MIAMI BEACH -- Researchers have refined a method for measuring telomeres -- repetitive genetic fragments at the ends of chromosomes -- which may provide a better understanding of disease progression in AIDS. It may also provide a new prognostic marker for the disease, especially in children.
By measuring the length of telomeres, researchers at the National Cancer Institute (NCI), the National Institute of Allergy and Infectious Diseases, and the University of Florida College of Medicine, Gainesville, Fla., have found that in HIV-infected children and monkeys, there appears to be far less rapid turnover of immune system cells than suggested before. This was especially apparent in blood cells known as CD4 T lymphocytes, which orchestrate the body's immune response and which are infected and destroyed by HIV, the AIDS virus. A current hypothesis of why AIDS develops holds that CD4 cell counts decline because HIV kills them off in such great numbers that surviving cells are forced to reproduce much more rapidly than usual, eventually exhausting their reproductive capacity.
Our major finding is that we saw much smaller changes in telomere length than we expected," said Dimiter Dimitrov, Ph.D., a principal investigator at NCI. These findings are in broad agreement with recently published data on telomere lengths in HIV-infected adults by the groups of Jenis Giorgi, M.D., University of California Los Angeles School of Medicine; Frank Miedema, M.D., University of Amsterdam; and Richard Hodes, M.D.,the director of the National Institute on Aging, who also maintains an intramural lab at NCI. However, Dimitrov stressed that his group's data are preliminary and more research is needed.
Telomeres protect chromosomes from unraveling and buffer them against the loss of important genes during cell replication. Over the course of an individual's lifetime, telomeres shorten, gradually becoming so short that they trigger the cell's death.
Dimitrov and his colleagues theorized that because children have longer telomeres and AIDS develops more rapidly in them than in adults, their telomeres would decrease faster, allowing for better detection of changes in the telomere length (if any) and also providing a way to estimate the turnover rate in immune cells as well. In HIV-infected pediatric patients, this meant the shorter the telomeres, the more likely a high turnover rate, immune dysfunction, and advanced disease. "The telomere length could serve as an independent marker of how rapidly these cells divide," Dimitrov said.
The researchers did find an accelerated decline in the telomere lengths of unseparated peripheral blood mononuclear cells, which included monocytes, T and B cells, in several pediatric patients who progressed rapidly to AIDS, and also in two monkeys who developed AIDS-like disease and died after infection with a chimeric virus containing components of Simian immunodeficiency virus, a close cousin of HIV. However, they found that in most cases the alteration in the telomere length of CD4, CD8, and B cells was not statistically significant although there was a trend of decline. This finding, Dimitrov said, suggests that the hypothesis that the depletion of CD4 cells in AIDS progression is due to rapid turnover in the CD4 population may be incorrect. There may be other reasons for a loss of the regenerative capacity of these cells, he said.
A major obstacle in the interpretation of these results is the difficulty in accurately measuring the telomere lengths and individual variations. Even though the researchers measured more than 1,000 samples during the past two years, more experiments and further refinements in the methodology are needed before making any definite conclusions.
To accurately measure the telomeres of children and monkeys, the researchers used a special method of electrophoresis, called pulsed field electrophoresis, allowing for better separation of long DNA molecules, and then measured the signal by a quantitative imaging technique. They developed a sophisticated mathematical analysis of the data which allows accurate calculation of the telomere length by calibration with markers of known length in two dimensions. These studies, presently funded by the Pediatric Aids Foundation in Santa Monica, Ca., will also examine which cell populations have the greatest changes in telomere length by looking at telomere lengths in other groups such as non-infected children, monkeys, and HIV-infected gay men.
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