A study published in Glia has identified the mechanism responsible for the loss of white matter in patients with HIV. This reduction in white matter has been well-documented, but the exact mechanism of action has been unknown until now, according to the study authors. Loss of white matter is associated with motor and cognitive impairment in patients with HIV.
“Even when people with HIV have their disease well-controlled by antiretrovirals, they still have the virus present in their bodies, so this study came out of our interest in understanding how HIV infection itself affects white matter,” said Kelly Jordan-Sciutto, PhD, in a press release. “By understanding those mechanisms, we can take the next step to protect people with HIV infection from these impacts.”
White matter consists of a fatty substance called myelin that coats neurons, which offers protection and assists in transmitting signals quickly and efficiently. The investigators found that HIV prevents oligodendrocytes—the cells that produce myelin—from maturing, which results in decreased white matter production.
“When people think about the brain, they think of neurons, but they often don't think about white matter, as important as it is,” said Judith Grinspan, PhD, in the release. “But it's clear that myelination is playing key roles in various stages of life: in infancy, in adolescence, and likely during learning in adulthood too. The more we find out about this biology, the more we can do to prevent white matter loss and the harms that can cause.”
Because the virus does not directly infect neurons or oligodendrocytes, the study authors hypothesized that HIV's impact on the brain arose indirectly through the activity of human macrophages, one of the major cell types that HIV infects. In order to learn how this process may specifically affect white matter, they took the fluid in which macrophages infected with HIV were growing and applied it to rat oligodendrocyte precursor cells, which mature into oligodendrocytes. This did not kill the precursor cells, but it did block them from maturing into oligodendrocytes, which resulted in a reduction in myelin production.
The study found that HIV-infected macrophages secrete glutamate, which is known to have neurotoxic effects at high levels, according to the researchers. Further, there was evidence that the integrated stress response had been triggered in oligodendrocyte precursor cells. This response results in changes in gene expression that serve to protect the cell from stress or to prompt the cell to die, depending upon the intensity of the stress. When a compound blocking glutamate was introduced, the stress response did not activate, and cells were again able to mature.
In order to apply the findings of this study and potentially test drug targets that can address HIV-related cognitive impairments, the researchers hope to use a well-characterized rat model of HIV infection.
“HIV is a human disease, so it's a hard one to model,” Grinspan said in the release. “We want to find out if this model recapitulates human disease more accurately than others we've used in the past.”
Through tracking white matter in the animal model and comparing it to imaging studies done on patients with HIV, the investigators plan to get at a better understanding of what factors shape white matter loss. The ultimate goal of this research is to differentiate between impacts on white matter from antiretroviral therapy (ART)—a suite of drugs that many people with HIV use daily—and the impact of the virus itself, in order to better evaluate the risks of each.
“When we put people on ART, especially kids or adolescents, it's important to understand the implications of doing that," Jordan-Sciutto said in the release. "Antiretrovirals may prevent the establishment of a viral reservoir in the central nervous system, which would be wonderful, but we also know that the drugs can cause harm, particularly to white matter. And then of course we can't forget the 37 million HIV-infected individuals who live outside the United States and may not have access to antiretrovrials like the patients here. We want to know how we can help them too.”
How HIV infection shrinks the brain's white matter [news release]. EurekAlert; June 2, 2021. Accessed June 3, 2021. https://www.eurekalert.org/pub_releases/2021-06/uop-hhi060221.php