# HIV-1 mediated synaptodendritic injury and microglial activation:  Role of extracellular vesicle miRNAs

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $386,785

## Abstract

Abstract:
Reversible synaptodendritic injury and glial activation have emerged as important phenotypes and correlates of
HAND. Furthermore, persistent inflammation that has been implicated as a major underlying factor in the
progression and pathology of HAND, is likely attributable to the fact that following virus infection and formation
of the proviral DNA, antiretroviral therapy (ART) has no effect on the expression of viral gene products such as
Tat or gp120 that are lurking in tissues such as the CNS. Intriguingly, similar to HIV+ subjects on ART, SIV-
infected rhesus macaques on ART also demonstrate loss of synaptophysin, increased glial activation and
dysregulation of various signature microRNAs (miRs). MiR-mediated regulation of disease pathogenesis
represents an evolving area of research that has ramifications for the identification of potential therapeutic targets
for various neurodegenerative disorders, for which, currently there exists no cure. Parallel to the advances made
in miRNA research, there has also been the advent of the field of extracellular vesicles (EVs). EVs represent an
important mode of intercellular communication, by serving as conduits for the transfer of membrane and cytosolic
proteins, lipids and RNA (including miRs), between cells. Based on miRNA array data obtained from the brains
(basal ganglia) of SIV+ macaques, we hypothesize that HIV proteins modulate HAND neuropathology via two
complementary miR-associated mechanisms: a) HIV Tat-exposed astrocytes upregulate the expression and
release of miRs regulating synaptic plasticity in the EVs, which, following uptake by the neurons, cause
synaptodendritic injury and, b) HIV Tat-exposed astrocytes also upregulate the expression and release of
inflammation related miRs in the EVs, which, following uptake by the microglia (Mg), leads to their activation via
the TLR7-dependent pathway. The innovative aspect of this proposal is based on our unique observation that
HIV-protein exposed astrocytes release EVs containing a signature cargo of miRs, which are taken up by
neighboring neurons and Mg to induce synaptodendritic injury and activation, respectively. These experiments
will be brought full circle with an examination of functional studies aimed at uncovering the underlying
mechanisms of EV/miR-mediated synaptodendritic injury and glial activation in a Tat inducible transgenic model.

## Key facts

- **NIH application ID:** 10087000
- **Project number:** 5R01MH112848-05
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Shilpa J Buch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $386,785
- **Award type:** 5
- **Project period:** 2016-12-20 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10087000

## Citation

> US National Institutes of Health, RePORTER application 10087000, HIV-1 mediated synaptodendritic injury and microglial activation:  Role of extracellular vesicle miRNAs (5R01MH112848-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10087000. Licensed CC0.

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