The role of shed PrPc in the neuropathogenesis of HIV infection

Bezawit W. Megra, Eliseo Eugenin, Joan W. Berman

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

HIV-1 enters the CNS soon after peripheral infection and causes chronic neuroinflammation and neuronal damage that leads to cognitive impairment in 40-70% of HIV-infected people. The nonpathogenic cellular isoform of the human prion protein (PrPc) is an adhesion molecule constitutively expressed in the CNS. Previously, our laboratory showed that shed PrPc (sPrPc) is increased in the cerebrospinal fluid of HIV-infected people with cognitive deficits as compared with infected people with no impairment. In this article, we demonstrate that CCL2 and TNF-α, inflammatory mediators that are elevated in the CNS of HIV-infected people, increase shedding of PrPc from human astrocytes by increasing the active form of the metalloprotease ADAM10.We show that the consequence of this shedding can be the production of inflammatory mediators, because treatment of astrocytes with rPrPc increased secretion of CCL2, CXCL-12, and IL-8. Supernatants from rPrPc-treated astrocytes containing factors produced in response to this treatment, but not rPrPc by itself, cause increased chemotaxis of both uninfected and HIV-infected human monocytes, suggesting a role for sPrPc in monocyte recruitment into the brain. Furthermore, we examined whether PrPc participates in glutamate uptake and found that rPrPc decreased uptake of this metabolite in astrocytes, which could lead to neurotoxicity and neuronal loss. Collectively, our data characterize mediators involved in PrPc shedding and the effect of this sPrPc on monocyte chemotaxis and glutamate uptake from astrocytes. We propose that shedding of PrPc could be a potential target for therapeutics to limit the cognitive impairment characteristic of neuroAIDS.

Original languageEnglish (US)
Pages (from-to)224-232
Number of pages9
JournalJournal of Immunology
Volume199
Issue number1
DOIs
StatePublished - Jul 1 2017
Externally publishedYes

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Astrocytes
HIV Infections
HIV
Monocytes
Chemotaxis
Glutamic Acid
Metalloproteases
Interleukin-8
Cerebrospinal Fluid
HIV-1
Protein Isoforms
Therapeutics
Brain
Infection
Cognitive Dysfunction

ASJC Scopus subject areas

  • Immunology

Cite this

The role of shed PrPc in the neuropathogenesis of HIV infection. / Megra, Bezawit W.; Eugenin, Eliseo; Berman, Joan W.

In: Journal of Immunology, Vol. 199, No. 1, 01.07.2017, p. 224-232.

Research output: Contribution to journalArticle

Megra, Bezawit W. ; Eugenin, Eliseo ; Berman, Joan W. / The role of shed PrPc in the neuropathogenesis of HIV infection. In: Journal of Immunology. 2017 ; Vol. 199, No. 1. pp. 224-232.
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