# Blood brain barrier injury in HIV infection complicated by diabetes: Mechanisms and protective strategies preventing cognitive impairment

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $525,220

## Abstract

Despite combined antiretroviral therapy (ART) achieving efficient HIV replication control, HIV-
associated neurocognitive disorders (HAND) continue to be highly prevalent in HIV-infected
patients. One of the explanations could be constant compromise of blood brain barrier (BBB)
driven by chronic inflammatory responses documented in HIV-infected individuals even with
well-controlled virus replication yet with HAND progression. Chronic neuroimmune activation is
present in ART-treated patients as indicated by elevated levels of soluble inflammatory factors
in the cerebrospinal fluid and blood. Diabetes mellitus (DM) is a well-known comorbidity of
HAND in HIV-infected patients. BBB dysfunction has been linked recently to dementia
development, specifically in DM patients. BBB injury has been documented in animal models of
diabetes showing memory deficits and was associated with dysfunction of brain pericytes
supporting endothelial cells. Taking together clinical and experimental data, BBB injury exists
both in HIV and DM, likely contributing to cognitive decline. However, its extent, exact cellular
targets and mechanisms are largely unknown. We propose that cognitive impairment in HIV-
infected individuals is mediated by BBB injury that is further aggravated by metabolic alterations
associated with DM causing HAND. Preliminary data support this idea showing elevated
glucose levels correlated with increased BBB permeability, cognitive impairment, microglia
activation and loss of pericytes in animal models for DM types 1 and 2. We found a decrease in
pericyte coverage and expression of tight junction proteins in human brain tissues from HIV
patients with DM and evidence of HAND. Using our in vitro BBB models, we demonstrated
diminution of barrier integrity, enhanced monocyte adhesion, changes in cytoskeleton and
overexpression of adhesion molecules after exposure to HIV and DM-relevant stimuli. We
hypothesize that prevention of BBB compromise in DM/HIV will diminish neurocognitive decline
independently of tight glucose control. We will identify biomarkers of such BBB injury, correlate
with barrier damage and cognitive decline, define signaling pathways associated with BBB injury
in DM/HIV and test novel treatment approaches. We will study the contribution of DM- and HIV-
mimicking conditions on cognition and BBB injury in cross-validating experiments using well-
established in vitro systems (co-culture of human primary brain microvascular endothelial
cells/primary human brain pericytes), functional assays, animal models of DM types 1 and 2
combined with HIV brain exposure and `humanized' NSG mice with chronic HIV infection and
diabetes. Results of such studies will open opportunities for very much needed individualized
treatment for HAND.

## Key facts

- **NIH application ID:** 9918455
- **Project number:** 5R01MH115786-03
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Yuri Persidsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $525,220
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918455

## Citation

> US National Institutes of Health, RePORTER application 9918455, Blood brain barrier injury in HIV infection complicated by diabetes: Mechanisms and protective strategies preventing cognitive impairment (5R01MH115786-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9918455. Licensed CC0.

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