Brain virus burden and indoleamine‐2,3‐dioxygenase expression during lentiviral infection of rhesus monkey are concomitantly lowered by 6‐chloro‐2′,3′‐dideoxyguanosine

Abstract

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.

IDO expression in the brain: a double-edged sword

“…On the other hand, stimulated microglia synthesize high amounts of QUIN [46]. This in vitro observation is in line with the immune histological identification of IDO-positive microglia/macrophages in EAE and viral encephalitis [15,72]. Unfortunately, no marker exists to differentiate between intrinsic microglia and recruited macrophages.…”

“…HIV-infected macrophages within the CNS express IDO. The way of its induction by the virus is currently not clear, but it is plausible that IFN-γ or even virus particles themselves trigger it [72]. However, HIV-1 is known to persist within the CNS [73], and as discussed above, its persistence seems to involve IDO-mediated immune deviation [30].…”

Astrocyte Indoleamine 2,3-Dioxygenase Is Induced by the TLR3 Ligand Poly(I:C): Mechanism of Induction and Role in Antiviral Response

“…Paraffin-embedded sections of HIVE and control brains were obtained from the Manhattan HIV Brain Bank. Sections were boiled in citrate buffer for antigen unmasking and then incubated with anti-IDO antibody (78) for 16 h at 4°C followed by additional incubation at 37°C for 2 h. The staining was completed using the ABC methods described elsewhere (19). Control HIVE sections stained with normal mouse IgG1 revealed no immunoreactivity (not shown).…”

“…In the CNS, IDO has been shown to be induced in brain macrophages in simian immunodeficiency virus encephalitis (SIVE) in macaques, and its expression correlates with that of IFN-␥ (8,19). Consistent with a role for IDO in T-cell suppression, the IDO inhibitor 1-methyl tryptophan has recently been shown to increase viral clearance in a murine model of human immunodeficiency virus encephalitis (HIVE) (62).…”

Function of indoleamine 2,3‐dioxygenase in corneal allograft rejection and prolongation of allograft survival by over‐expression

“…Immunohistochemistry was performed as previously described [41]. Briefly, tissue embedded in paraffin was cut in 3-5-lmthick sections, dried at 55 C for 2 h and then deparaffinized in xylene for 20 min, followed by hydration through graded alcohols.…”