Manipulation of the body’s own natural killer cells to destroy cells containing the HIV virus

Mayo Clinic researchers have identified a way to manipulate the body’s own natural killer cells to destroy cells containing the HIV virus.

Current treatments for HIV block the virus from replicating, but don’t kill the cells that contain HIV. The existence of these HIV-harboring cells -- often called the “latent” or “resting reservoir” -- is regarded by many to be the main obstacle to finding a cure for HIV.

“These drugs used to treat patients today -- which do an excellent job on suppressing replicating virus -- do nothing for the infectious virus contained within the latent reservoir,” says Andrew Badley, M.D., the lead immunovirologist of the Mayo Clinic research team. “If we can find a way to kill the virus that is present within the latent reservoir, we are on to a promising path towards a cure for HIV.”

To address the latent reservoir problem, Dr. Badley’s team built upon their earlier findings that showed a molecule named TRAIL to be a potential agent for treating HIV within the resting reservoir. The experiment was performed on cells taken from HIV-infected patients and then treated in laboratory test tubes. Results showed the molecule was effective in killing the HIV cells in a majority of samples. While successful in test tubes, this approach is many years away from being tested on patients in clinical trials. The research findings appear today in the online edition of the June 11 issue of the Journal of Virology (http://jvi.asm.org).

Significance of the Mayo Clinic Research
The “resting reservoir” refers to HIV virus particles within cells that have stopped replicating. Consequently, the HIV within these cells eludes current drug treatments because these drugs only work on actively replicating HIV. This allows the HIV to hide in a dormant or resting stage in certain cells. The resting reservoir serves as a kind of HIV time bomb that can detonate if a patient stops HIV treatment or becomes resistant to current drugs.

The TRAIL molecule
TRAIL is a naturally-occurring molecule made by many cells of the immune system. For reasons that are as yet unclear, it possesses the ability to kill only abnormal cells, such as cancer cells or those containing HIV. It sends signals to prompt cell death in the abnormal cells, while leaving healthy cells alone.

This seek-and-destroy ability of TRAIL is also under investigation for the treatment of certain cancers, but the Mayo Clinic researchers are the first to publish results on TRAIL as a possible immunotherapeutic treatment for HIV infection and AIDS.

The Experiment
The team set out to discover if TRAIL could work against human cells in a test tube and also if the body could be prompted to produce more TRAIL.

The researchers treated cells from HIV-infected patients with recombinant TRAIL, and in all cases, such treatments reduced the amount of virus present. “And in three out of five test tube samples, we were able to destroy all signs of HIV. Therefore TRAIL shows promise as a way of disabling the latent reservoir in the test tube,” Dr. Badley says.

To investigate the second point, the researchers investigated two compounds to see how they increase the function of natural killer cells both from HIV-infected patients, and from non-HIV-infected patients. Like many other immune system members, natural killer cells make TRAIL. Researchers wanted to find a way to induce them to produce more TRAIL. The two compounds they thought might be able to do that belong to the same family of Interleukins, specialized proteins which are widely known to be important players in the immune system for communicating messages. The research team compared the effectiveness of Interleukin-15 (IL-15) and Interleukin-7 (IL-7) at increasing the immune system’s ability to kill HIV infection. Results show that both enhance NK cell function, but that they work differently. Of the two, IL-15 increases the expression of TRAIL. “It therefore may be the more promising immunotherapeutic agent for HIV,” Dr. Badley says.

Currently neither TRAIL nor Interleukin-15 has been tested in patients. “We hope to pursue such work in the future. But in the here and now, I’d simply say we are very encouraged by our results,” says Dr. Badley.

Other authors of the study are, from Ottawa Health Research Institute, University of Ottawa: Julian J. Lum, Zilin Nie (also of Mayo Clinic), Jaime Sanchez-Dardon, Georgina L. Mbisa, Nanci Hawley, Shanil Narayan; from the National HIV/AIDS Laboratories, Health Canada: Jennifer Mihowich and John E. Kim; and from Immunex Corporation, Seattle: David H. Lynch.

Dr. Badley is supported by grants from the National Institutes of Health and the Doris Duke Charitable Foundation.