| AJTR Copyright © 2009-present, All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711 |
Am J Transl Res 2012;4(3):302-315
Original Article
HIV-1 Tat-induced microglial activation and neuronal damage is
inhibited via CD45 modulation: a potential new treatment target for
HAND
Jingji Jin, Lucy Lam, Edin Sadic, Frank Fernandez, Jun Tan, Brian Giunta
Department of Psychiatry and Behavioral Neurosciences, Neuroimmunology Laboratory, University of South
Florida, Morsani College of Medicine, Tampa Bay, FL, 33613, USA; Department of Psychiatry and Behavioral
Neurosciences, Rashid Developmental Neurobiology Laboratory, Silver Child Development Center, University of
South Florida, Morsani College of Medicine, Tampa Bay, FL 33613, USA; Department of Molecular Medicine,
University of South, Morsani College of Medicine, Tampa Bay, FL 33613, USA; James A Haley Veterans
Administration Hospital, Tampa Bay, FL, 33612 USA
Received June 26, 2012; accepted July 19, 2012; Epub July 22, 2012; Published July 30, 2012
Abstract: Activated microglia represent a highly accurate correlate to neuronal death in HIV associated
neurocognitive disorders (HAND). Severity of dementia in persons with HAND is strongly correlated with the
number of activated microglia. Moreover, activation of microglial cells by HIV is associated with astrogliosis, and
severe neuronal loss. One cell surface receptor implicated in inhibiting microglial activation is the protein-tyrosine
phosphatase (PTP) protein, CD45. It is especially effective at inhibiting microglial activation because its action
takes place far upstream from proinflammatory intracellular mediators. To investigate the possible role of CD45
in microglial responsiveness to HIV-1 Tat protein, we treated BV2 microglia with a tyrosine phosphatase inhibitor
[potassium bisperoxo (1,10-phenanthroline) oxovanadate (phen), 5 micrometer] and HIV-1 Tat protein (700ng).
We found a synergistic pro-inflammatory microglial activation as supported by tumor necrosis factor alpha (TNF-
α) and interleukin 1-beta (IL-1β) release, both of which were dependent on p44/42 mitogen-activated protein
kinase (MAPK) activation. Stimulation of microglial CD45 by anti-CD45 antibody markedly inhibits these Tat or
Tat/Phen effects via inhibition of p44/42 MAPK, suggesting CD45 negatively regulates microglial activation. As a
validation of these findings in vivo, brains from a transgenic mice deficient for CD45 through complete genetic
ablation or by CNS delivery of CD45siRNA demonstrate markedly increased production of TNF-alpha 24 hours
after intracerebroventricular injection of HIV-Tat protein (5μg/mouse) compared to control mice. This increased
microglial activation was accompanied by astrogliosis and a significant loss of cortical neurons due to apoptosis
in CD45 deficient animals. These results suggest therapeutic agents that activate CD45 PTP signaling may be
effective in suppressing microglial activation associated with HAND. (AJTR1206006).
Keywords: HIV, dementia, CD45, microglia, HIV associated neurocognitive disorders
Address all correspondence to:
Dr. Brian Giunta
Department of Psychiatry and Behavioral Neurosciences
University of South Florida Morsani College of Medicine
3515 E. Fletcher Ave., MDT14, Tampa, FL 33613, USA.
Tel: +1 813 974 0616; Fax: +1 813 974 1130
E-mail: bgiunta@health.usf.edu
Original Article
HIV-1 Tat-induced microglial activation and neuronal damage is
inhibited via CD45 modulation: a potential new treatment target for
HAND
Jingji Jin, Lucy Lam, Edin Sadic, Frank Fernandez, Jun Tan, Brian Giunta
Department of Psychiatry and Behavioral Neurosciences, Neuroimmunology Laboratory, University of South
Florida, Morsani College of Medicine, Tampa Bay, FL, 33613, USA; Department of Psychiatry and Behavioral
Neurosciences, Rashid Developmental Neurobiology Laboratory, Silver Child Development Center, University of
South Florida, Morsani College of Medicine, Tampa Bay, FL 33613, USA; Department of Molecular Medicine,
University of South, Morsani College of Medicine, Tampa Bay, FL 33613, USA; James A Haley Veterans
Administration Hospital, Tampa Bay, FL, 33612 USA
Received June 26, 2012; accepted July 19, 2012; Epub July 22, 2012; Published July 30, 2012
Abstract: Activated microglia represent a highly accurate correlate to neuronal death in HIV associated
neurocognitive disorders (HAND). Severity of dementia in persons with HAND is strongly correlated with the
number of activated microglia. Moreover, activation of microglial cells by HIV is associated with astrogliosis, and
severe neuronal loss. One cell surface receptor implicated in inhibiting microglial activation is the protein-tyrosine
phosphatase (PTP) protein, CD45. It is especially effective at inhibiting microglial activation because its action
takes place far upstream from proinflammatory intracellular mediators. To investigate the possible role of CD45
in microglial responsiveness to HIV-1 Tat protein, we treated BV2 microglia with a tyrosine phosphatase inhibitor
[potassium bisperoxo (1,10-phenanthroline) oxovanadate (phen), 5 micrometer] and HIV-1 Tat protein (700ng).
We found a synergistic pro-inflammatory microglial activation as supported by tumor necrosis factor alpha (TNF-
α) and interleukin 1-beta (IL-1β) release, both of which were dependent on p44/42 mitogen-activated protein
kinase (MAPK) activation. Stimulation of microglial CD45 by anti-CD45 antibody markedly inhibits these Tat or
Tat/Phen effects via inhibition of p44/42 MAPK, suggesting CD45 negatively regulates microglial activation. As a
validation of these findings in vivo, brains from a transgenic mice deficient for CD45 through complete genetic
ablation or by CNS delivery of CD45siRNA demonstrate markedly increased production of TNF-alpha 24 hours
after intracerebroventricular injection of HIV-Tat protein (5μg/mouse) compared to control mice. This increased
microglial activation was accompanied by astrogliosis and a significant loss of cortical neurons due to apoptosis
in CD45 deficient animals. These results suggest therapeutic agents that activate CD45 PTP signaling may be
effective in suppressing microglial activation associated with HAND. (AJTR1206006).
Keywords: HIV, dementia, CD45, microglia, HIV associated neurocognitive disorders
Address all correspondence to:
Dr. Brian Giunta
Department of Psychiatry and Behavioral Neurosciences
University of South Florida Morsani College of Medicine
3515 E. Fletcher Ave., MDT14, Tampa, FL 33613, USA.
Tel: +1 813 974 0616; Fax: +1 813 974 1130
E-mail: bgiunta@health.usf.edu
 | |  | |  | |  | |  | |  | |  |