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

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

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Article number1522
JournalNature communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

human immunodeficiency virus
Amyloid beta-Protein Precursor
Viruses
HIV-1
constrictions
proteins
Amyloid Precursor Protein Secretases
Amyloid
Alzheimer Disease
gag Gene Products
Macrophages
Poisons
Microglia
disorders
rafts
Virion
Neurons
HIV Infections
macrophages
degeneration

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

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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.",
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HIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration. / Chai, Qingqing; Jovasevic, Vladimir; Malikov, Viacheslav; Sabo, Yosef; Morham, Scott; Walsh, Derek; Naghavi, Mojgan H.

In: Nature communications, Vol. 8, No. 1, 1522, 01.12.2017.

Research output: Contribution to journalArticle

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AU - Morham, Scott

AU - Walsh, Derek

AU - Naghavi, Mojgan H.

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