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

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.

Friend, Foe or Both? Immune Activity in Alzheimer’s Disease

“…In vitro studies show Aβ as having a greater potency compared to the archetypal human AMP LL-37 against microbes (Soscia et al, 2010). Further, in vivo and in vitro studies demonstrate how AMPs promote amyloid fibrilization for use in disruption of microbial cell membranes, neutralization of bacterial endotoxins and pathogen entrapment (Sood et al, 2008;Wang et al, 2014;Chai et al, 2017). Additionally, Aβ42-overexpressing cells are resistant to killing by yeast and bacteria (Eimer et al, 2018).…”

Persistent EcoHIV infection induces nigral degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated mice

“…(Kalia and Lang, 2015; Khanlou et al , 2009). However, there are few published reports that investigate the interplay between low-level HIV infection and development of neurodegenerative disease in animal and cellular model systems (Chai et al , 2017; Dickens et al , 2017; Jones et al , 2007; Meeker and Hudson, 2017). Therefore, we investigated the potential interactions between virus and chemically induced neurodegeneration.…”

HIV Neuroinfection and Alzheimer’s Disease: Similarities and Potential Links?

“…This led to cognitive impairment, as measured by recognition and Morris water maze tests (Zeinolabediny et al, 2017 ). Recently, APP metabolism in macrophage and microglia was reported to be modulated by HIV-1 Gag protein (Chai et al, 2017 ). The Gag polyprotein was shown to increase Aβ production and associated neurotoxicity by the activation of secretases.…”

“…The Gag polyprotein was shown to increase Aβ production and associated neurotoxicity by the activation of secretases. APP on the other hand, was reported to act as an antiviral factor by sequestering Gag in lipid rafts and restricting HIV-1 release (Chai et al, 2017 ). The balance between these two mechanisms (restriction and evasion), as well as the impact on Aβ peptide genesis will need further investigation.…”