title: HIV-1 infected immune competent mononuclear phagocytes influence the pathways to neuronal demise.
abstract: Secretory products from HIV-1-infected immune-competent mononuclear phagocytes (MP) damage neuronal dendritic arbor (Zheng et al., 2001). The mechanism behind neuronal injury and whether it is species and/or viral strain dependent is not fully understood. To these ends, we investigated whether HIV-1-infected and lipopolysaccharide (LPS)-activated MDM elicit neuronal injury in primary human neurons. Neuronal damage was compared to that seen in rat neurons. Utilizing a spectrum of HIV-1 strains to infect human monocyte-derived macrophages (MDM), productive viral replication proved necessary, but not sufficient, for neuronal injury. Neuronal demise was induced by virion-free HIV-1-infected and immune-activated MDM culture supernatants. Maximal alterations in glutamate mediated neuronal signaling, resulted from exposure to secretory products from HIV-1-infected and immune-activated MDM. Apoptosis was the predominant mechanism of cell death induced by HIV-1-infected and LPS-treated MDM. Importantly, neuronal injury and increases in calcium influx mediated by HIV-1-infected and immune-activated MDM culture supernatants was partially blocked by the N-methyl D-aspartate (NMDA) receptor antagonist, MK 801. These data support a primary role for immune-activation in MP neurotoxic activities. The upregulation of NMDA receptor sensitive soluble factors and neuronal apoptosis by HIV-1-infected and immune-activated MDM provide unique insights into links between soluble factors, produced as a consequence of MP immunity, and neuronal demise in HAD.
authors.affiliation: The Center for Neurovirology and Neurodegenerative Disorders, Department of Pathology and Microbiology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5215, USA. jzheng@unmc.edu
authors.forename: J
authors.initials: J
authors.lastname: Zheng
authors.forename: M R
authors.initials: MR
authors.lastname: Thylin
authors.forename: Y
authors.initials: Y
authors.lastname: Persidsky
authors.forename: C E
authors.initials: CE
authors.lastname: Williams
authors.forename: R L
authors.initials: RL
authors.lastname: Cotter
authors.forename: W
authors.initials: W
authors.lastname: Zink
authors.forename: L
authors.initials: L
authors.lastname: Ryan
authors.forename: A
authors.initials: A
authors.lastname: Ghorpade
authors.forename: K
authors.initials: K
authors.lastname: Lewis
authors.forename: H E
authors.initials: HE
authors.lastname: Gendelman