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Further, they say, rising numbers of these immune system cells may serve as an early warning for dementia before the brain is damaged.
In the March 8 issue of The Lancet, the researchers report that they found much larger numbers of a subgroup of "monocyte" cells in the blood of AIDS patients suffering from dementia than in uninfected volunteers or AIDS patients with no dementia. Further, they found that this subgroup of monocytes produced a substance that turned on certain genes in brain cells grown in laboratory flasks, causing the brain cells to program themselves for self destruction.
Called apoptosis, this self destruction may also play a role in Alzheimer's disease and the damage caused by strokes, said study leader Lynn Pulliam, Ph.D., chief of microbiology at the San Francisco VA Medical Center and UCSF associate professor of laboratory medicine.
"Our finding is actually good news," she said, "because apoptosis is a slow process. If a rising number of these monocytes can serve as a signal that apoptosis is starting, we may be able to develop drugs to target the monocytes before brain cells are destroyed."
Some 15-30 percent of people infected with HIV will develop a devastating dementia, Pulliam notes. The virus appears to enter the brain through monocyte "offspring" called macrophages, which can cross the blood-brain barrier. Unlike CD4 lymphocytes, which are the cells infected and killed by HIV, infected macrophages are not destroyed by the virus.
Using a human brain cell "model" they developed to study neurological diseases, Pulliam and her colleagues previously had found that virus-free fluid drawn from cultures of HIV-infected macrophages damaged or killed human brain cells (Journal of Clinical Investigation, February, 1991), but exactly how the cells were killed remained unclear.
In their new study, the researchers explored whether the damage might be caused by macrophages derived from a particular subset of monocytes. They found that a subgroup of monocytes, denser and more granular than their counterparts, were numerous in the blood of 11 AIDS patients with dementia, averaging 69 percent of the monocytes in a blood sample. In contrast, this subgroup of monocytes averaged only seven percent of the total monocytes in blood of 10 people without HIV and eight percent in 12 patients with AIDS but no dementia.
The researchers then added virus-free fluid from cultures containing these monocytes to brain cells grown in lab flasks and found it triggered genes within the brain cells to program a gradual march to self destruction.
The team plans further studies of people with HIV to determine whether rising numbers of the monocytes herald onset of dementia. Further work also is needed, Pulliam notes, to determine whether the monocyte subgroup can serve as an early warning for other types of dementias, whether they can be selectively destroyed and whether the "self-destruct" genes can be turned off once activated in brain cells.
Pulliam's colleagues included Ron Gascon and Marcia Subblebine, UCSF staff research associates; Dawn McGuire, M.D., UCSF clinical instructor of neurology and director of clinical affairs at Nuerex Corporation; and Michael McGrath, M.D., Ph.D., UCSF associate professor of laboratory medicine at the affiliated San Francisco General Hospital.
(End of advance for release 6:30 EST March 6)
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