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Related Experiment Video

Updated: Jan 11, 2026

Humanized NOG Mice for Intravaginal HIV Exposure and Treatment of HIV Infection
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HIF-1 Targeting Intervention Renders Protection From Alzheimer's-Like Pathology in a Humanized Mice Model of HIV

Sudipta Ray1, Mohit Kumar1, Divya T Chemparathy1

  • 1Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Nebraska, USA.

Journal of Extracellular Vesicles
|November 11, 2025
PubMed
Summary

This study shows that delivering HIF-1α siRNA via astrocyte-derived extracellular vesicles (ADEVs) can reduce Alzheimer's-like pathology and neurodegeneration in HIV-infected mice, offering a potential therapy for HIV-associated neurocognitive disorders (HAND).

Keywords:
ADEVsAlzheimer's‐like pathologyHANDHIF‐1αsynaptodegeneration

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Area of Science:

  • Neuroscience
  • Virology
  • Genetics

Background:

  • HIV-associated neurocognitive disorders (HAND) are common, with Alzheimer's-like pathology as a significant comorbidity.
  • Hypoxia-inducible factor-1 alpha (HIF-1α) is implicated in HIV-1 Tat-mediated amyloid production and subsequent neurodegeneration.

Purpose of the Study:

  • To investigate if astrocyte-derived extracellular vesicles (ADEVs) carrying HIF-1α-targeting siRNA can alleviate HIV-1-induced Alzheimer's-like pathology and neurodegeneration.
  • To evaluate the therapeutic potential of ADEV-mediated siRNA delivery for HAND.

Main Methods:

  • Intranasal administration of mCherry-TSG101-tagged ADEVs in HIV-1 infected CD34+ NSG humanized mice.
  • Assessment of brain delivery, HIF-1α suppression, amyloid and tau pathology markers, glial activation, synaptic protein restoration, and behavioral deficits.

Main Results:

  • Intranasal ADEVs effectively delivered siRNA to the brain, particularly the hippocampus and cortex.
  • HIF-1α siRNA-loaded ADEVs suppressed HIF-1α, reduced amyloid precursor protein (APP), Aβ, and hyperphosphorylated tau (pTau).
  • Glial activation was dampened, synaptic proteins were partially restored, and behavioral deficits showed improvement.

Conclusions:

  • HIF-1α is a key mediator of HIV-associated Alzheimer's-like pathology and neurodegeneration in this model.
  • ADEV-mediated HIF-1α siRNA delivery represents a promising non-invasive therapeutic strategy for HAND.