HIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration.
Nat Commun
; 8(1): 1522, 2017 11 15.
Article
em En
| MEDLINE
| ID: mdl-29142315
ABSTRACT
While beta-amyloid (Aß), 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 Aß 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 Aß isoforms. This Gag-mediated Aß 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
HIV-1
/
Precursor de Proteína beta-Amiloide
/
Microglia
/
Produtos do Gene gag do Vírus da Imunodeficiência Humana
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article