Every cell contains a tiny cellular clock called a telomere, which shortens each time the cell splits in two. Located at the end of the cell's chromosome, the telomere limits the number of times a cell can divide.
"Immune cells that fight HIV are under constant strain to divide in order to continue performing their protective functions. This massive amount of division shortens these cells' telomeres prematurely," explained Dr. Rita Effros, Plott Chair in Gerontology and professor of pathology and laboratory medicine at the David Geffen School of Medicine at UCLA. "So the telomeres of a 40-year-old person infected with HIV resemble those of a healthy 90-year-old person."
Most scientists agree that telomeres evolved to avert the rampant cell growth that often leads to cancer. Yet many cancers continue growing because they undergo genetic changes and start to produce telomerase, which regenerates their cells' telomeres.
Effros and first author Mirabelle Dagarag, Ph.D., hypothesized that harnessing telomerase's power over telomeres may provide a potent weapon in helping the AIDS patient's exhausted immune system defend itself against HIV. The researchers extracted immune cells from the blood of HIV-infected persons and tested what would happen if telomerase remained permanently switched on in the cell.
"By exploiting telomerase's growth influence on telomeres, we thought we might be able to keep the immune cells youthful and active as they replicated under attack," said Dagarag, a postgraduate researcher. "We used gene therapy to boost the immune cell's telomerase and then exposed the cell to HIV."
What Dagarag and Effros saw delighted them.
"We found that the immune cells could divide endlessly," said Effros, a member of the UCLA AIDS Institute. "They grew at a normal rate and didn't show any chromosomal abnormalities that might lead to cancer."
"We also saw that telomerase stabilized the telomere length," added Dagarag. "The telomere didn't shorten each time the cell divided, which left the cell able to vigorously battle HIV much longer."
The UCLA work is the first to prove that maintaining telomerase activity in immune cells from HIV-infected persons prevents telomeres from shortening.
"This is the first step toward developing other telomerase-based strategies for controlling HIV disease," said Dagarag. "Increasing the amount of telomerase in certain immune cells may one day hold the key to treating AIDS."
"To battle HIV infection effectively, we must strengthen the human immune system -- not just suppress the virus as current drugs do," said Effros. "We need a two-pronged approach to attack the disease from both sides of the medical equation."
Effros and the Geron Corporation, which collaborated on this study, are also testing several non-genetic methods of activating telomerase as potential treatments for persons infected with HIV.
The UCLA team's approach could provide the foundation for immunotherapy as a treatment for HIV and related diseases that rely on lasting protection by the same immune cells. These include cancer and latent cytomegalovirus, a viral infection that often strikes organ-transplant patients and persons with AIDS.
The study was funded by the National Institute of Allergy and Infectious Diseases, the Universitywide AIDS Research Program, the Geron Corporation and a University of California Discovery Grant.
Journal
The Journal of Immunology