EGCG mitigates neurotoxicity mediated by HIV-1 proteins gp120 and Tat in the presence of IFN-gamma: role of JAK/STAT1 signaling and implications for HIV-associated dementia.
Human immunodeficiency virus (HIV)-1 infection of the central nervous system occurs in the vast majority of HIV-infected patients. HIV-associated dementia (HAD) represents the most severe form of HIV-related neuropsychiatric impairment and is associated with neuropathology involving HIV proteins and activation of proinflammatory cytokine circuits. Interferon-gamma (IFN-gamma) activates the JAK/STAT1 pathway, a key regulator of inflammatory and apoptotic signaling, and is elevated in HIV-1-infected brains progressing to HAD. Recent reports suggest green tea-derived (-)-epigallocatechin-3-gallate (EGCG) can attenuate neuronal damage mediated by this pathway in conditions such as brain ischemia. In order to investigate the therapeutic potential of EGCG to mitigate the neuronal damage characteristic of HAD, IFN-gamma was evaluated for its ability to enhance well-known neurotoxic properties of HIV-1 proteins gp120 and Tat in primary neurons and mice. Indeed, IFN-gamma enhanced the neurotoxicity of gp120 and Tat via increased JAK/STAT signaling. Additionally, primary neurons pretreated with a JAK1 inhibitor, or those derived from STAT1-deficient mice, were largely resistant to the IFN-gamma-enhanced neurotoxicity of gp120 and Tat. Moreover, EGCG treatment of primary neurons from normal mice reduced IFN-gamma-enhanced neurotoxicity of gp120 and Tat by inhibiting JAK/STAT1 pathway activation. EGCG was also found to mitigate the neurotoxic properties of HIV-1 proteins in the presence of IFN-gamma in vivo. Taken together, these data suggest EGCG attenuates the neurotoxicity of IFN-gamma augmented neuronal damage from HIV-1 proteins gp120 and Tat both in vitro and in vivo. Thus EGCG may represent a novel natural copound for the prevention and treatment of HAD.
Giunta
Brian
B
Neuroimmunology Laboratory, Silver Child Development Center, Institute for Research in Psychiatry, Department of Psychiatry and Behavioral Medicine, University of South Florida, 3515 East Fletcher Avenue Tampa, Florida, 33613, USA.
Obregon
Demian
D
Neuroimmunology Laboratory, Silver Child Development Center, Institute for Research in Psychiatry, Department of Psychiatry and Behavioral Medicine, University of South Florida, 3515 East Fletcher Avenue Tampa, Florida, 33613, USA.
Hou
Hauyan
H
Neuroimmunology Laboratory, Silver Child Development Center, Institute for Research in Psychiatry, Department of Psychiatry and Behavioral Medicine, University of South Florida, 3515 East Fletcher Avenue Tampa, Florida, 33613, USA.
Zeng
Jin
J
Neuroimmunology Laboratory, Silver Child Development Center, Institute for Research in Psychiatry, Department of Psychiatry and Behavioral Medicine, University of South Florida, 3515 East Fletcher Avenue Tampa, Florida, 33613, USA.
Sun
Nan
N
Neuroimmunology Laboratory, Silver Child Development Center, Institute for Research in Psychiatry, Department of Psychiatry and Behavioral Medicine, University of South Florida, 3515 East Fletcher Avenue Tampa, Florida, 33613, USA.
Nikolic
Veljko
V
Neuroimmunology Laboratory, Silver Child Development Center, Institute for Research in Psychiatry, Department of Psychiatry and Behavioral Medicine, University of South Florida, 3515 East Fletcher Avenue Tampa, Florida, 33613, USA.
Ehrhart
Jared
J
Neuroimmunology Laboratory, Silver Child Development Center, Institute for Research in Psychiatry, Department of Psychiatry and Behavioral Medicine, University of South Florida, 3515 East Fletcher Avenue Tampa, Florida, 33613, USA.
Shytle
Douglas
D
Neuroimmunology Laboratory, Silver Child Development Center, Institute for Research in Psychiatry, Department of Psychiatry and Behavioral Medicine, University of South Florida, 3515 East Fletcher Avenue Tampa, Florida, 33613, USA.|Center for Excellence in Aging and Brain Repair, Department of Neurosurgery; University of South Florida, 3515 East Fletcher Avenue Tampa, Florida, 33613, USA.
Fernandez
Francisco
F
Neuroimmunology Laboratory, Silver Child Development Center, Institute for Research in Psychiatry, Department of Psychiatry and Behavioral Medicine, University of South Florida, 3515 East Fletcher Avenue Tampa, Florida, 33613, USA.
Tan
Jun
J
Neuroimmunology Laboratory, Silver Child Development Center, Institute for Research in Psychiatry, Department of Psychiatry and Behavioral Medicine, University of South Florida, 3515 East Fletcher Avenue Tampa, Florida, 33613, USA.|Center for Excellence in Aging and Brain Repair, Department of Neurosurgery; University of South Florida, 3515 East Fletcher Avenue Tampa, Florida, 33613, USA.
D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002392:Catechin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002478:Cells, Cultured; D005260:Female; D015696:Gene Products, tat / Q000276:immunology / Q000633:toxicity; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000633:toxicity; D015497:HIV-1 / Q000276:immunology*; D007371:Interferon-gamma / Q000009:adverse effects / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009498:Neurotoxins / Q000276:immunology / Q000633:toxicity; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D015699:HIV Envelope Protein gp120; D018696:Neuroprotective Agents; D009498:Neurotoxins; D050794:STAT1 Transcription Factor; D054322:tat Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma; D002392:Catechin; C045651:epigallocatechin gallate; D053612:Janus Kinases