# The role of amyloid precursor protein in HIV-1 replication and associated neurodegeneration

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $420,169

## Abstract

In many infected individuals, human immunodeficiency virus type 1 (HIV-1) enters the brain and can cause a
broad spectrum of HIV-1-associated neurocognitive disorders (HAND) ranging from mild impairments to severe
HIV-associated dementia (HAD). While widespread use of combination antiretroviral therapy (cART) has
effectively increased the life span of people living with HIV-1/AIDS (acquired immunodeficiency syndrome), the
prevalence of milder forms of HAND has also increased in the cART era. Indeed, recent epidemiological
studies indicate that greater than 50% of HIV-1 infected people in the USA develop HAND. As HIV-1 does not
infect neurons, HIV-1 infected macrophages and microglia (and possibly astrocytes) are thought to contribute
to neuronal dysfunction and death via a direct mechanism (production of viral proteins) or an indirect
“bystander” effect (production of cytokines and chemokines). Pathology studies have also shown that a chronic
state of HIV replication in the brain increases intra and possibly extracellular β-amyloid (Aβ), a classic hallmark
of Alzheimer's disease (AD) and dementia. However, how and why Aβ production is elevated by HIV-1
infection, and whether this contributes to neurodegeneration, remains unclear. Our preliminary data identifies
amyloid precursor protein (APP) as an innate restriction factor for both early and late HIV-1 infection in human
cells, including microglia. Moreover, we establish that HIV-1 overcomes this restriction by reducing APP levels,
but in doing so generates Aβ40 and Aβ42 products that are toxic to primary cortical neurons. In identifying the
underlying mechanism for further study, we find that APP is a novel HIV-1 matrix (MA) associated protein that
blocks early infection. By transfection of an infectious HIV-1 clone or Gag-expressing plasmids, we find that
increasing APP expression also binds HIV-1 Gag through its MA domain and potently suppresses late stage
HIV-1 budding, trapping Gag in specific membrane compartments. To escape this restriction, HIV-1 infection or
Gag alone promotes γ-secretase-dependent processing of APP. This results in elevated secretion of Aβ40 and
Aβ42 as determined by western blotting and ELISA, and can be blocked by γ-secretase inhibitors. Fractionated
supernatants from Gag-expressing cells cause toxicity in cultured primary cortical neurons, and is blocked by
treating Gag-expressing cells with γ-secretase inhibitors. Finally, regression analysis shows that neurotoxicity
in supernatants correlates precisely with Aβ levels under a variety of conditions in this system. In this proposal
we aim to determine the underlying mechanisms by which APP restricts HIV-1 infection, and how viral evasion
of this restriction through degradation of APP results in altered Aβ metabolism and neuronal damage. These
aims will make use of a wide range of innovative approaches including high-resolution live cell imaging and co-
culturing of microglia with neuronal cells in microfluidic chambe...

## Key facts

- **NIH application ID:** 9850647
- **Project number:** 5R01NS099064-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Mojgan Hosseini Naghavi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $420,169
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850647

## Citation

> US National Institutes of Health, RePORTER application 9850647, The role of amyloid precursor protein in HIV-1 replication and associated neurodegeneration (5R01NS099064-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9850647. Licensed CC0.

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