Study Offers Hope For Immune Reconstitution After HIV Infection

December 16, 1998

A new study offers hope that an HIV-ravaged immune system can rebuild itself after successful treatment with anti-HIV drugs. Researchers supported by the National Institute of Allergy and Infectious Diseases (NIAID) have found that the thymus gland, which produces the immune system's T cells, appears to remain functional well into adulthood rather than just during infancy and early childhood, as current theory holds. They also found evidence that although HIV infection may adversely affect the thymus, the gland continues to produce new T cells after the infection is suppressed by intensive anti-HIV therapy. A report of their findings is published in the Dec. 17, 1998, issue of Nature.

"This is a very promising finding because it confirms that the thymus is active in adults and potentially can partially reconstitute an HIV-infected individual's T cells after his or her viral load has been driven down by highly active antiretroviral therapy (HAART)," says NIAID Director Anthony S. Fauci, M.D. "Moreover, the technique developed to track newly produced T cells could prove to be a valuable research tool for monitoring immune reconstitution in HIV-infected people."

A research team led by Richard A. Koup, M.D., and Daniel C. Douek, M.D., Ph.D., of the University of Texas Southwestern Medical Center in Dallas, measured a genetic byproduct of T-cell development in blood samples from 10 HIV-infected and 30 uninfected individuals. Before they are released from the thymus, T cells generate circular fragments of DNA, dubbed T-cell receptor rearrangement excision circles, or TRECs. Previous studies showed that TRECS are stable and are not reproduced during subsequent cycles of cell division. Drs. Koup, Douek and their colleagues hypothesized that the presence of TRECS would identify T cells that had recently left the thymus and thus serve as a marker of thymic output.

Using sensitive DNA tests, the scientists showed that TRECs are present in naïve T cells - those that have not yet encountered their specific antigen - but not in memory T cells - the cloned descendants of cells that have already had such encounters.

"The fact that memory T cells lack these specific sequences," the authors note, "suggests that TRECs are diluted during the switch from naïve to memory phenotype, presumably as a result of cellular proliferation accompanying this process."

The researchers also found that TREC quantity declines significantly with age. Still, they detected TREC-containing T cells in blood samples from persons as old as 73 years. Elderly persons with intact thymus glands had significantly higher TREC levels than did elderly individuals whose thymus glands had been removed during heart surgery or other medical procedures.

Analysis of blood samples from a group of HIV-infected individuals showed that their TREC levels were significantly lower than TREC levels in blood from age-matched healthy individuals. After receiving HAART, however, all but one of the HIV-infected individuals showed a rapid and sustained increase in TRECs.

"Our findings suggest that thymic function is suppressed in HIV-infected individuals and can be improved by reduction of viral load," says Dr. Koup. "Therapies that directly improve thymic function may increase the rate of immune reconstitution after HAART."

The study's project officer, Patricia D'Souza, Ph.D., of NIAID's Division of AIDS, adds, "The next obvious question is to find out what is going on in children being treated for HIV infection. The thymus is much more active in children compared with adults. This technique provides an exciting opportunity to monitor thymic output and immune reconstitution in that population."

NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
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References:
DC Douek, RD McFarland, PH Kelser, EA Gage, JM Massey, BF Haynes, MA Polis, AT Haase, MB Feinberg, JL Sullivan, BD Jamieson, JA Zack, LJ Picker and RA Koup. Changes in thymic function with age and during the treatment of HIV infection. Nature 396, 690-95 (1998).

HR Rodewald. The thymus in the age of retirement (editorial). Nature 396, 630-31 (1998).

Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
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NIH/National Institute of Allergy and Infectious Diseases

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