HIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration

Qingqing Chai,Derek Walsh,Mojgan H Naghavi,Yosef Sabo,Scott Morham,Vladimir Jovasevic,Viacheslav Malikov

doi:10.1038/s41467-017-01795-8

Abstract

While beta-amyloid (Aβ), a classic hallmark of Alzheimer’s disease (AD) and dementia, has long been known to be elevated in the human immunodeficiency virus type 1 (HIV-1)-infected brain, why and how Aβ is produced, along with its contribution to HIV-associated neurocognitive disorder (HAND) remains ill-defined. Here, we reveal that the membrane-associated amyloid precursor protein (APP) is highly expressed in macrophages and microglia, and acts as an innate restriction against HIV-1. APP binds the HIV-1 Gag polyprotein, retains it in lipid rafts and blocks HIV-1 virion production and spread. To escape this restriction, Gag promotes secretase-dependent cleavage of APP, resulting in the overproduction of toxic Aβ isoforms. This Gag-mediated Aβ production results in increased degeneration of primary cortical neurons, and can be prevented by γ-secretase inhibitor treatment. Interfering with HIV-1’s evasion of APP-mediated restriction also suppresses HIV-1 spread, offering a potential strategy to both treat infection and prevent HAND.

Highlights

While beta-amyloid (Aβ), a classic hallmark of Alzheimer’s disease (AD) and dementia, has long been known to be elevated in the human immunodeficiency virus type 1 (HIV-1)-infected brain, why and how Aβ is produced, along with its contribution to HIV-associated neurocognitive disorder (HAND) remains ill-defined
We identify a function for amyloid precursor protein (APP) as an innate antiviral defense factor in macrophages and microglia that restricts HIV-1 release
By identifying a viral evasion mechanism that leads to the production of neurotoxic Aβ42, our findings address fundamental questions about how and why Aβ levels are elevated in the brains of HIV-1-infected patients, and whether this contributes to neuronal damage

Summary

Introduction

While beta-amyloid (Aβ), a classic hallmark of Alzheimer’s disease (AD) and dementia, has long been known to be elevated in the human immunodeficiency virus type 1 (HIV-1)-infected brain, why and how Aβ is produced, along with its contribution to HIV-associated neurocognitive disorder (HAND) remains ill-defined. We reveal that APP is highly expressed in macrophages and microglia, natural target cells for HIV-1 infection in the brain, and acts as an innate restriction factor that sequesters the HIV-1 Gag polyprotein in lipid rafts to block virus production and spread. To evade this restriction, HIV-1 Gag subverts host secretases to cleave APP and clear membrane-associated CTFs, but in doing so results in increased Aβ production that causes the degeneration of cultured primary cortical neurons. Our findings explain how and why infection leads to Aβ production and its contribution to neuronal damage, revealing an antiviral activity of APP that could potentially be exploited to treat both HIV-1 infection and neurodegeneration

Methods

Results

Conclusion