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

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2022 · $516,729

## Abstract

Abstract
Human immunodeficiency virus-1 (HIV) infection of the central nervous system damages synapses and
promotes neuronal injury that culminates in HIV-associated neurocognitive disorders (HAND). How HIV
damages synapses is still under investigation. Viral proteins, including the envelope protein gp120, have
emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanisms remain unclear.
The balance between neuronal survival and damage is predominantly governed by neurotrophic factors, and in
particular, brain-derived neurotrophic factor (BDNF) and its precursor proBDNF. proBDNF, when bound to the
neurotrophin receptor p75 (p75NTR) activates a pro-apoptotic signal. We have shown that brains of HAND
subjects, as well as neurons exposed to gp120, exhibit a significant increase of proBDNF, which correlates
with a decreased expression of furin, a key enzyme in the processing of proBDNF. The removal of one allele
of p75NTR, the receptor for proBDNF, rescues the loss of synapses seen in gp120 transgenic mice.
Therefore, we hypothesize that HIV damages synapses through the ability of gp120 to increase
proBDNF and therefore activating p75NTR. This is an important line of research because synaptic
degeneration dysfunction has been linked to numerous neurodegenerative diseases but only preliminarily to
HAND. The molecular and cellular mechanisms of how gp120 causes impairs/damages synapses remain
under investigation. This application proposes a comprehensive set of experiments to test the main hypothesis.
In particular (AIM 1), we will test the hypothesis that gp120 reduces furin levels by directly binding to this
endoprotease. We will utilize (AIM 2) p75NTR-/- neurons and p75NTR antagonists to examine the mechanisms
and signaling of gp120 neurotoxicity. We will perform behavioral studies for memory function (AIM 3) in gp120
transgenic (gp120tg) mice intercrossed with p75NTR null mice to investigate whether the removal of one allele
for p75NTR rescues the memory impairment observed in gp120tg mice. Finally, (AIM 4) we will use human
samples including the cerebrospinal fluid (CSF) to determine whether the levels of proBDNF are altered in
different subgroups of HAND subjects. Levels of gp120 will also be measured in the CSF. These experiments
might establish a correlation between levels of proBDNF, gp120 and neurocognitive impairment. We expect to
provide new significant data on the role of p75NTR in HIV-mediated synaptic simplification.

## Key facts

- **NIH application ID:** 10414965
- **Project number:** 5R01NS079172-09
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Italo Mocchetti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $516,729
- **Award type:** 5
- **Project period:** 2012-09-30 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10414965

## Citation

> US National Institutes of Health, RePORTER application 10414965, Role of proBNDF and p75NTR in HIV-mediated Axonal/Dendritic Degeneration (5R01NS079172-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10414965. Licensed CC0.

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