Important note: Information in this article was accurate in February 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, February 22, 1999
Daniel J. DeNoon, Senior Editor
For more than a decade, immunologic studies of HIV disease have focused on the dynamics of effector CD8(+) T cells. But understanding the much smaller pool of HIV specific memory CD8(+) T cells - virtually invisible until recently - now appears to be far more important.
"I think the key to understanding what is happening in HIV infected people is understanding the failure of T-cell memory," said Rafi Ahmed, director of the Emory University Vaccine Center.
Ahmed spoke in a plenary address to the 6th Conference on Retroviruses and Opportunistic Infections, held January 31-February 4, 1999, in Chicago, Illinois.
Ahmed's research team employed a novel technique - invented by Emory's John D. Altman - that was the talk of this year's Retrovirus Conference. The technique permits the visualization of antigen- specific cells by marking them with tetrameric MHC class I molecules loaded with viral peptides that bind and mark for visualization virus- specific cells in serum samples.
Studies using this assay already have revolutionized immunology. In a mouse model of chronic viral infection, Ahmed and colleagues showed that the size of the initial CD8(+) cytotoxic lymphocyte (CTL) expansion in response to a novel antigen determines the size and persistence of the pool of memory CD8(+) T cells (see AIDS Weekly Plus, April 6, 1998).
"This expansion can be tremendous," Ahmed said, noting that half of the T-cell pool can become specific for one viral epitope. "These are the soldiers of the immune system. You need a lot of them to fight an infection."
Vaccines can induce CD8(+) memory, but this ability differs from vaccine to vaccine. The dynamics of acute infection suggest that this difference is due to the strength of the initial CD8(+) CTL response to the vaccine. Moreover, the epitope for specific expansion is selected very soon after antigen exposure.
"What we want the vaccine to do is to provide the largest initial response possible," Ahmed said. "I would predict that if the CTL epitope is in the booster vaccine, you will never have a very high number of CD8(+) memory cells."
As the initial CTL response succeeds, antigen diminishes and some 95 percent of the expanded cell population is eliminated via the process known as programmed cell death or apoptosis. Less than 5 percent of the antigen-specific cells become memory cells. This raises the question of how immunologic memory persists: do the cells live for a very long time, as do some memory B cells, or do they turn over and somehow pass on their memory to their replacements?
Using the antigen/MHC I tetramer assay, Ahmed and colleagues showed that CD8(+) memory cells turn over at the same rate as other CD8(+) cells.
"Essentially all the cells turn over: it does not seem to be a cycling effect," Ahmed said.
Amazingly, this turnover does not depend on MHC class I molecules or upon help from CD4(+) cells. Can such cells actually function?
"Yes, they are remarkably functional," Ahmed said. "If you show them peptides [for which they are specific], within four hours there is enormous activity."
Thus it becomes critically important to understand the dynamics of this pool of memory CD8(+) cells.
"The key issue is understanding the mechanisms of homeostatic maintenance of the CD8(+) T-cell pool," Ahmed said. One of his colleagues, Rustom Antia, has developed mathematical models that offer insights into this phenomenon (see AIDS Weekly Plus, December 21, 1998).
Unfortunately, this is not the only issue. CD8(+) T cells die or become nonfunctional in the absence of CD4(+) T-cell help: the central immune deficiency in HIV disease.
"The challenge for us now is how to turn these cells back on," Ahmed said. "When one is designing [an HIV] vaccine, one should include CD4 epitopes, so that later or when a person is exposed there is adequate CD4 help."
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