AIDSWEEKLY Plus, Monday, 10 March 1997
Daniel J. DeNoon, Senior Editor
The principal component of antiviral immunity prematurely ages in most people infected with the virus, according to new data from the Multicenter AIDS Cohort Study (MACS).
But early intervention with therapies including protease inhibitors may prevent this untimely aging.
CD8(+) T cells attack viral infections by secreting soluble antiviral factors and by killing virus-infected cells directly.
Long-term nonprogressors enrolled in the MACS study - a longitudinal study of a large cohort of men who have sex with men - retain intact CD8(+) lymphocyte responses. Most of the HIV(+) MACS participants, however, lost them over time, according to Janis V. Giorgi of the University of California, Los Angeles.
Giorgi reported the findings in a presentation to the Fourth Conference on Retroviruses and Opportunistic Infections, held January 22-26 in Washington, D.C.
Her UCLA research team found that CD8(+) T cells from the nonprogressors differed from those of the progressors in one important way: nonprogressor CD8(+) cells had minimal cell- membrane expression of activation markers.
"This suggests that loss of anti-HIV immune responses occurs due to CD8(+) T lymphocyte activation and cell division and ultimately leads to immunologic exhaustion," Georgi et al. wrote in their presentation abstract.
The researchers measured terminal restriction fragment (TRF) lengths in CD8(+) lymphocyte subpopulations. TRF measurement estimates loss of telomeres (the distal ends of chromosome arms), and is analogous to counting tree rings. Successive rounds of cell division shorten telomere length; very old cells have such short telomeres that they are no longer able to replicate.
TRF analysis showed that CD8(+) lymphocytes in MACS participants with HIV disease had undergone extensive cell divisions. This was particularly true for the CD28(-) subset, which in most people with HIV disease mediate most of the anti-HIV cytotoxic activity.
"This cell subset has a median TRF length [in progressors] that is compatible with replicative senescence - defined as loss of the potential for further cell division," Giorgi et al. wrote. "Thus, excessive cell activation appears to be the mechanism that underlies loss of anti-HIV-directed CD8(+) cell responses."
The finding has implications for HIV vaccine development. It is generally accepted that such a vaccine should stimulate cell-mediated immunity, particularly CD8(+) lymphocyte responses. But it now appears that vaccines must not add to the hyperactivation described by Giorgi et al.
There are also implications for AIDS therapies. Giorgi et al. noted that HIV(+) individuals receiving protease inhibitors have reduced CD8(+) lymphocyte activation and turnover.
"Consideration should be given to whether antiretroviral therapies are more effective long-term if administered with CD8(+) T lymphocyte responses are still intact," they wrote.
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