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HIF‐1 Targeting Intervention Renders Protection From Alzheimer's‐Like Pathology in a Humanized Mice Model of HIV Infection
Sudipta Ray, Mohit Kumar, Divya T. Chemparathy, Prasanta K. Dash, Susmita Sil. Journal of Extracellular Vesicles, 2025-11-01
Topic: Brain proteins, microglia and lab models
HIV-associated neurocognitive disorders (HAND) affect 30%-50% of individuals living with HIV on combination antiretroviral therapy, with Alzheimer 's-like pathology as a potent comorbidity of HAND. Our previous studies have implicated hypoxia-inducible factor-1 alpha (HIF-1α) as a central regulator of HIV-1 Tat-mediated amyloid production in astrocytes, which are further released via astrocyte-derived extracellular vesicles (ADEVs), inducing synaptodendritic injury and Alzheimer's-like pathology in naive mice. Based on this premise, we hypothesized that ADEVs carrying HIF-1α-targeting small interfering RNA (siRNA) would alleviate HIV-1-induced Alzheimer's-like pathology and neurodegeneration in CD34+ NSG HIV-infected humanized mice. Intranasally administered mCherry-TSG101-tagged ADEVs in mice demonstrated efficacy of brain delivery, especially to the hippocampus and cortex. In CD34+ NSG mice infected with HIV-1, intranasal delivery of HIF-1α siRNA-loaded ADEVs suppressed HIF-1α, reduced amyloid precursor protein (APP), AβmoC64, Aβ fibrils, and hyperphosphorylated tau (pTau), dampened glial activation as indicated by reduced GFAP and IBA1 expression, and partially restored synaptic proteins, which were dysregulated due to HIV-1 infection. Trends of improvement were also observed in behavioural deficits in spatial memory, anxiety-like behaviour, and sensorimotor gating induced by HIV-1. These findings position HIF-1α as a pivotal mediator of HIV-associated Alzheimer's-like pathology and neurodegeneration in the CD34+ NSG mice and underscore the promising role of ADEV-mediated HIF-1α siRNA delivery as a non-invasive therapeutic strategy for HAND.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Ray, S., Kumar, M., Chemparathy, D. T., Dash, P. K., & Sil, S. (2025). HIF‐1 Targeting Intervention Renders Protection From Alzheimer's‐Like Pathology in a Humanized Mice Model of HIV Infection. Journal of Extracellular Vesicles. https://doi.org/10.1002/jev2.70191
Vancouver
Ray S, Kumar M, Chemparathy DT, Dash PK, Sil S. HIF‐1 Targeting Intervention Renders Protection From Alzheimer's‐Like Pathology in a Humanized Mice Model of HIV Infection. Journal of Extracellular Vesicles. 2025. doi:10.1002/jev2.70191. PMID: 41216864.
BibTeX
@article{ray2025-41216864,
author = {Ray, Sudipta and Kumar, Mohit and Chemparathy, Divya T. and Dash, Prasanta K. and Sil, Susmita},
title = {{HIF‐1 Targeting Intervention Renders Protection From Alzheimer's‐Like Pathology in a Humanized Mice Model of HIV Infection}},
journal = {Journal of Extracellular Vesicles},
year = {2025},
doi = {10.1002/jev2.70191},
pmid = {41216864},
url = {https://doi.org/10.1002/jev2.70191}
}
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Key findings
- Intranasally administered mCherry-TSG101-tagged ADEVs in mice demonstrated efficacy of brain delivery, especially to the hippocampus and cortex.
- These findings position HIF-1α as a pivotal mediator of HIV-associated Alzheimer's-like pathology and neurodegeneration in the CD34+ NSG mice and underscore the promising role of ADEV-mediated HIF-1α siRNA delivery as a non-invasive therapeutic strategy for HAND.
Why it matters
In a humanized mouse model of HIV infection, intranasal delivery of extracellular vesicles carrying HIF-1alpha siRNA reduced Alzheimer's-like pathology including amyloid and tau, and partially restored synaptic proteins. This is an early animal study, and trends of improvement in behavioral deficits were observed, but it does not establish benefit in people with Alzheimer's disease.
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Study details
- Evidence strengthLow
How this study scored 37/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of Extracellular Vesicles) |
| Journal's citation record | 2 / 4 | Journal of Extracellular Vesicles: journal h-index 171 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “mice”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 6 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 3.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 6 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Susmita Sil: h-index 25 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | University of Nebraska Medical Center: institution h-index 666 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41216864) |
| Free to read | 2 / 2 | Free to read |
| Total | 37 / 100 | — |
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Read the original
- DOI: 10.1002/jev2.70191
- PubMed: 41216864
- Original source →
- Free full text: Journal of Extracellular Vesicles →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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