Brain virus burden and indoleamine-2,3-dioxygenase expression during lentiviral infection of rhesus monkey are concomitantly lowered by 6-chloro-2',3'-dideoxyguanosine.
Increased kynurenine pathway metabolism has been implicated in the aetiology of lentiviral encephalopathy. Indoleamine-2,3-dioxygenase (IDO) initiates the increased production of kynurenine pathway metabolites like quinolinic acid (QUIN). QUIN itself is elevated in AIDS-diseased monkey and human brain parenchyma and cerebrospinal fluid at levels excitotoxic for neurons in vitro. This study investigates the cellular origin of IDO biosynthesis in the brain of rhesus monkeys infected with simian immunodeficiency virus (SIV) and explores the effects of CNS-permeant antiretroviral treatment. IDO transcript and protein were absent from the brain of non-infected and SIV-infected asymptomatic monkeys. IDO biosynthesis was induced in the brain of monkeys exhibiting AIDS. Nodule and multinucleated giant cell-forming macrophages were the main sources of IDO synthesis. Treatment with the lipophilic 6-chloro-2',3'-dideoxyguanosine suppressed IDO expression in the brain of AIDS-diseased monkeys. The effectiveness of this treatment was confirmed by the reduction of virus burden and SIV-induced perivascular infiltrates, mononuclear nodules and multinucleated giant cells. Our data demonstrate that brain IDO biosynthesis is induced in a subset of monocyte-derived cells, depends on viral burden and is susceptible to antiretroviral treatment. Thus, IDO induction is associated with reversible overt inflammatory events localized to areas of active viral replication in the SIV-infected brain.
Depboylu
Candan
C
Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University, Marburg, Germany.
Reinhart
Todd A
TA
Takikawa
Osamu
O
Imai
Yoshinori
Y
Maeda
Hitomi
H
Mitsuya
Hiroaki
H
Rausch
Dianne
D
Eiden
Lee E
LE
Weihe
Eberhard
E
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000821:virology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D053379:Chromogranin A; D002864:Chromogranins / Q000378:metabolism; D004268:DNA-Binding Proteins; D016049:Didanosine / Q000627:therapeutic use; D015224:Dideoxynucleosides / Q000627:therapeutic use*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006651:Histocytochemistry / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016180:Lentivirus Infections / Q000188:drug therapy; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000378:metabolism; D008840:Microfilament Proteins; D018613:Microscopy, Confocal / Q000379:methods; D012333:RNA, Messenger / Q000096:biosynthesis; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects*; D013997:Time Factors; D014366:Tryptophan Oxygenase / Q000096:biosynthesis* / Q000097:blood; D014759:Viral Envelope Proteins / Q000378:metabolism
C113088:6-chloro-2',3'-dideoxyinosine; C112986:AIF1 protein, human; D000998:Antiviral Agents; D002135:Calcium-Binding Proteins; D053379:Chromogranin A; D002864:Chromogranins; D004268:DNA-Binding Proteins; D015224:Dideoxynucleosides; D005904:Glial Fibrillary Acidic Protein; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D012333:RNA, Messenger; D014759:Viral Envelope Proteins; C069623:gp120 protein, Simian immunodeficiency virus; D014366:Tryptophan Oxygenase; D016049:Didanosine