EphB2-Ephrin-B1 Signaling in Microglia and Implications for NeuroHIV

Why It Matters

Understanding EphB2’s role links persistent neuroinflammation to cognitive decline in treated HIV, offering a novel target to protect brain health in millions of patients worldwide.

Key Takeaways

• HIV neurocognitive disorders affect ~50% despite viral suppression
• Microglia activation drives neuronal injury via cytokines and glutamate
• EphB2‑ephrin‑B1 signaling modulates microglial inflammatory responses
• Elevated EphB2 expression correlates with brain pathology in HIV patients
• Targeting EphB2 may mitigate neuroinflammation and cognitive decline

Summary

The seminar presented Dr. Marcus Call’s recent work on EphB2‑ephrin‑B1 signaling in microglia and its relevance to neuroHIV. While antiretroviral therapy has reduced systemic viral loads, roughly half of people living with HIV still develop neurocognitive impairment, ranging from asymptomatic deficits to dementia, underscoring a persistent central nervous system challenge.

Call highlighted that infected or activated microglia release viral proteins, cytokines, and excess glutamate, disrupting calcium homeostasis and synaptic integrity. In this inflammatory milieu, the EphB2 receptor and its ephrin‑B1 ligand, traditionally studied in neural development, emerge as key regulators of microglial activation. Mouse models expressing HIV proteins showed pronounced dendritic loss, astrocyte activation, and up‑regulated EphB2 pathways, mirroring human neuropathology.

A striking observation came from post‑mortem brain samples: EphB2 mRNA levels were modest in HIV‑negative controls and HIV‑positive brains without pathology, but significantly elevated in specimens displaying neurodegeneration. Moreover, EphB2 knockout mice exhibited attenuated inflammatory cytokine production and reduced fibrosis in liver injury models, suggesting a broader pro‑inflammatory role. Dr. Call likened HIV’s impact on the brain to an “unpredictable storm,” emphasizing the nonlinear, multifactorial damage.

These findings position EphB2‑ephrin‑B1 signaling as a promising therapeutic target to dampen microglial‑driven neuroinflammation. Intervening in this pathway could complement existing antiretroviral regimens, potentially preserving cognitive function and improving quality of life for the growing population of aging individuals with HIV.

Original Description

EphB2-ephrin-B1 Signaling in Microglia and Implications for NeuroHIV | Marcus Kaul, Ph.D. (3/4/26) #neurohiv #johnshopkins #microglia http://https//www.hopkinsmedicine.org/neurology-neurosurgery/research/jhu-nimh/seminar-series