# Astrocytic HIF-1a as a therapeutic target for Alzheimer's-like comorbidity of HAND

> **NIH NIH R21** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $420,895

## Abstract

Abstract
Although the lifespan of individuals living with HIV-1 has increased significantly owing to effective combination anti-
retroviral therapy (cART), paradoxically however, in almost 50% of infected individuals there is increased prevalence
of HIV-1-associated neurocognitive disorders (HAND), which remains an important comorbidity. It is suggested that
persistence of cytotoxic viral protein such as HIV-1 Tat that accumulates despite cART, could likely contribute to this
process. Additionally, reports on Alzheimer’s like pathology in patients with HAND are also extant, likely attributable
to the action of both HIV-1 infection and the cytotoxic viral Tat protein in neurons and endothelial cells. A recent study
from our lab has shown that HIV-1 Tat could also induce amyloidosis in yet another cell type, the astrocytes, via the
HIF-1α-BACE1-antisense (AS) pathway in an in vitro model. Validation of these findings was also demonstrated in
the brains of SIV-infected macaques & HIV-infected patients’ samples, and this amyloids could be an important
contributing factor to neurotoxicity associated with HAND. Based on our recent report that astrocytes can produce
amyloids following exposure to Tat, we hypothesized that the toxic amyloid forms secreted by Tat-stimulated
astrocytes in the astrocyte-derived extracellular vesicles (ADEVs) could be taken up by the neuorns, resulting in
exacerbated neuronal injury. The concept of uptake by neurons of astrocyte released amyloids via the ADEVs is a
novel idea and has never been explored before. In this exploratory R21 proposal, we will test the hypothesis in two
aims: Aim 1: a) Determine how HIF-1α regulates HIV-1 Tat-mediated release of ADEVs carrying neurotoxic amyloids
(Aβ 1-42) cargoes which, in turn, can be taken up by the neurons, leading to synaptodendritic injury, and Aim 2: b)
Determine how the delivery of HIF-1A siRNA via the ADEV cargoes can inhibit amyloidosis and the associated
cognitive decline in two relevant rodent models of HAND- inducible transgenic Tat mice model as well as the
humanized mice model of HIV infection. These findings could have ramifications for future development of adjunctive
therapeutic interventions targeting astrocytic HIF-1α for treatment of neurological disorders in HIV patients on cART
therapy.

## Key facts

- **NIH application ID:** 10161502
- **Project number:** 1R21AG069541-01A1
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Susmita Sil
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $420,895
- **Award type:** 1
- **Project period:** 2020-09-10 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10161502

## Citation

> US National Institutes of Health, RePORTER application 10161502, Astrocytic HIF-1a as a therapeutic target for Alzheimer's-like comorbidity of HAND (1R21AG069541-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10161502. Licensed CC0.

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