August 7, 2000
Volume 52, No. 39
Scholarship & Research
Yerkes researchers look for HIV's Trojan horse
By Poul Olson
According to Greek legend, after many years of unsuccessfully trying to penetrate the fortified city of Troy, Agamemnon switched tactics and built the massive wooden horse whose name became synonymous with stealth and surprise. In its siege, HIV follows a similar strategy to penetrate and destroy another fortress-the brain-by using the body's own immune system against itself.
A protective, blood-brain barrier normally shields the brain from pathogens like viruses and bacteria. HIV, however, doesn't mount a frontal assault. Like a Trojan horse, the virus hides inside immune bodies called macrophages and deftly slips through the barrier and into the brain, where it replicates and damages vital neurons.
Shawn O'Neil and a team of Yerkes investigators are using a simian immunodeficiency virus (SIV) model in pigtail macaques to examine this process and the effect of antiretroviral drugs on virus in the brain.
Within days of infection SIV, like HIV, targets the brain. To gain passage through the blood-brain barrier, both viruses incorporate their genetic material into macrophages.
Once in the brain, HIV alters the barrier, causing it to leak and allowing more infected cells to enter. HIV also damages neurons by producing viral proteins and stimulating the release of toxic cytokines from macrophages. This eventually causes difficulty in both cognitive and body-movement control.
"The brain is such an important organ that there's no way to compensate when an area is lost or damaged," said O'Neil. "As a result, the virus can have a profound impact when it affects even a small area."
The neurological complications of HIV infection, or "neuro-AIDS," affect a large segment of the HIV-positive population. Dementia is the most common and devastating manifestation, affecting about a quarter of those infected.
Despite HIV's keen ability to penetrate the blood-brain barrier, many people have a natural resistance to brain infection. O'Neil speculated that this may be because their immune systems are able to limit viral production during the early stages of infection, or provide protective help to the blood-brain barrier, or a combination of the two.
He believes genetic factors determine whether HIV will infect the brain. One particularly compelling hypothesis suggests that a mutation in a key receptor responsible for ushering HIV into immune cells may, for some people, make it difficult for the virus to gain a foothold.
In studies with SIV-infected macaques, O'Neil found that monkeys with weak initial immune responses had severe brain infections and progressed rapidly to full-blown AIDS. Animals with strong immune responses, on the other hand, rarely developed brain infections and progressed slowly to AIDS.
In addition to its direct effects on the brain, HIV establishes a viral reservoir in the brain by infecting resident macrophages and other brain cells. In this latent state, the infected cells do not always manufacture virus but can be activated to produce virus at a later time.
An important but unanswered question is whether virus in the brain is susceptible to highly active antiretroviral therapy (HAART), given that most antiretroviral drugs are unable to cross the blood-brain barrier.
Clinical observations suggest that the incidence of AIDS-related dementia has fallen with the use of HAART. But an Australian study concluded that dementia and neoplasia were the only HIV complications that had not declined with HAART. O'Neil said more research is needed to study the medication's effect.
Researchers agree that effective HIV treatment must address the viral reservoir in the brain as well as other areas of the body. In collaboration with Yerkes researchers Frank Novembre, Dan Anderson and Harold McClure, O'Neil is examining the effect of antiretroviral medications on SIV replication in the brain.
"Antiretroviral agents are toxic drugs with many side effects,"
O'Neil said. "The goal is to wean people off these drugs and allow
their immune system to take over control of virus suppression. But if HIV
infection continues unchecked in the central nervous system, virus from
the brain may re-seed the lymphoid tissues as soon as HAART is discontinued."