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By exploiting telomerase's growth influence on telomeres, researchers were
able to keep the immune cells youthful and active as they replicated under
HIV attack.
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UCLA scientists have shown that a protein called telomerase prevents
the premature aging of the immune cells that fight HIV, enabling the
cells to divide indefinitely and prolong their defense against
infection.
Published Nov. 15 in the Journal of Immunology, the research suggests
a future therapy for boosting the weakened immune systems of
HIV-positive people.
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.
Study details
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."
Hope for the future
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.
References
Mirabelle Dagarag, Tandik Evazyan, Nagesh Rao, and Rita B. Effros.
Genetic Manipulation of Telomerase in HIV-Specific CD8+ T Cells:
Enhanced Antiviral Functions Accompany the Increased Proliferative
Potential and Telomere Length Stabilization. J Immunol 2004 173:
6303-6311.
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