| |
Aids virus is a 'double hit' to the brain
|
| |
| |
Washington (http://www.int.iol.co.za) - The Aids virus damages the brain in two ways, by not only killing brain cells but by preventing the birth of new cells, United States researchers reported on Wednesday.
The study, published in the journal Cell Stem Cell, helps shed light on a condition known as HIV-associated dementia, which can cause confusion, sleep disturbances and memory loss in people infected with the virus.
It is less common in people taking drug cocktails to suppress the virus, and why HIV damages brain function is not clearly understood.
The virus kills brain cells but it also appears to stop progenitor cells, known as stem cells, from dividing, the team at Burnham Institute for Medical Research and the University of California at San Diego found.
"It's a double hit to the brain," researcher Marcus Kaul said in a statement. "The HIV protein both causes brain injury and prevents its repair."
The cocktail of drugs known as highly active antiretroviral therapy or HAART that treats HIV does not infiltrate the brain well, allowing for a "secret reservoir" of virus, said Stuart Lipton, who worked on the study.
HIV-associated dementia is becoming more common, as patients survive into their older years.
Working in mice, the researchers found that the virus directly interferes with the birth of new brain cells from stem cells.
"The breakthrough here is that the Aids virus prevents stem cells in the brain from dividing; it hangs them up," Lipton said. "It's the first time that the virus has ever been shown to affect stem cells."
The culprit is gp120 - a protein found on the outside of the Aids virus, the researchers found.
"Knowing the mechanism, we can start to approach this therapeutically," Lipton said.
"This indicates that we might eventually treat this form of dementia by either ramping up brain repair or protecting the repair mechanism," Kaul added.
Can the Ravages of Dementia in HIV/AIDS Be Arrested?
A process known to kill adult nerve cells also halts stem cell growth, causing neurodegeneration.
By Nikhil Swaminathan
http://www.sciam.com
ARRESTED DEVELOPMENT: A protein on the surface of the HIV virus is not only capable of killing mature neurons in the brain, it can also halt the proliferation of stem cells developing into neurons, causing a dementia.
Despite improved therapies that have resulted in improved prognoses in patients with the human immune virus (HIV), which in many cases leads to AIDS, there is still an organ of the body affected by the condition that goes largely unaddressed: the brain.
According to Stuart Lipton, a professor at the Burnham Institute for Medical Research's Del E. Webb Center for Neuroscience and Aging Research in La Jolla, Calif., antiviral medications do not successfully cross the blood-brain barrier, allowing the HIV virus to stow away in the brain for up to several years, quietly wreaking havoc. The result: HIV-associated dementia, characterized by, among other symptoms, memory loss, blurred vision, concentration deficits, speech difficulties and motor impairments.
Lipton and colleagues report in this week's Cell Stem Cell that HIV-associated dementia is triggered by the death of adult neurons in patients' brains as well as by the arrested development of neural stem cells, which normally would mature and replace the disabled nerve cells. Perhaps more compelling, he says, is that the deadly virus uses a protein on its surface to attack the same molecular pathway in both the nascent and fully developed cells.
"HIV is very clever to use such a system to stop proliferation," says Shu-ichi Okamoto, co-author of the new study and a Burnham research assistant postdoc. Blocking this process, he notes, could lead to new therapies to supplement antivirals and reduce the neurological damage.
Neurogenesis (the birth of new nerve cells whereby the brain can heal itself) takes place in specific regions of the adult brain, such as the olfactory bulb (responsible for odor perception) and the dentate gyrus section of the hippocampus, a midbrain area involved in episodic memory and spatial reasoning. Brain tissue of recently deceased HIV/AIDS patients-as well as those of sufferers of neurological disorders, such as Alzheimer's-showed a smaller number of maturing cells, indicating that neurogenesis was disrupted.
Lipton and co-author Marcus Kaul, an assistant professor of infectious and inflammatory diseases at Burnham, revealed in the late-1990s that a glycoprotein found on the surface of HIV called gp120 caused neuronal death (and subsequent dementia) by triggering release of the enzyme p38 mitogen-activated protein kinase (MAPK), which interferes with the normal cell cycle. MAPK serves as a sort of checkpoint that can stop cell proliferation, if need be. Cancer cells, for instance, co-opt normal stem cell mechanisms, dampening MAPK and producing more and more cancerous cells.)
In the new study, the team bred a transgenic mouse that produced HIV's gp120 protein in its brain without having to be infected by the virus. These altered mice produced far fewer proliferating stem cells than their normal counterparts. The team further determined that their frozen stem cells produced more MAPK than stem cells in a normal mouse brain. "That glycoprotein binds to the progenitor and induces some signaling to stop the proliferation," Okamoto says, noting that's the opposite of what occurs in cancer cells.
The fact that gp120 and MAPK caused mature neuronal death and stopped proliferation of young neural stem cells indicates there may be a single therapeutic target to aim at in treating HIV-associated dementia.
"If you find some inhibitor for this cascade [initiated by MAPK], it would be useful to reinitiate the proliferation" and prevent adult cells' destruction, Okamato says. MAPK suppressors are already being tested in mice for use in treating several autoimmune diseases, among them rheumatoid arthritis and a skin disease called pemphigus vulgaris, a blistering disorder of the skin and mucous membranes that can lead to a slow, painful death.
|
|
| |
| |
|
|
|
