Lipocalin-2 mediates HIV-1 induced neuronal injury and behavioral deficits by overriding CCR5-dependent protection

Brain Behav Immun. 2020 Oct;89:184-199. doi: 10.1016/j.bbi.2020.06.016. Epub 2020 Jun 11.

Abstract

People living with HIV (PLWH) continue to develop HIV-associated neurocognitive disorders despite combination anti-retroviral therapy. Lipocalin-2 (LCN2) is an acute phase protein that has been implicated in neurodegeneration and is upregulated in a transgenic mouse model of HIV-associated brain injury. Here we show that LCN2 is significantly upregulated in neocortex of a subset of HIV-infected individuals with brain pathology and correlates with viral load in CSF and pro-viral DNA in neocortex. However, the question if LCN2 contributes to HIV-associated neurotoxicity or is part of a protective host response required further investigation. We found that the knockout of LCN2 in transgenic mice expressing HIVgp120 in the brain (HIVgp120tg) abrogates behavioral impairment, ameliorates neuronal damage, and reduces microglial activation in association with an increase of the neuroprotective CCR5 ligand CCL4. In vitro experiments show that LCN2 neurotoxicity also depends on microglia and p38 MAPK activity. Genetic ablation of CCR5 in LCN2-deficient HIVgp120tg mice restores neuropathology, suggesting that LCN2 overrides neuroprotection mediated by CCR5 and its chemokine ligands. RNA expression of 168 genes involved in neurotransmission reveals that neuronal injury and protection are each associated with genotype- and sex-specific patterns affecting common neural gene networks. In conclusion, our study identifies LCN2 as a novel factor in HIV-associated brain injury involving CCR5, p38 MAPK and microglia. Furthermore, the mechanistic interaction between LCN2 and CCR5 may serve as a diagnostic and therapeutic target in HIV patients at risk of developing brain pathology and neurocognitive impairment.

Keywords: Behavior; CCR5; HIV gp120-transgenic; HIV neuropathology; HIV-associated neurocognitive disorders; Knockout; Lipocalin-2; Neurodegeneration; Sexual dimorphism; p38 MAPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Proteins / genetics
  • Animals
  • HIV Infections* / complications
  • HIV-1* / metabolism
  • Humans
  • Lipocalin-2 / genetics
  • Mice
  • Neurons / metabolism
  • Receptors, CCR5 / genetics

Substances

  • Acute-Phase Proteins
  • CCR5 protein, human
  • Lipocalin-2
  • Receptors, CCR5