Occludin's Protective Role in HIV and Ischemic Stroke via Mitochondrial Signaling
Overview
Occludin, traditionally viewed as a structural blood–brain barrier protein, actively modulates innate immune responses against HIV and ischemic stroke through mitochondrial antiviral signaling pathways. Loss of occludin impairs mitochondrial function and antiviral defenses, leading to increased HIV replication and worsened stroke outcomes.
Background
People living with HIV have an elevated risk of cerebrovascular disorders such as ischemic stroke, even when viral replication is suppressed by antiretroviral therapy. The blood–brain barrier (BBB) protein occludin, beyond its structural role, influences cellular responses to viral infections. HIV can infect brain pericytes, which maintain BBB integrity, but the mechanisms linking occludin, mitochondrial function, and HIV pathophysiology have been unclear. Recent research explores how occludin modulates innate immunity and mitochondrial bioenergetics to affect HIV persistence and stroke severity.
Data Highlights
Model
Occludin Status
HIV Replication
Ischemic Stroke Outcome
Mitochondrial Function
Human brain pericytes
Silenced
Increased
Not applicable
Dysfunctional bioenergetics and impaired autophagy
Eco-HIV-infected mice
Occludin-deficient
Elevated viral loads
Worsened stroke outcomes
Impaired mitochondrial antiviral signaling
Key Findings
Occludin regulates innate immune responses in brain pericytes by modulating interferon-stimulated genes and the RIG-I mitochondrial antiviral signaling pathway.
Silencing occludin disrupts mitochondrial bioenergetics and autophagy, weakening antiviral defenses and increasing HIV replication.
Eco-HIV-infected occludin-deficient mice exhibit higher viral loads and significantly worse ischemic stroke outcomes, independent of the gp120 protein.
Pericytes, despite lower CD4 and co-receptor expression than T cells, support both productive and latent HIV infections, impacting BBB integrity.
Occludin also serves as a gatekeeper against other neurotropic viruses, such as SARS-CoV-2, highlighting its broader role in preventing viral neuroinvasion.
Mitochondrial dysfunction emerges as a key factor linking occludin loss to impaired innate immunity and cerebrovascular injury in HIV infection.
Clinical Implications
Maintaining or enhancing occludin expression may strengthen blood–brain barrier integrity and improve innate immune responses against HIV, potentially reducing cerebrovascular complications. Therapeutic strategies targeting mitochondrial function and occludin pathways could offer dual benefits in managing HIV-associated neurological disorders and ischemic stroke risk.
Conclusion
This study redefines occludin as an active regulator of mitochondrial antiviral signaling and innate immunity in the brain, linking its dysfunction to increased HIV replication and worsened ischemic stroke outcomes. Targeting occludin-mediated pathways holds promise for improving neurological health in people living with HIV.
