New evidence suggests that a tiny protein located on the outside of the AIDS virus may be partly responsible for the loss of mental functioning seen in a growing number of AIDS patients.
Estimates vary, but many doctors believe that about 60 percent of AIDS patients will eventually suffer from dementia -- the loss of mental functioning characterized by such changes as diminished memory, loss of motor coordination and depression. In many patients the effects are obvious to their friends and family; in more subtle cases, changes can be picked up with various psychological tests, including tests of drawing ability and other challenges to coordination.
For 10 to 20 percent of AIDS patients, these mental symptoms are the first signs of the disease.
At first, many AIDS researchers questioned whether some of the mental symptoms experienced by AIDS patients were a direct result of the HIV infection, a normal reaction to having a fatal illness or the result of one of the many opportunistic infections that strike AIDS patients.
But several studies, including one by Dr. Richard Johnson at Johns Hopkins Medical Institutions in Baltimore, have now shown that 50 to 70 percent of patients who tested positive for exposure to the AIDS virus also had the virus in their cerebrospinal fluid -- an indication that the virus is also in the brain.
"It's not going to be likely that these findings are based on depression or anxiety about having the disease," said Dr. Frederick Goodwin, scientific director at the National Institute of Mental Health.
But the question that has continued to mystify researchers is how AIDS damages the brain.
In a recent seminar, sponsored by NIMH, researchers described how a tiny protein located on the outside of the virus envelope and called gp120 is a potent poison for brain cells, particularly developing brain cells. Researchers know that the AIDS virus often sheds this envelope protein, releasing it into the surrounding area.
"Very, very small amounts of gp120 are required to kill brain cells," said Dr. Douglas Brenneman, a pharmacologist at the National Institute of Child Health and Human Development, who presented his findings at the NIMH seminar. "It is extraordinarily potent."
Researchers theorize that infected white blood cells -- particularly macrophages and T4 cells -- carry the virus across the protective blood-brain barrier into the brain. Or they may remain in the cerebrospinal fluid, which bathes the brain. In either case, the infected cells are able to secrete the damaging gp120 and perhaps other poisons as well.
These poisons, and not the virus itself, appear to cause the damage, and they do it indirectly, says Dr. Alison Wichman, a neurologist at the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS), who studies AIDS patients with dementia.
Exactly how gp120 and other substances secreted by the human immunodeficiency virus may damage brain cells is not known. But NIMH researchers have some important clues. The key seems to be a naturally occurring substance in the body called VIP -- vasoactive intestinal peptide.
In the stomach, VIP helps regulate how quickly food and water are moved through the intestinal tract. In the brain, cells apparently can't survive -- or thrive -- without it. "VIP is an incredibly important brain growth hormone," Dr. Candace Pert, an NIMH guest researcher, told the seminar. The HIV-secreted poisons apparently block VIP's action in brain cells, she said.
There are at least two subtypes of receptors on the surface of brain cells that can recognize and attach to VIP, according to studies by Pert and her colleague, Dr. Joanna Hill.
The protein gp120 is close enough in chemical structure to VIP to trick the VIP receptors on the surface of the brain cell. Like slipping a Hyundai engine into the body of a Porsche, the gp120 molecule may look similar to VIP, but it performs very differently.
Once attached to the receptor, scientists theorize, the gp120 protein blocks VIP from working in the brain cells. This may somehow affect portions of the brain cells that are important for communication. Scientists theorize that gp120 may change a part of the brain cell known as the dendrites -- tiny, wispy extensions of brain cells that receive and transmit information from cell to cell. It may also change the networks of cells in the brain, changing the patterns in which messages flow through the brain.
Evidence for this theory comes from studies by Dr. Ronald Mervis at Ohio State University Medical School in Columbus.
In a presentation at the Society for Neurosciences annual meeting last fall, Mervis described how the brain cells of a 2-year-old boy who died of AIDS were distorted. The areas of the brain affected most were the cortex, the part of the brain used for thinking, and the cerebellum, which is responsible for muscle coordination.
"These are all subtle changes," said Mervis, who is director of the Brain, Aging and Neuronal Plasticity Research Group at Ohio State. Other studies have shown that these kinds of brain changes "affect brain function and communication between neurons," he said.
Studies of adults who had died of AIDS showed similar but less extensive brain cell damage. "That's not unexpected, since the child's brain is rapidly developing and always seems to be more vulnerable to insult than the adult's," he said.
Like the brain cells in the child, the configuration of the adult cells were also altered. There were significant changes on the dendrites. Lollipop-like structures called spines were missing. Those that remained in place had grown shorter. "They looked like little mounds," Mervis said. Electrical signals between brain cells are dependent on the configuration of the spines. "If you change the configuration, it changes the signal coming into that cell," he said.
Changes in the spines on brain cells have also been linked to other mental disorders, including Alzheimer's disease, the debilitating and fatal dementia that afflicts older adults. In addition, Dr. Dominick Purpura at Albert Einstein Medical Center in New York City has shown that children with psychomotor retardation have spines on their brain cells that are abnormally long and thin. "It's as though distortion in either direction of the spines distorts the information coming into the cell," says Mervis.
Neuroscientists struggling to treat AIDS dementia are looking for ways to prevent or reverse this brain damage.
Two drugs are now under study: AZT, the only approved AIDS drug now on the market, and Peptide T, an experimental drug undergoing phase I, or preliminary, tests in AIDS patients in the United States and Sweden. AZT, a cancer drug, was first used against AIDS by Dr. Samuel Broder at the National Cancer Institute. Peptide T was developed by NIMH researcher Pert and her colleagues.
Peptide T is composed of eight amino acids -- the building blocks of protein. Its chemical structure is also a part of the larger VIP molecule. Laboratory studies conducted by NICHD's Brenneman indicate that Peptide T can block the action of gp120 in developing brain cells, apparently because it, too, competes for the VIP receptor.
Whether Peptide T will be safe or nontoxic in humans is still not known. Tests are being conducted by the NIMH at the University of Southern California in Los Angeles. So far, nine AIDS patients in the United States and Sweden have been given the drug.
So far, there is "no evidence of toxicity," said Dr. Peter Bridge, deputy AIDS coordinator for the Alcohol, Drug Abuse and Mental Health Administration and a co-investigator of the Peptide T trial, told the NIMH seminar. But he added: "These are early results of a study in progress and are not the conclusions of the study."
Some neuropsychological tests used to assess the toxicity of Peptide T also showed some improvement in memory and attention.
"It's far too early to know what these results mean," Bridge said, "but we will consider them in further testing of the drug."
AZT, which prevents the virus from reproducing itself, is also being studied for its effect on AIDS dementia. Last month, researchers at NINCDS reported in the journal Lancet that four patients taking AZT for dementia showed "dramatic improvement" on several measures including a measure of memory, motor coordination and attention.
The patients also "felt better and performed better better on tests," said Dr. Jordan Grafman, a senior staff fellow in the institute's medical neurology branch. Three of the patients have since died, from a variety of causes. For some, the AZT became too toxic and they had bone marrow suppression, Grafman said. But the fourth patient is still on AZT 18 months later and remains stable.
"These results suggest," Grafman says, "that at least in some cases persons with AIDS dementia can improve and be stable for a least a year and a half. Perhaps we can improve the quality of life if not the duration."