Neurotherapeutics

, Volume 7, Issue 4, pp 392–398

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
Review Article

DOI: 10.1016/j.nurt.2010.08.001

Cite this article as:
Gelbard, H.A., Dewhurst, S., Maggirwar, S.B. et al. Neurotherapeutics (2010) 7: 392. doi:10.1016/j.nurt.2010.08.001

Summary

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.

Key Words

HIV-1 HIV-1 associated neurocognitive disease (HAND) microglia mixed lineage kinase type 3 neuroinflammation neurotrophins synapse tat 
Download to read the full article text

Copyright information

© Springer 2010

Authors and Affiliations

  • Harris A. Gelbard
    • 1
    • 2
    • 3
    • 4
  • Stephen Dewhurst
    • 4
  • Sanjay B. Maggirwar
    • 4
  • Michelle Kiebala
    • 4
  • Oksana Polesskaya
    • 4
  • Howard E. Gendelman
    • 5
  1. 1.Center for Neural Development and DiseaseUniversity of Rochester School of Medicine and DentistryRochester
  2. 2.Department of Neurology (Child Neurology Division)University of Rochester School of Medicine and DentistryRochester
  3. 3.Department of PediatricsUniversity of Rochester School of Medicine and DentistryRochester
  4. 4.Department of Microbiology and ImmunologyUniversity of Rochester School of Medicine and DentistryRochester
  5. 5.Department of Pharmacology and Experimental NeuroscienceUniversity of Nebraska Medical CenterOmaha

Personalised recommendations