Anti-HIV drug could improve recovery after stroke | Science

The treatment of stroke is a race against the clock. In the hours following a stroke, tissue plasminogen activator (tPA) can reduce brain damage. But once the harm is done, no medication promotes recovery. New research suggests that such therapy could come from an unlikely target: a cellular protein called CCR5 that allows HIV to infect cells. Scientists have found that in mice, CCR5 inhibition helps the surviving neurons to establish new connections and that people with a CCR5 mutation can better recover from a stroke.

"This is the first true molecular target to improve recovery after stroke," says Argye Hillis, a stroke neurologist at the Johns Hopkins University School of Medicine in Baltimore, UK. Maryland, who did not participate in the work. A clinical trial will soon test its promises by giving stroke patients an anti-HIV drug that blocks CCR5.

White blood cells display CCR5 on their surface to intercept the signals of molecules called chemokines and coordinate an immune response. But HIV exploits CCR5 and seizes it to invade host cells. People with a mutation that paralyzes the CCR5 are protected from infection, so Chinese scientist He Jiankui has recently sought to mutate CCR5 in controversial human experiences.

The new findings on the CCR5 began with a hunt for "intelligent mice", animals with genetic mutations that apparently reinforce their ability to learn and remember. Neuroscientist Alcino Silva and his team at the University of California at Los Angeles (UCLA) wanted to determine which of the 148 strains of mice had such improvements. In 2016, they reported that reducing levels of CCR5 in a healthy mouse brain improved memory training and learning.

Thomas Carmichael, a stroke neurologist at UCLA, was intrigued. "When you look at recovering patients after a stroke, it seems like they are relearning how to walk or relearn the language," he says. In fact, the surviving neurons close to the wound sprout tendrils to establish new contacts in the brain. A drug targeting CCR5 seemed promising for recovery from stroke, and this drug was already available. Maraviroc, which blocks CCR5, was approved by US regulatory authorities in 2007 for use with other antiretroviral drugs to treat HIV infections.

In Cell This week, Silva, Carmichael, and their collaborators showed that CCR5 levels in mouse neurons soared after a stroke and could remain high for weeks, and that the protein seemed to hinder recovery. The team blocked CCR5 with maraviroc or a gene that interferes with its production, and then subjected the mice to motor tests (for example, counting the number of times their feet slipped when they The treated mice showed motor improvements greater than those of the controls at the end of the 9 week test period.

Although researchers waited 3 weeks after a stroke to deliver maraviroc to animals, their performance was improved. In previous studies, nothing seemed to help at that time, says Dale Corbett, a neuroscientist specializing in stroke recovery at the University of Ottawa. The new findings, he says, suggest "that it may be feasible to reopen this window of recovery in people."

Blocking CCR5 seemed to help maintain connections between neurons adjacent to the injured site. In addition, the neurons of the motor regions have been able to project more projections on the opposite side of the brain, which could help a mouse to relearn his lost movements.

What CCR5 does in the post-stroke brain is unclear. CCR5 surgery is part of the inflammatory response to stroke, says Robyn Klein, a neuroimmunologist at the University of Washington Medical School in St. Louis, Missouri. Inflammatory molecules may induce neurons to express more of this chemokine receptor. In the developing brain, chemokines are known to influence the migration and connection of neurons. After a stroke, they seem to decrease the number of connection sites on neurons close to the damage. (How this process prevents regrowth and recovery is not clear.)

Carmichael notes that blocking CCR5 has also caused neurons to express genes that increase their excitability, making them easier to use. He suspects neurons of stimulating the CCR5 after a stroke to slow their activity and being too low to avoid a lethal cell binge called excitotoxicity. But because the protein then stays in the vicinity, this protective mechanism hampers recovery.

The findings in mice often have no meaning in humans, but when the Carmichael group was associated with researchers responsible for the Tel Aviv Brain Stroke Cohort (TABASCO) in Israel, they found encouraging signs. About 10% of Europeans have a genetic deletion that paralyzes CCR5, and this number is higher among Jews of East European origin. The TABASCO team identified 68 people in its cohort of stroke survivors with at least one copy of the CCR5 mutation. Compared to people without mutation, their motor and sensory skills test scores and cognitive abilities were slightly better at six months and one year after a stroke, according to the new study.

"It was not better than gangbusters, but … the fact that they found something is awesome," says Steven Cramer, neuroscientist at UC Irvine.

Carmichael and colleagues are developing a clinical trial that will allow maraviroc of 30 people to start leaving an inpatient rehabilitation facility, usually about 4 weeks after a stroke. The team hopes to launch the lawsuit this year.

Some researchers expect the story of CCR5 to inspire a broader search for brain repair strategies based on learning and memory genes. "We have always been talking about a tPA-like moment for recovery after stroke," Corbett said. "Whether it is or not, I do not know, but at least it gives us hope."