For release: Thursday, February 8, 2007
In a move that could lead to better treatments for neurological complications of AIDS, researchers have identified a protein variant in HIV that is associated with brain infection and dementia in people with the disease.
Dana Gabuzda, M.D., a Professor of Neurology at the Dana Farber Cancer Institute and Harvard Medical School in Boston, led a group that analyzed genetic material left behind by HIV in the brains of deceased AIDS patients. Lead author Rebecca Dunfee found that a variant of Env – a protein on the surface of HIV – was more common in patients with dementia than in those without dementia. The investigators’ results were reported in The Proceedings of the National Academy of Sciences.*
HIV causes AIDS by killing white blood cells, destroying the body’s ability to fight off infections. The virus also infects cells in the brain, and causes dementia or a milder form of cognitive impairment in up to 40 percent of AIDS patients. Antiretroviral therapy can prevent HIV from multiplying, and has significantly improved the length and quality of life for many people with AIDS.
Still, “dementia remains a significant complication of HIV infection because most antiretroviral drugs do not penetrate effectively into the brain,” said Dr. Gabuzda, whose study was supported by the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Gabuzda is hopeful that the work will lead to drugs that can cross from the blood into brain and attach to the Env protein, stopping HIV from infecting brain cells.
In clinical trials, researchers have attempted to treat AIDS-related dementia with drugs that promote the growth of brain cells or protect them from oxygen free radicals.
“But there’s nothing that clearly works,” said Michael Nunn, a program director in the NINDS Division of Extramural Research. “This is a novel approach in that it would target the AIDS virus specifically, rather than the brain cells that are damaged by the disease.”
Inside and outside of the brain, the Env protein is an essential part of a lock-and-key mechanism that enables HIV to infect cells.
White blood cells become infected when Env – part of HIV’s outer envelope – attaches to a protein on the cells’ surface called the CD4 receptor. This attachment allows the virus to inject its own genetic material into the cells, which become factories for viral replication and are ultimately destroyed.
In the brain, HIV attacks macrophages and microglia, cells that normally aid in the immune response and have relatively low levels of CD4. Infection of macrophages and microglia leads to dementia because the infected cells stimulate inflammation and produce substances that are toxic to neurons, said Dr. Gabuzda.
“Drugs that target the CD4 binding site on the HIV envelope and inhibit HIV’s entry into cells might be a promising approach to treat AIDS-related dementia,” said Dr. Gabuzda. She also noted that because antiretroviral drugs generally have poor access to the brain, “reservoirs” of HIV can form there, making it difficult to reduce the body’s viral load, even in patients without neurological symptoms. So, a drug that helps clear HIV from the brain might improve the overall effectiveness of antiretroviral therapy.
Dr. Gabuzda began her experiments by isolating Env genes from the autopsied brain tissue of AIDS patients. Then, in cell culture experiments, she tested how the Env proteins made by those genes reacted to cells carrying the CD4 receptor. She observed that some Env proteins responded only to high levels of CD4, while others responded to the low levels typically found on macrophages and microglia. The common denominator among these souped-up Env proteins was a single conserved amino acid – N283 – at a site within Env where it binds to the CD4 receptor. (Amino acids are the building blocks for proteins.)
In other experiments, the group showed that the N283 variant of Env sticks more tightly to CD4 than do other variants.
Finally, Dr. Gabuzda examined the prevalence of the N283 variant in brain tissue from 66 AIDS patients. The variant accounted for 41 percent of all Env protein in the brain in patients with dementia, compared to only 8 percent in patients without dementia. She also found that N283 was more common in the brain than in blood or lymphatic tissues (such as the spleen).
Dr. Gabuzda said that future research will focus on identifying other factors that influence whether or not HIV infection leads to dementia.
“There are likely to be some additional variants in other HIV proteins that are associated with a risk of neurological complications,” she said. “Host factors [among people infected with HIV] may also influence susceptibility to infection and neuro-inflammation.”
*Dunfee RL, Thomas ER, Gorry PR, Wang J, Taylor J, Kunstman K, Wolinsky SM, and Gabuzda D. “The HIV Env variant N283 enhances macrophage tropism and is associated with brain infection and dementia.” PNAS, October 10, 2006, Vol. 103, no. 41, pp. 15160-15165.
-By Daniel Stimson, Ph.D.
Last Modified February 15, 2007