CU Boulder researchers tackle HIV-related cognitive decline
Assistant Professor Kayla Sprenger
Assistant Professors Kayla Sprenger and Laurel Hind, of CU Boulder’s Department of Chemical and Biological Engineering, are on a collaborative mission to explore solutions for mitigating cognitive decline in individuals living with HIV. This decline can be caused by both the virus itself and the antiretroviral (ARV) drugs used to treat it.
“We're thrilled that this collaborative research is finally happening,” Sprenger said. “It's exciting to work on this together.”
The two secured a $396,000, two-year National Institutes of Health R21 grant to uncover the features of ARVs that impact their interactions with efflux proteins(which remove substances like medications from cells)and lipids in the blood-brain barrier. This knowledge is poised to revolutionize the design of new ARVs, endowing them with an enhanced ability to cross the blood-brain barrier and effectively combat HIV infection in the brain, Sprenger said.
Assistant Professor Laurel Hind
ARVs work by hindering the ability of HIV to replicate. Despite their effectiveness in controlling the virus, 50 to 60 percent of the aging HIV population experiences some form of neurocognitive decline, partly attributed to the treatment, she added.
“ARVs play a crucial role in extending the life expectancy of individuals living with HIV,” Sprenger said. “However, they are accompanied by adverse effects, notably inhibition of host cell proteins that causes neurological impairment. If we can design better ARVs that not only mitigate these side effects but also address neurological complications arising from the presence of HIV itself within the brain, it's like a double whammy of goodness.”
Their research seeks to identify the molecular mechanisms by which ARVs transport across the blood-brain barrier—a critical investigation given the barrier’s role in safeguarding the brain by removing harmful substances, paradoxically including life-saving drugs like ARVs. Beginning with the evaluation of existing ARVs, their approach involves computationally modeling how these drugs diffuse across the blood-brain barrier.
The interdisciplinary project merges Hind’s experimental expertise with Sprenger’s computational approaches. Sprenger has long aspired to conduct computational analyses on how ARVs enter the brain, but has faced challenges in obtaining adequate data. Recognizing this need, Hind provided a model capable of generating experimental data, enabling the collective advance of this research. The experimental data, derived from Hind’s microfluidic blood-brain barrier model, will be crucial in establishing parameters for the development of more biologically-informed computational models.
“Obtaining ‘good data’ has proven challenging due to a scarcity of human data and the limitations inherent in animal models,” Hind said. To address this, the researchers are utilizing a cutting-edge approach, featuring human brain cells within a physiologically-relevant microfluidic model. This approach aims to more accurately replicate the physiological conditions of the blood-brain barrier in their experimental model.
Their ultimate goal is to design new ARVs that can prevent HIV from entering the brain or have an improved ability to diffuse across the blood-brain barrier to stop HIV from replicating within brain-resident cells, all while ensuring that the drug itself doesn’t cause neuronal damage.