Soluble HIV-1 infected macrophage secretory products mediate blockade of long-term potentiation: A mechanism for cognitive dysfunction in HIV-1-associated dementia

Huangui Xiong, Yong Chun Zeng, Jialin Zheng, Michael Thylin, Howard E. Gendelman

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

It is generally accepted that viral and cellular products from immune competent mononuclear phagocytes (MP) (brain macrophages and microglia) underlie the neuropathogenesis of HIV-1-associated dementia (HAD). What remains unanswered, however, is the composition of and mechanisms for such MP-induced neurological dysfunctions. In attempts to address these issues culture fluids from HIV-1(ADA)-infected monocyte derived macrophages (MDMs) (depleted or enriched with progeny virus) were placed onto the CA1 area of rat hippocampal brain slices (the site of mammalian learning and memory) and neuronal long-term potentiation (LTP) assayed. LTP was induced by high frequency stimulation (HFS). Lipopolysaccharide (LPS) served as a surrogate macrophage activator. Synaptic strength was assayed by the initial slope of evoked field excitatory postsynaptic potentials (EPSPs). Synaptic potentiation following HFS was observed in slices incubated with uninfected (control) MDM culture fluids. The magnitude of the LTP response was 150.2 ± 21.10% compared to basal levels (n = 6). Synaptic strength was enhanced in virus-infected (135.7 ± 28.9%, n = 8) and LPS-activated MDM (123.3 ± 5.1%, n = 7) but at lower levels than controls. The lowest levels of LTP were in brain slices incubated with virus-infected and LPS-activated MDM fluids at (109.5 ± 9.9% n = 12). Interestingly, bath application of progeny HIV-1 virions showed minimal LTP effects. Virus-infected, LPS-activated MDM fluids, with progeny virus, reduced synaptic strength but were not statistically different than replicate culture fluids depleted of virus. In contrast, IL-1β and quinolinic acid, significantly diminished synaptic strength. These results, taken together, suggest that soluble HIV-1-infected MDM secretory products, but not virus per se, significantly affect LTP. This electrophysiological system, which monitors neuronal function following cell exposure to HIV-1 infected materials could provide a novel testing ground for therapeutics designed to protect brain function in HAD.

Original languageEnglish (US)
Pages (from-to)519-528
Number of pages10
JournalJournal of neurovirology
Volume5
Issue number5
DOIs
StatePublished - Oct 1999

Keywords

  • HIV-1-associated dementia
  • Hippocampal slices
  • Human immunodeficiency virus
  • Long-term potentiation
  • Monocyte-derived macrophages
  • Neurotoxicity

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Virology

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