A team of researchers who have spent a decade trying to develop the world’s first treatment designed specifically to prevent or ease the neurological effects of HIV have just received word that the project will continue for another five years, thanks to $6.7 million in new funding from the National Institute of Mental Health.
Over the last 20 years, scientists and doctors have assembled a powerful combination of treatments that can nearly stop the progression of HIV for most patients. This combination antiretroviral therapy, or CART, can bring down virus levels in the body to less than a thousandth of what it would otherwise be. This translates into many more healthy years for those with HIV.
However, these positive effects aren’t duplicated in the brain, where the virus continues to cause decline despite aggressive treatment. About half of patients with HIV experience negative cognitive symptoms, such as difficulty thinking or concentrating. So far, almost a dozen studies in people have failed in finding an effective drug for the condition, known as HIV-associated neurocognitive disorder.
The problem lies in the way the brain reacts to HIV. As the brain detects the virus, the body releases immune cells that flood in to attack the problem and remove the threat. Unfortunately, the response itself becomes the problem when the immune cells attack healthy brain cells. Intricate structures called synapses, which are central to brain cell communication, are especially vulnerable.
Although HIV’s effects on the brain are rapid, brain cells don’t experience complete death. Instead, brain cells called neurons get ‘sick.’ Specifically, they lose important structures called dendrites, which creates a dysfunction in brain cell communication. Because it is a gradual process, there is hope for a reversal in symptoms, as these ‘sick’ cells have been shown in studies to return to health once inflammatory assault is stopped.
The allowance for further research comes at an important time. The team, led by Neurologist Harris A. “Handy” Gelbard, M.D., Ph.D. of the University of Rochester Medical Center, and which includes the Rochester group and scientists from the University of Nebraska and the Califia Bio Inc., has just developed a compound that shows great promise in laboratory studies. Scientists hope to begin a clinical trial in people within five years – an extremely important step for a condition that has no approved treatment.
“Most patients are able to cope with the cognitive effects of HIV, but oftentimes their cognitive abilities are diminished. Their ability to take on new tasks, to really concentrate, or to juggle several tasks at once, may be reduced,” said Gelbard, director of the Center for Neural Development and Disease.
“HIV infects the brain early on and goes on to wreak havoc there despite our best treatments. It’s a serious problem for the more than 30 million people worldwide infected with HIV.”
“Synapses are the currency of neurologic function,” Gelbard added. “The more damage to the synapses, the more symptoms patients will notice.”
The test compound is developed to slow down or get rid of inflammation by booting out an enzyme known as MLK3, which is responsible for the inflammatory process. Scientists believe that when this enzyme is abnormally active, it becomes a crucial switch, causing cells that would normally nourish the brain’s neurons to instead attack the neurons and synapses.
In the search for a compound to stop MLK3, the team found help in other researchers’ work with an experimental drug designed to stop the enzyme in Parkinson’s disease. Although the compound didn’t end up helping patients, it provided the team with crucial clues on how to better target MLK3.
The team took those clues and screened thousands of compounds, using the results to build a stronger compound able to stop MLK3. The team has shown that this compound is successful getting into the brain and staying there at levels required to knock out MLK3. In tests, the compound is successful in dramatically reducing inflammation and preserving synapse structure.
Gelbard points out that these new findings regarding HIV-related dementia is likely to pay off for other conditions as well. He adds that inflammation and MLK3 both play a large role in Alzheimer’s and Parkinson’s diseases. And he notes that this compound shows very early promise for treating heart failure as well.