Investigating the mechanisms involved in HIV infection and cerebral endothelial dysfunction in a 3D human brain neurovascular spheroid.

Despite successfully suppressing HIV infection with antiretroviral therapy (ART), cerebrovascular disease, including stroke and cognitive impairment, remains a dominant complication in this population.

I have shown that HIV is a leading risk factor of stroke in the young and can contribute to 15-30% of overall stroke presentations in endemic regions. There is good evidence that atherogenesis is part of the mechanism.

Chronic inflammation and antiretrovirals are amongst confounders that obscure delineating the exact pathway to atherogenesis.

The Neurovascular Unit (NVU) which consists of the cerebrovascular endothelium supported by astrocytes and pericytes is pivotal to maintaining blood vessel function and impeding HIV to enter the brain.

To date, scientific advancement has been limited by developing experimental systems that replicates the NVU in its normal environment.

My fellowship proposes to use a powerful new in vitro multicellular 3D model of the NVU, with blood brain barrier (BBB) properties similar to those found in vivo, to investigate how HIV crosses the BBB, establishes NVU infection, and triggers endothelial dysfunction, a precursor for atherogenesis.

Finally, I will exploit an established cohort of HIV patients with ART and phenotyped for cerebrovascular disease in Malawi, to verify the mechanistic insights from my in vitro findings.