Apr 19 2004
Ever since the AIDS epidemic began more than two decades ago, scientists have been trying to understand why as many as one-quarter of those infected with HIV develop dementia.
Now, researchers at Jefferson Medical College may have an answer.
Investigators led by virologist Roger J. Pomerantz, M.D., director of the Division of Infectious Diseases and Environmental Medicine at Jefferson Medical College of Thomas Jefferson University in Philadelphia, have shown that the virus produces proteins that turn on specific biochemical pathways in the brain, leading to brain cell death.
Dr. Pomerantz and his co-workers report their results April 19 in an early online edition of the Proceedings of the National Academy of Sciences.
According to Dr. Pomerantz, professor of medicine, biochemistry and molecular pharmacology and director of the Center for Human Virology and Biodefense at Jefferson Medical College, researchers have been trying for more than two decades to find an explanation for why and how HIV causes “neuronal drop out” and dementia.
He explains that HIV in the brain causes hardly any inflammation or white blood cell increase, unlike in other brain infections, such as in meningitis or herpes infection.
“Neurons die,” he says, “and the brain atrophies. It’s extremely unusual. Infectious agents don’t do this, but HIV does.” He notes that the effect “is clearly due to HIV.” In patients taking the anti-retroviral HAART cocktail of drugs, which halts retroviral replication, fewer individuals develop dementia than those who do not take the drugs.
“The overarching hypothesis has been that HIV infects brain cells called macrophages and microglia,” he explains. These cells produce an array of substances called cytokines and chemokines, which kill neurons. “It’s thought that HIV doesn’t kill neurons directly, but rather, it’s due to what the macrophages and microglia make.”
Dr. Pomerantz and his group decided to find out whether the virus itself was causing the neurons to die, or whether the cell death was indeed caused by the substances from infected cells. He and his co-workers had previously published work suggesting that certain HIV proteins are toxic to neurons, causing apoptosis, or “programmed cell death.”
Dr. Pomerantz’s team examined HIV-infected macrophages and human T-lymphocytes in the laboratory. Using a technique called ultracentrifugation, they removed the virus, leaving some macrophages with virus and their chemicals, and other samples of only macrophages without virus. They subsequently treated human neurons in culture with macrophages that contained virus plus macrophage-produced chemicals, and other neurons with only cytokines and chemokines. They found that the majority of brain disease was due to the virus and its associated proteins – not cytokines and chemokines.
Similarly, the scientists removed virus from some T-cells. They then treated neurons with infected T-cells and with normal T-cells. “When we looked at T-cells, the only thing that killed neurons was the virus,” he says. “Once the virus is removed, nothing from the T-cells would kill neurons.”
They next looked for the mechanism behind the cell death. Using microarray technology, they determined that most of the cytokines and chemokines were at relatively low levels in the brain cells and unlikely to be a major cause of disease.
The researchers then turned to the neurons themselves to look for the mechanism behind the cell death. They found that two “well described” pathways leading to programmed cell death called the intrinsic and extrinsic systems were activated by viral proteins.
“We feel that it’s mainly the virus and viral proteins causing the neuronal cell death, and now may know the precise pathways involved,” Dr. Pomerantz says. “Now we can rationally design inhibitors of these pathways to lead to neuroprotection.
“Now, we not only have the ability to block HIV encephalopathy by blocking the virus, but we also have a way of designing drugs to specifically protect neurons even if virus is there,” says Dr. Pomerantz. “That’s our next step.”
He notes that no one knows how to predict which HIV-infected individuals go on to develop dementia, though it’s likely that certain unidentified genetic differences make some individuals more susceptible.
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