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

doi:10.1038/s41467-017-01795-8

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 journal › Article › peer-review

46 Scopus citations

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 language	English (US)
Article number	1522
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-01795-8
State	Published - Dec 1 2017

Funding

We thank Olivier Schwartz, Thomas Hope and Robert Vassar for reagents and advice and Katherine Sadleir and Kayla Schipper for technical help. The following reagent was obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: pNL4-3 from Dr. Malcom Martin, pNL4-3.Luc.R−.E− from Dr. Nathaniel Landau, and TZM-bl from Dr. John C. Kappes, Dr. Xiaoyun Wu and Tran-zyme Inc. This study was supported by National Institute of Health (NIH) grant P01GM105536 to D.W. and grant R01GM101975, P01GM105536 and R01NS099064 to M.H.N. and with help from the Third Coast Center for AIDS Research (cFAR), an NIH funded center (P30AI117943).

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-017-01795-8

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.",

author = "Qingqing Chai and Vladimir Jovasevic and Viacheslav Malikov and Yosef Sabo and Scott Morham and Derek Walsh and Naghavi, {Mojgan H.}",

note = "Funding Information: We thank Olivier Schwartz, Thomas Hope and Robert Vassar for reagents and advice and Katherine Sadleir and Kayla Schipper for technical help. The following reagent was obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: pNL4-3 from Dr. Malcom Martin, pNL4-3.Luc.R−.E− from Dr. Nathaniel Landau, and TZM-bl from Dr. John C. Kappes, Dr. Xiaoyun Wu and Tran-zyme Inc. This study was supported by National Institute of Health (NIH) grant P01GM105536 to D.W. and grant R01GM101975, P01GM105536 and R01NS099064 to M.H.N. and with help from the Third Coast Center for AIDS Research (cFAR), an NIH funded center (P30AI117943). Publisher Copyright: {\textcopyright} 2017 The Author(s).",

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AU - Morham, Scott

AU - Walsh, Derek

AU - Naghavi, Mojgan H.

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N2 - 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

Abstract

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UN SDGs

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