Rebuilding synaptic architecture in HIV-1 associated neurocognitive disease: a therapeutic strategy based on modulation of mixed lineage kinase.
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.
Gelbard
Harris A
HA
Center for Neural Development and Disease, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA. harris_gelbard@urmc.rochester.edu
Dewhurst
Stephen
S
Maggirwar
Sanjay B
SB
Kiebala
Michelle
M
Polesskaya
Oksana
O
Gendelman
Howard E
HE
D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology* / Q000821:virology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D004791:Enzyme Inhibitors; D020930:MAP Kinase Kinase Kinases; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11