Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis

Abstract

IntroductionThe pathogenesis of HIV-1 infection is linked to dysfunction and depletion of CD4 ϩ T lymphocytes. [1][2][3] The virus persists and disseminates over years, despite an apparently intact host immune response. The inability to eliminate HIV-1 suggests that negativeregulatory (tolerogenic) signals may shield HIV-1 from adaptive immune clearance. 4,5 However, the specific mechanisms by which the virus might protect itself from clearance remain unresolved.HIV-1 is known to persist at low levels within the central nervous system (CNS) during most of the disease course. 6 Significant productive HIV-1 replication occurs in brain mononuclear phagocytes (MPs; perivascular macrophages and microglia) during late stages of infection only in a subset of individuals with severe immune suppression and high peripheral viral loads. Secretory viral and cellular products from HIV-1-infected and immune competent brain MPs are known to induce neuronal dysfunction and injury. [7][8][9] These include virotoxins such as Tat, Nef, and gp120 and cellular toxins such as proinflammatory cytokines, chemokines, arachidonic acid and its metabolites, platelet activating factor, nitric oxide, and quinolinic acid. Indoleamine 2,3-dioxygenase (IDO) is the first and the rate-limiting enzyme in the generation of quinolinic acid from tryptophan via the kynurenine pathway. 10 An increase of functional IDO enzymatic activity in the brain could lead to enhanced production of neurotoxins, resulting in neurocognitive dysfunction and HIV-1-associated dementia (HAD). 11-13 Signs of increased IDO activity correlate with tryptophan depletion, progression of systemic and brain HIV-1 infection, and HAD. 14,15 Accumulating evidence suggests that IDO serves immunoregulatory and tolerogenic functions. [16][17][18][19][20][21] It appears that certain antigen presenting cells (APCs) may regulate T-cell responses through the expression of IDO. 22 A number of studies indicate that IDO overexpression by APCs may result in immune suppression and reduced T-cell responses. 17,18,20,[23][24][25] Therefore, HIV-induced IDO activity in the brain may participate not only in local neurotoxicity, but also in the failure of the immune system to clear HIV from this reservoir.A strong association between HAD and profound immunodeficiency supports the notion that a lack of effective adaptive immune responses is associated with ongoing viral replication in the brain. One plausible explanation is that circulating HIV-1-specific CD8 ϩ cells could be partially anergic and may be unable to eliminate HIV-1-infected cells in vivo in the setting of functionally impaired helper CD4 ϩ T cells during late stages of infection. 26,27 Based on these observations, we hypothesize that IDOexpressing APCs (specifically, HIV-1-infected macrophages) might help to create a protected reservoir for HIV-1 persistence in the brain. To test this idea we used a mouse model of HIV-1 For personal use only. on June 19, 2019. by guest www.bloodjournal.org From encephalitis (HIVE) in which nonobese di...

The Tryptophan Metabolite 3-Hydroxyanthranilic Acid Plays Anti-Inflammatory and Neuroprotective Roles During Inflammation

“…Data were expressed as percentage of inhibition by 3-HAA calculated as follows: 100 ϫ (1 Ϫ cytokine produced in the presence of 3-HAA/cytokine produced by stimulus alone). The compiled results from multiple [5][6][7] independent experiments are shown in Figure 2, B and C. A single-sample t-test was performed to determine whether the inhibition by 3-HAA was significant.…”

“…IDO expressed in antigen-presenting cells (dendritic cells, macrophages, and microglia) can suppress T-cell immunity against viruses, tumors, or transplanted tissues by suppressing T-cell proliferation. 1,6,7 IDO induces immune tolerance through tryptophan depletion from T cells but also through generation of KP metabolites, such as 3-hydroxyanthranilic acid (3-HAA). 8,9 In line with these findings, administration of 3-hydroxykynurenine (3-HK), 3-HAA, or its synthetic analog in mice has been shown to induce a T-cell phenotype change from T H 1 to T H 2 and to ameliorate experimental autoimmune encephalomyelitis in an animal model of multiple sclerosis.…”

Insights into End-Organ Injury in HIV Infection

“…16 Although host-specific differences exist between HIV and SIV infection, the macaque model provides a more relevant model for human disease as compared to other models (like humanized mouse models where infectious HIV-1 is used), 19 which do not allow studies of macrophage turnover in the natural host, limiting their utility for studies performed by Nowlin et al 3 Findings by Nowlin et al 3 also emphasize that development of SIVE is a late event in the infection process, secondary to the loss of immune function and lack of virus suppression in the periphery. 18 Monocytes (particularly more mature CD16 þ monocytes) 20 can be infected with HIV. Their pattern of migration or organ infiltration might be different from other subpopulations in peripheral blood.…”

“…4 Before introduction of ART, an uncontrolled infection in the brain leads to HIV-1 encephalitis, which occurs in immunosuppressed patients because of the depletion of CD4 þ T lymphocytes, thereby resulting in inadequate immune control over HIV-1 replication in the CNS and other organs. 18 Diagnostic hallmarks of HIV-1…”

Natural Product-Inspired Pyranonaphthoquinone Inhibitors of Indoleamine 2,3-Dioxygenase-1 (IDO-1)

“…[6] The overexpression of IDO-1 has now been identified in a range of human pathologies including Alzheimer's disease, asthma, depression, age-related cataract formation, and HIV-encephalitis. [7][8][9][10][11] It has also been found to be upregulated in a wide range of human tumours and has recently emerged as a possible explanation for the immune escape exhibited by cancer cells, in a mechanism similar to that found in fetal tissue. This hypothesis, together with its expression in such a large number of human diseases has firmly established IDO-1 as an appealing drug target.…”