April 12, 2002

VUMC research implicates unique subset of T lymphocytes in HIV infection and AIDS

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Dr. Derya Unutmaz is leading the research at Vanderbilt. (photo by Dana Johnson)

VUMC research implicates unique subset
of T lymphocytes in HIV infection and AIDS

A team of Vanderbilt researchers, led by Dr. Derya Unutmaz, assistant professor of Microbiology and Immunology, has found evidence that a unique subset of blood cells may be a target for the virus that causes AIDS. The cells, known as natural killer T cells, appear to be severely depleted in HIV-infected patients, which might affect the course of HIV infection.

Results from the researchers’ studies, published in the current issue of the Journal of Experimental Medicine, confirm the presence of known HIV receptors on NKT cells and document the susceptibility of the cell type to infection, as well as its deficit in HIV-infected individuals.

Depletion of the NKT cell population, which appears to have a novel but integral place in the body’s defense system, might increase vulnerability to secondary infections and the likelihood of developing AIDS, according to Unutmaz.

“You can imagine that if these NKT cells are playing an important role against several viruses or pathogens or against autoimmunity,” he said, “then the lack of these cells might make these affected individuals more susceptible to those pathogens, or indeed, their chances of developing acquired autoimmune disease.”

The function of NKT cells in the immune system is not fully understood. The cells are closely related to the much larger population of conventional T lymphocytes, yet they appear to regulate how other T cells do their jobs. “It’s like the bureaucrats controlling the generals,” Unutmaz said.

Previous studies have shown that NKT cells decline under certain disease conditions, especially autoimmune diseases. There have also been reports suggesting that they play a role during infection. They have no single pathogenic target—they have been shown to respond to a number of viruses, bacteria, and parasites. Until this study, though, no one had investigated the role of NKT cells in HIV infection.

NKT cells express the CD4 receptor that HIV is known to use as a port of entry for infecting other T cells, but it wasn’t known whether NKT cells express the other receptor necessary for infection, CCR5. Using alpha-galactosylceramide, a molecule isolated from a marine sponge that naturally binds and stimulates NKT cells, Unutmaz and his lab were able to purify and expand the cells to large numbers for their studies.

“To our surprise,” he said, “not only did NKT cells express CCR5, but they expressed it at a higher level than conventional T cells.”

Through a series of experiments, they found that the cells were also highly infectable compared to conventional T cells, probably because they have such high levels of CCR5.

“The NKT cells were, for some reason, much more susceptible to the virus,” Unutmaz said. “Of course, if I were the virus, I would look for a cell that has many doors that I could enter. I think that was what was happening with these cells, at least in vitro.”

The next step was to determine what happens in patients during HIV infection. Dr. David Haas, director of Clinical Infectious Disease Services, provided blood from infected individuals at various stages of the disease for the lab to study. The researchers found a severe deficit of NKT cells in HIV-infected patients—in fact, 50 percent of patients had undetectable levels.

“We were quite excited about this because we think this is the second T cell type that’s being depleted during HIV infection, in addition to the CD4 positive helper T cells,” Unutmaz said.

The findings have triggered other questions about the role of NKT cells in HIV infection. For instance, do these cells facilitate transmission of the virus? Not only do the cells present the perfect receptors for HIV, the cells are unique in that they are continuously activated—that is, the cellular machinery stays revved up and ready to react to an invading organism. And NKT cells appear to be present in organs and in mucosal tissues where the virus might first find entry into the body.

It’s possible that NKT cells might also facilitate the progress of HIV infection and AIDS. That is, because the cells are depleted after HIV infection, is the immune system as a whole less able to keep the virus in check?

One puzzling aspect of the findings is that only a portion of the NKT cells expresses the CD4 receptor—about half, on average—yet in the patients that Unutmaz studied, both CD4 positive and CD4 negative subsets of NKT cells were lost. In other words, the cells that one would not expect to be directly affected by the virus were also being depleted.

Unutmaz has plans to conduct a longitudinal study of HIV-infected patients to determine when, during the course of HIV infection, NKT cells begin to be depleted. He’ll be following “long-term non-progressors”—patients who receive anti-retroviral drugs and do not develop disease for a very long period—as well as “exposed uninfecteds”—those individuals who have been exposed multiple times to the virus but nevertheless remain uninfected.

Understanding in-depth how NKT cells are involved in HIV infection and disease development might contribute to the development of more effective therapeutic treatments, says Unutmaz.

“If we find these cells are important in protection, you might imagine that it would be beneficial to stimulate this population or to replenish them in the patient. If we find that they are harmful during transmission, we might be able to develop a drug that would block the entry of the virus into the cell.”

Other Vanderbilt researchers listed as co-authors on the publication include Alison Motsinger, David Haas, Aleksandar Stanic, Luc Van Kaer, and Sebastian Joyce. The work was supported by grants from the NIH.