# Role of proBNDF and p75NTR in HIV-mediated Axonal/Dendritic Degeneration

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2024 · $623,359

## Abstract

Abstract
Human immunodeficiency virus (HIV) does not infect neurons, yet dendritic simplification and loss of synapses
are still seen in a subset of people living with HIV, despite antiretroviral therapies. HIV can also cause
neurocognitive, motor, and behavioral impairments, a constellation of clinical signs grouped under a disease
termed HIV-associated neurocognitive disorder (HAND). Nevertheless, the underlying causes of the pathological
alterations observed in these individuals are poorly comprehended. Viral proteins, including the envelope protein
gp120, have emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanisms
remain unclear. Experimental evidence has shown that gp120 is endocytosed into neurons and is transported
within the axon to the endoplasmic reticulum (ER) where it causes a dysfunction of endoproteases such as furin,
among others. Furin is crucial for the processing of pro-brain-derived neurotrophic factor (BDNF) to mature
BDNF. proBDNF activates the neurotrophin receptor p75 (p75NTR), which has been shown to promote the loss
of synapses. In the previous grant cycle, we have shown that the removal of one allele of p75NTR rescues the
loss of dendritic synapses seen in gp120 transgenic mice. Therefore, we hypothesize that HIV, through gp120,
damages p75NTR positive synapses, thus driving synapto-dendritic degeneration observed in HAND. However,
the molecular and cellular mechanisms of how gp120, through p75NTR, damages synapses remain under
investigation. This application proposes a comprehensive set of experiments to test the main hypothesis. In
particular (Aim 1), we will utilize gp120 transgenic mice crossed with p75NTR-/- mice to investigate the molecular
mechanisms whereby activation of p75NTR by gp120-induced proBDNF leads to neuronal degeneration.
Because p75NTR plays a role in amyloid beta (Ab) processing, we will test the hypothesis that the loss of synapses
in HAND is due to Ab accumulation. In Aim 2, we will confirm that gp120 impairs the function of the ER by
carrying out a comprehensive analysis of ER stress in both gp120 transgenic mice and cortical neuronal cultures.
In Aim 3, we will use HIV negative and HIV positive human samples, including the cerebrospinal fluid (CSF), to
establish whether the presence of gp120 in human brains correlates with the degree of neurocognitive
impairments. We will determine the levels of gp120, markers of neuronal damage (e.g. microtubule associated
protein-2), inflammation, and levels of Ab in different subgroups of HAND subjects. Particular attention will be
paid to HAND subjects with APOE alleles that are considered neuroprotective (e.g. e2) or risk factors (e4). We
expect to provide new significant data on the role of p75NTR in HIV-mediated synaptic simplification. Knowledge
into the diverse role of p75NTR in HAND and other neurodegenerative diseases is likely to provide a better
understanding of these diseases and elucidate primary and adjuvant p7...

## Key facts

- **NIH application ID:** 11084650
- **Project number:** 2R01NS079172-11
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Italo Mocchetti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $623,359
- **Award type:** 2
- **Project period:** 2012-09-30 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11084650

## Citation

> US National Institutes of Health, RePORTER application 11084650, Role of proBNDF and p75NTR in HIV-mediated Axonal/Dendritic Degeneration (2R01NS079172-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11084650. Licensed CC0.

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