719

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Under the guidance of Carl H. June, MD, the translational research program at the Leonard and Madlyn Abramson Family Cancer Research Institute seeks to accelerate the transfer of laboratory discoveries into clinical treatments. Currently, June's group is developing cancer vaccines for clinical trials at specialized facilities created by the Abramson Institute.

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