Rebuilding Synaptic Architecture in HIV-1 Associated Neurocognitive Disease: A Therapeutic Strategy Based on Modulation of Mixed Lineage Kinase

Harris A. Gelbard, Stephen Dewhurst, Sanjay B. Maggirwar, Michelle Kiebala, Oksana Polesskaya, Howard E. Gendelman

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Work from our laboratories has validated mixed lineage kinase type 3 (MLK3) as an enzyme pathologically activated in the CNS by human immunodeficiency virus 1 (HIV-1) neurotoxins. In this review, we discuss MLK3 activation in the context of the neuropathogenesis of HIV-1 associated neurocognitive deficits (HAND). We use findings from the literature to substantiate the neuropathologic relevance of MLK3 to neurodegenerative disease, with an emphasis on Parkinson's disease that shares a number of important phenotypic and neuropathologic characteristics with HAND. We discuss signal transduction pathways downstream from MLK3 activation, with an emphasis on their involvement in microglia and neurons in preclinical models of HAND. Finally, we make a case for pharmacologic intervention targeted at inhibition of MLK3 as a strategy to reverse HAND, in light of the fact that combination antiretroviral therapy, despite successfully managing systemic infection of HIV-1, has been largely unsuccessful in eradicating HAND.

Original languageEnglish (US)
Pages (from-to)392-398
Number of pages7
JournalNeurotherapeutics
Volume7
Issue number4
DOIs
StatePublished - Oct 2010

Keywords

  • HIV-1
  • HIV-1 associated neurocognitive disease (HAND)
  • Microglia
  • Mixed lineage kinase type 3
  • Neuroinflammation
  • Neurotrophins
  • Synapse
  • Tat

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

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