Induction of interleukin-1β by human immunodeficiency virus-1 viral proteins leads to increased levels of neuronal ferritin heavy chain, synaptic injury, and deficits in flexible attention

Lindsay Festa, Christopher J. Gutoskey, Alessandro Graziano, Barry D. Waterhouse, Olimpia Meucci

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Synaptodendritic pruning and alterations in neurotransmission are the main underlying causes of HIV-associated neurocognitive disorders (HAND). Our studies in humans and nonhuman primates indicated that the protein ferritin heavy chain (FHC) is a critical player in neuronal changes and ensuing cognitive deficit observed in these patients. Here we focus on the effect of HIV proteins and inflammatory cytokines implicated in HAND on neuronal FHC levels, dendritic changes, and neurocognitive behavior. In two well characterized models of HAND (HIV transgenic and gp120-treated rats), we report reductions in spine density and dendritic branches in prefrontal cortex pyramidal neurons compared with age-matched controls. FHC brain levels are elevated in these animals, which also show deficits in reversal learning. Moreover, IL-1β, TNF-α, and HIV gp120 upregulate FHC in rat cortical neurons. However, although the inflammatory cytokines directly altered neuronal FHC, gp120 only caused significant FHC upregulation in neuronal/glial cocultures, suggesting that glia are necessary for sustained elevation of neuronal FHC by the viral protein. Although the envelope protein induced secretion of IL-1β and TNF-α in cocultures, TNF-α blockade did not affect gp120-mediated induction of FHC. Conversely, studies with an IL-1β neutralizing antibody or specific IL-1 receptor antagonist revealed the primary involvement of IL-1β in gp120-induced FHC changes. Furthermore, silencing of neuronal FHC abrogates the effect of gp120 on spines, and spine density correlates negatively with FHC levels or cognitive deficit. These results demonstrate that viral and host components of HIV infection increase brain expression of FHC, leading to cellular and functional changes, and point to IL-1β-targeted strategies for prevention of these alterations.

Original languageEnglish (US)
Pages (from-to)10550-10561
Number of pages12
JournalJournal of Neuroscience
Volume35
Issue number29
DOIs
StatePublished - Jul 22 2015

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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