As the HIV-infected population ages, cognitive issues are arising that affect the quality of life for individuals. To tackle this problem, Michael Nonnemacher, an assistant professor in microbiology and immunology at Drexel University, is developing in vitro models to study the mechanisms of the blood-brain barrier and the impact of HIV on the barrier’s function.

The project also will look at the role aging plays on the barrier’s ability to regulate what gets in and out of the central nervous system through the lens of the viral protein Tat, which is secreted from HIV-infected cells. Tat, research has shown, has a role in weakening the blood-brain barrier and causing inflammation in the central nervous system.

“We’re looking at it specifically from the genetic variation of a protein that has been shown to impact the blood-brain barrier,” Nonnemacher says.

That barrier separates the circulating blood from the brain fluid in the central nervous system and is made up of three compartments: blood, a layer of endothelial cells and astrocyte and pericyte cells in the brain that support the endothelium and effectively tightly stitch together a protective wall.

When working properly, only certain molecules can pass through, such as immune cells that patrol for pathogens, drugs and other small molecules, Nonnemacher says. But in HIV-infected people, the barrier’s permeability is disrupted, likely due to cellular changes.

Cells infected with HIV have altered cytokines, which are proteins that help regulate the immune system. They also produce virus particles and secrete Tat.

Tat, in particular, degrades the tight junction proteins, essentially the astrocytes that hold together the endothelial blood-brain barrier, and disrupts the barrier’s structure. Once it is damaged, cell migration across the wall increases the quantity of infected cells, viral proteins and viruses that reach the central nervous system.

“As these cells senesce, what we don’t know is what kind of loss of function does that provide to the barrier,” says Nonnemacher. “Is there a breach? Or is the barrier intact?”

The genetic variation of Tat, related to the HIV virus’s hallmark ability to mutate, is an important factor in the severity of HIV-related cognitive deficits. Nonnemacher’s project, funded through a $20,000 grant from Temple University’s Comprehensive NeuroAIDS Center, will focus on developing cell models to understand how HIV affects the blood-brain barrier and ultimately the central nervous system, particularly in an aging population.

“We’re asking basic mechanistic questions: Is the barrier that regulates the in and out of the brain differently working in an aged versus non-aged person in an HIV-infected model?”

“We’re asking basic mechanistic questions: Is the barrier that regulates the in and out of the brain differently working in an aged versus non-aged person in an HIV-infected model?” he says.

Patient data suggest the answer is yes, Nonnemacher says. Once researchers figure out what exactly is going on, then the next question that he hopes to attack is this: “Is there something we can do to fix it?”