GET THE APP

Immune Modulators of HIV Infection: The Role of Reactive Oxygen S
Journal of Clinical and Cellular Immunology

Journal of Clinical and Cellular Immunology
Open Access

ISSN: 2155-9899

+44 1223 790975

Research Article - (2012) Volume 3, Issue 2

Immune Modulators of HIV Infection: The Role of Reactive Oxygen Species

Siham Salmen* and Lisbeth Berrueta*
Institute of Clinical Immunology, University of Los Andes, Merida, Venezuela
*Corresponding Author(s): Siham Salmen, Instituto de Inmunología Clínica, Universidad de Los Andes, Edificio Louis Pasteur, Merida, Venezuela, Tel: (58) 274-2403188, Fax: (58) 274-2403187 Email:
Lisbeth Berrueta, Instituto de Inmunología Clínica, Universidad de Los Andes, Edificio Louis Pasteur, Merida, Venezuela, Tel: (58) 274-2403226, Fax: (58) 74-403226 Email:

Abstract

A continue loss of CD4+ T lymphocytes, immune response dysfunction and chronic immune activation (IA) are hallmarks of untreated chronic HIV-1 infection. ROS and the subsequent oxidative stress have been connected with chronic activation of the immune system, viral replication, immune dysfunction, programmed cell death, and neurological damage, all considered to be major contributing issues in HIV-1 diseases progression. It has been demonstrated that HAART partially restore the antioxidant capacity by suppressing HIV, and it has been suggested that antioxidant therapy in combination with HAART could protect the blood brain barrier from oxidative stressinduced damage. Several mechanisms have been proposed to explain how HIV could modulate ROS generation and several HIV proteins have been shown to modulate ROS production. This review is intended to highlight the role played by ROS as modulators of the immune system during the course of HIV infection, which could explain its contribution to disease progression, opening the scope to new strategies for drug design and future treatment.

Keywords: HIV-1; Reactive oxygen species (ROS); Immune activation IA; AIDS; Nef; Tat; Treg

Introduction

Since the human immunodeficiency virus-1 (HIV-1) pandemic developed more than twenty-five years ago, millions have died from Acquired Immunodeficiency Syndrome (AIDS), and an estimate of 34 million people worldwide are living with HIV in 2010 [1]. HIV- 1 is responsible for a chronic disease and is an important causes for morbidity and mortality worldwide [2], due to a progressive immunodeficiency associated to both quantitative and qualitative deficit of CD4+ T lymphocytes, compromising innate immunity mechanisms as well [3]. Direct infection, apoptosis of activated cells (infected or non-infected cells) [4], cytotoxicity of infected cells [5], impaired renewal due to deficient thymopoiesis [6], and thymic involution [6,7], can result in a massive depletion of CD4+ T cells [8]. Typically, untreated individuals infected with HIV-1 develop AIDS, which is associated with opportunistic infections, malignancies and, eventually death; while paradoxically; a few others maintain undetectable plasma viral loads without any therapy and remain asymptomatic for many years [9].

Although a variety of clinical trials have been conducted in order to control the progression of HIV infection by focusing on oxidative stress, their precise targets and reaction mechanism have remained unclear [10]. The aim of this review is to discuss and highlight the role of ROS as modulators of the immune system during the course of HIV infection, which could explain its contribution to the immunopathogenesis of the disease, opening the scope to new strategies for drug design and treatment.

ROS are a group of highly reactive free radicals [11], produced mainly by phagocytic cells such as neutrophils and macrophages [12]. There are several sources of ROS within the intracellular compartment, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs), xanthine oxidase, the mitochondrial electron transport chain, peroxisomes, and the endoplasmic reticulum (ER) [12,13]. Due to its highly unstable nature, superoxide readily produces a number of other compounds [14]; when it is catalyzed by superoxide dismutase (SOD) results in hydrogen peroxide (H2O2) production, which promotes either oxidation or disulfide bond formation [15]. Additionally, H2O2 generates hypochloric acid (HOCl) when it is combined with Cl- in a reaction catalyzed by myeloperoxidase; both H2O2 and HOCl are present in the phagosome to kill microbes. H2O2 also interacts with transition metal ions, such as ferrous and ferric ions, to produce hydroxyl radicals (OH•), which is the most highly oxidizing member of the ROS family, reacting rapidly with DNA, lipids, and proteins [16].

NOXs and mitochondria are major cellular sources of ROS [17]. The NOX family comprises seven members (NOX1-5 and DUOX1- 2) with NOX2 NADPH-oxidase [18]; each of these isoforms have a core catalytic subunit called NADPH oxidase (NOX) and dual oxidase (DUOX) subunits, and even five regulatory subunits. Several NADPH oxidase isoforms depend on a small GTPase (Rac1 or Rac2) for their activation [19]. NOX2 NADPH oxidase is composed by functional transmembrane heterodimers, gp91phox and p22phox (also known as cytochrome b558), and four regulatory cytosolic subunits p40phox, p47phox, p67phox, and Rac2. The components can further be located in different biological membranes, such as: nuclear, endoplasmic reticulum, endosome, phagosome, and mitochondria, which has been associated with its function within these intracellular and extracellular locations [20].

Some members of the NADPH oxidase family are expressed in virtually all mammalian cells [19]. Brain tissue (that is, neurons, astrocytes and microglia), constitutively express NOX1 oxidase, NOX2 oxidase and NOX4 oxidase [21], presumably reflecting physiological roles for NOX oxidase-derived ROS.

General effects of ROS in immune response

ROS have a critical role in several physiological events such as regulation of redox-dependent signaling cascades, by acting as cofactors for hormones production [19], intracellular signaling post- T-cell activation [22], antigen cross-presentation [23], autophagy [16], both apoptotic and necrotic cell death pathways [24-26] and chemotaxis [27], by increasing CCR5, and CXCR4 expression [28,29], major determinants of HIV interaction with mononuclear phagocytes and T lymphocytes.

ROS can also orchestrate Th2 responses, by inducing lipid oxidization which trigger thymic stromal lymphopoietin (TSLP) production by epithelial cells, a cytokine known to be involved in Th2 differentiation, which suppresses the production of Th1 molecules such as IL-12 and CD40 by DCs, in lymph node; and induce DCderived chemokine CCL7, which mediates basophils recruitment [30]. Interestingly, NOX2 oxidase-derived superoxide from macrophages is essential for Treg generation, contributing to control T cell-mediated inflammation [31]. Besides, NOX2 deficiency affects both FoxP3 and RORγt expression in CD4+ T cells, which is traduced as increased Th17 cells and diminished Treg development in a ROS-dependent and T-cell–intrinsic manner [32].

On the other hand, excessive ROS production by an overactive NADPH oxidase system, both in phagocytic and non-phagocytic cells, may set in motion a vicious cycle of radical and non-radical oxidant generation in various cellular compartments, which disrupts redox circuits that are normally controlled by thiol-dependent antioxidant defenses, and induces a state of oxidative stress. In fact, many adverse effects of ROS are attributable to the oxidation of important signaling proteins, including kinases and phosphatases, and activation of the pro-inflammatory redox-dependent transcription factor NF-κB; this leads to the expression of adhesion molecules, leukocytes proliferation and migration [19,33]. ROS may also oxidize and activate matrix metalloproteinases, responsible for tissue remodeling [34]. ROS may initiate the assembly of multiprotein signaling complexes known as inflammasomes, which activate caspase-1, leading to the processing and secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 [35].

Several studies suggest that ROS affect the intrinsic apoptotic pathway in neuronal cells, with mitochondria being the major source and primary target [36]. ROS may oxidize mitochondrial pores that lead to cytochrome c release and caspase-9 activation due to the disruption of the mitochondrial membrane potential [37,38]. ROS generation change the intracellular redox status as well, with subsequent effects on specific kinases, phosphatases, and transcription factors, increasing cell susceptibility to apoptotic stimuli [39-41]. ROS are also involved in T lymphocytes cell death process [22], hence, inhibition of superoxide generation upon T-cell receptor engagement, rescue from activationinduced cell death [42]. Sustained Jun N-terminal kinase (JNK) activation is ROS dependent in T cells and, during T cell neglectinduced death increased levels of ROS has been detected [43].

Thus, ROS are important signaling molecules that regulate many signal-transduction pathways and play critical roles in cell survival, death, and immune defenses [17], involving them in many different diseases including cancer, neurological disorders, among many others [44,45].

ROS and HIV-1 infection

An increased oxidative stress condition has been repeatedly described in chronically HIV-1-infected patients, based on: elevated extracellular and intracellular ROS levels [46-53], systemic reduction in glutathione (GSH) and thioredoxin concentrations [54], disturbance of mitochondrial membrane potential [55], and changes in expression and activation status of cell death receptors [56], which may lead to host cell death [52,57]. An increased HIV-1 replication, induced by ROS, has been observed in reservoir cells [58]. These effect is mediated by H2O2-induced LTR activation during middle stage of infection, where a great deal of oxidative stress occurred [59].

It has been demonstrated that HAART partially restore the antioxidant capacity by suppressing HIV [60], and it has been suggested that antioxidant therapy in combination with HAART could protect the blood brain barrier from oxidative stress-induced damage, could be considered as a viable therapeutic option for patients with HIVassociated dementia (HAD) [61]. However protease inhibitors (PIs) for HIV, enhance ROS production in several types of cells including macrophages, vascular smooth muscle cells, umbilical vein endothelial cells, adipocytes, and pancreatic β-cells, and contributed to intestinal barrier integrity disruption [62] suggesting that ROS greatly contribute to HIV PIs-induced side effects [63].

Effects of HIV induced ROS on immunity

There is no doubt about the crucial role played by ROS in the immunopathogenesis of HIV infection. HIV induced ROS have been connected to decreased immune cell proliferation, loss of immune function [50,58,64], followed by a cellular dysfunction and cell death, loss of memory T cell response [65], T helper imbalance, related to premature Treg response [66], which are highly susceptible to HIV infection [67], premature ageing of immune system because of a direct and quantitative shortening of telomere [68], altogether disturbing the adaptative immune response.

ROS has been connected to several critical signaling pathways during HIV Infection. Thus, ROS induce HIV LTR activation by early NF-κB activation, by inducing both IkB degradation and covalent modification of p65, CBP/p300-induced hyperacetylation as well as phosphorylation of p65 [59], these events may explain the explosive increase in viral replication after the middle stage of infection [69] and, can promote HIV replication in macrophages [10]. Cross link of death receptors such as DR5, induced production of ROS and subsequent apoptosis in HIV-1 infected monocyte-derived macrophage, associated with JNK phosphorylation [70], a kinase known to be involved in the apoptotic signaling pathway initiated by stress or toxic stimuli [71]. Besides, HIV infection facilitates TRAIL-induced cell death in monocyte-derived macrophage (MDM) by down regulating the TRAIL decoy receptors and intracellular c-FLIP, dependent of ROS generation and subsequent JNK phosphorylation [70].

Excessive ROS production is also explained by polymorphonuclear chronic activation during HIV infection [48] or, through a pro-oxidant effect of TNF-α, as released by activated macrophages, which may be accompanied by a concomitant deficient antioxidant defense system [72]; altogether increasing the susceptibility to cell death. Indeed, oxidative stress is the common mediator of programmed cell death in HIV/AIDS on this subpopulation [57]. Previous results show that neutrophils from HIV infected patients have increased basal levels of superoxide production [73], particularly before AIDS is established, which is associated to their dysfunction [48]. In fact, apoptosis could be responsible for HIV-related neutropenia [74], which could occur either spontaneously or triggered via death receptors such as Fas/ FasL [75,76]. Spontaneous cell death during HIV infection is at least partially mediated by ROS, because it can be significantly reduced in the presence of oxygen radical scavengers [57].

Effects of HIV induced ROS on different cells

Oxidative stress not only affects HIV infected human CD4 T lymphocytes, macrophages, dendritic cells and neutrophils, human hepatocytes has been documented to be affected as well during the disease [77]. HIV virions and its envelope gp120 protein, induce ROS production within hepatocytes, hepatic stellate cells (HSC) and other immune cells through its interaction with CCR5 or CXCR4 chemokine receptors [78,79], and during HIV/HCV co-infection, leads to accelerated hepatic fibrosis development, higher rates of liver failure and death, compared with patients with HCV only [80]. Thus, HIV regulate hepatic fibrosis progression through the generation of ROS, in a NF-κB -dependent fashion, and a subsequent increment of profibrogenic genes [81]. Oxidative stress has been recently involved in endothelial cell dysfunction, vascular injury, and pulmonary arterial hypertension, during HIV infection [82]. A unifying mechanism of HIV-related ROS effects is currently unknown, despite the intensive efforts unraveling the immunopathogenesis of the disease; which may make difficult to design the appropriate therapeutic approach capable of controlling oxidative stress.

ROS and mucosal integrity during HIV infection

A prominent role of the intestinal mucosal integrity has been postulated has been connected with chronic immune activation during HIV infection. Gut mucosa is a compartment where the interchange between HIV and the host’s immune system, takes center stage [83,84]. Within 1–2 weeks, infection becomes systemic, with extensive viral replication and CD4+ T-cell depletion in the intestinal lamina propria [84-87], because of a direct infection or apoptosis of bystander cells [88]; associated to enteropathy [89] induced by proinflammatory molecules, and cytotoxic effects that provoke intestinal epithelial apoptosis [90], and immune activation. The T regulatory response that has been described as premature in this region, because the immunosuppressive effects of cellular immune response precede clearance or control of viral replication [88,91].

ROS play an important role in epithelial intestinal cells injury, contributing to gut mucosal barrier dysfunction. The ROS-induced gut mucosal injury, implies loss of epithelial integrity between the cellular tight junctions and enteric bacterial translocation, which can be attenuated by radical scavenger [92]. Oxidative stress is known to exist in IBD epithelium, and activate TACE (TNF-alpha converting enzyme), a pleiotropic metalloprotease also known as ADAM17, which is required for TNF-α production [93].

Current evidence also indicates that Th17 cells are even more profoundly depleted than CD4+CCR5+ T cells in the intestinal mucosa of HIV- infected individuals [94]. Loss of Th17 cells [95], is associated with loss of the integrity of the gut mucosal barrier, allowing microbial translocation products from the gut, associated to increased plasma levels of lipopolysaccharide (LPS) and soluble CD14 (sCD14), in the absence of overt bacteremia, which correlates with systemic immune activation [96,97] and mortality prediction in HIV infection [98]. NOX2 deficiency or ROS depletion significantly promotes development of effector Th subsets such as Th17 cells, and suppressed development of natural and inducible Treg cells. ROS is essential for immune homeostasis by controlling Th17/Treg balance. Increased generation of ROS attenuated Th17 cell differentiation and its related immune response [99]. It is likely that disruption of the precise fine-tuning between generation and elimination of ROS may cause inflammation in multiple tissues in a T-cell-dependent manner [32].

Effect of HIV proteins on ROS production

Several mechanisms have been proposed to explain how HIV could modulate ROS generation: 1) by inactivation of the GDP-bound form of RhoA and activation of p190 RhoGAP-A protein [100]. A previous report showed that Rac-dependent ROS production, leads to downregulation of RhoA through oxidative inactivation of low molecular-weight protein tyrosine phosphatase, and the subsequent activation of p190 RhoGAP-A [101]; 2) by phosphorylation of p47phox [52] and association with p22-phox [102] inducing a direct activation of the NADPH oxidase complex, 3) by activation of p66ShcA, a protein involved in phosphatidylinositol 3-kinase/Akt/PKB signaling module, a pathway which is upstream of NADPH [103], 4) by activating the PI3K/ Akt pathway, turning on the NF-κB Transcription factor [104] and inducing p42/44 MAPK activation [105].

Several HIV proteins (structural and regulatory) have been shown to modulate ROS production [61,102,105-109] (Figure 1). Thus, HIV regulatory protein Tat has pro-oxidant function, which could induce long terminal repeat region (LTR) transactivation, and this effect is prevented by NADPH oxidase inhibitors [104]. Furthermore, Tat can reduce SOD synthesis [110,111] and intracellular glutathione (GSH) levels [112]. Exposure of microglia and astrocytes to HIV-1 Tat leads to ROS generation, which activates signal transduction processes leading to expression of proinflammatory cytokines, as well as adhesion molecules on endothelial cells, microglia, and astrocytes [113-115]. On the other hand, inhibition of NADPH oxidase, significantly attenuates inflammatory mediators (TNF-α, IL-6, CXCL10, IFN-γ and MCP-1) in microglia, astrocytes and macrophages [116,117].

clinical-cellular-immunology-clavicular-osteolysis

Figure 1: Chest radiograph of the face: sequelae of parenchymal abnormalities and DDB costal and clavicular osteolysis.

HIV-1 Nef is another regulatory protein that also has pro-oxidant properties. The effect of Nef on ROS activation has been previously demonstrated in different cells [53,102,106,107]. Nef has been detected in brain, where it associates with astrogliosis and recruitment and activation of monocytes/macrophages [118]. HIV-1 Nef increases oxidative stress in primary human astrocytes [119] and led to their rapid cell death [120]. Furthermore, ROS-induced astrocyte death is thought to play a role in the occurrence of HAD [121,122].

Several pathways could explain Nef modulating effects on ROS: Nef may induce superoxide production by activating PAK (p21- activated kinase) in a Cdc42/Rac dependent manner [107]. Through the interaction with Hck (hemopoietic cell kinase), Nef may induce phosphorylation and membrane translocation of p47-phox, a mechanism that could explain activation of superoxide, bypassing the typical pathway stimulated by pro inflammatory cytokine GM-CSF [106]. Additionally, through its association with p22-phox [102], Nef could directly affect NADPH-activity, a possibility that requires further investigation.

A hypothetical predictive model of protein-protein association, between p22-phox and Nef, showing low values of free energy between the molecules (-1117.6), is shown in Figure 2. In particular, residues VRGE (126-129) from p22-phox (gray) corresponding to an intracellular portion of the protein and residues RRQDI (105-109) from Nef (black), demonstrated the highest probability of interaction.

clinical-cellular-immunology-Radiograph-right-arm

Figure 2: Radiograph of the right arm showing osteolytic bone at the humeral shaft.

Vpr an HIV protein that contribute to HIV-1 pathogenesis has been proven to increase ROS and HIF-1(a biomarker of oxidative stress) expression in human microglial cells, promoting mitochondrial dysfunction as well as oxidative stress [108,123]. Oxidized phosphatidylcholine (OxPC), formed from phospholipids in response to oxidative stress, were identified in atherosclerotic lesions [124] to be induced by rVpr, in a ROS-dependent manner, because it is reverted by the addition of N-acetyl-L-cysteine (NAC), a ROS scavenger molecule [125]. In this model, ROS are likely generated as a result of mitochondrial dysfunction, since Vpr binds ANT (adenine nucleotide translocator), a member of the permeability transition pore complex [126], and disrupts the MMP [127]. Additionally, HIV- 1 gp120-induced neurotoxicity use ROS as signaling and effector of oxidant damage. Antioxidant gene blocks gp120-induced proapoptotic signaling in vitro and protects cell viability in vitro and in vivo, therefore specifically hypersensitive to gp120-induced apoptosis, signaling for which involves ROS intermediates [109].

The triad: immune chronic activation, oxidative stress and HIV infection

A continue loss of CD4+ T lymphocytes, immune response dysfunction and systemic immune activation (IA) are hallmarks of untreated chronic HIV-1 infection [128], and it is now well established that chronic IA, is an important mechanism that contribute to immune response impairment and disease pathogenesis [129-131]. Within the multiple biological process described to be altered and involved in AIDS, a great deal of innate immune components have been clarified not only to be affected, but more importantly, to play a crucial role during disease progression [132,133]. Thus, IA is manifested in many ways including increased proinflammatory cytokines and chemokines [134] and oxidative stress [135,136], among others. Reactive oxygen species (ROS) are important molecules that regulate many signaltransduction pathways and play critical roles in cell survival, death, and immune defenses [17], and overproduction of ROS leads to oxidative stress, directly associated with toxic effects on cells and tissues [137], involving molecular damage of cellular components such as nucleic acids, proteins, or lipids [138,139]. Furthermore, ROS and the subsequent oxidative stress, have been connected with chronic IA during HIV [48], viral replication [125], immune dysfunction [1,140], programmed cell death [57,141], and neurological damage [142], all considered to be major contributing factors in HIV-1 diseases progression [143,144] (Figure 3).

clinical-cellular-immunology-diffuse-bone-defects

Figure 3: Skull radiograph showing diffuse bone defects of various sizes taking in places the appearance of macrogeodes

Immune system exhaustion [145] associated with constitutively activation of lymphocyte populations [146] and expression of programmed death-1 (PD-1)[147], has been associated with impaired immune reconstitution in patients on ART [148].

A number of factors have been identified for sustained chronic IA, which are both directly or indirectly related to HIV replication, they include: the innate and adaptive immune responses against HIV, the translocation of bacterial products as a consequence of compromised integrity of the mucosal barrier, and the potential bystander stimulation of lymphocytes and macrophages by HIV gene products [96,149]. Such IA is manifested in many ways including: increased T-cell turnover [96,150], increased frequencies of T-cells with activated phenotype [151], polyclonal B-cell activation [152], increased serum levels of proinflammatory cytokines and chemokines [96], enhanced oxidative stress [135,136] and premature development of regulatory T cells (Tregs) [151]. Immune exhaustion is an aberrant component of the immune chronic activation during HIV-1 infection and is associated with ongoing virus replication [153], and elevated intracellular cyclic AMP (cAMP), which inhibits T cell activation capability [154]. In T cells, cAMP triggers a protein kinase A-Csk-Lck inhibitory pathway that inhibits proximal T cell receptor (TCR) signaling events [155]. This mechanism may also be involved in the inhibitory function of Tregs [156]. Therefore, anti inflammatory therapy has been suggested to download the immune activation in order to improve T cell-dependent functions in vivo [157].

Chronic IA of innate immune cell is also evident during HIV infection. Hence, pDCs are highly susceptible to HIV-induced activation due to its interaction with the cellular receptor CD4, and the subsequent production of type I interferon. Also, pDCs during HIV infection show high levels of the chemokine receptor CCR7 [158], indoleamine 2,3-dioxygenase, tryptophan depletion and the subsequent suppressive effects by contributing with Treg generation. Increased levels of IDO and tryptophan depletion is mediated in part by TLR activation, [146] and by oxidative stress, which creates a niacin “sink” effect that depletes both niacin and tryptophan [159]. These events are associated with inhibition of HIV-induced CD4 T cell proliferative responses in vitro [160], and increment of regulatory T cells (Treg) in lymphoid tissues, where IDO is overexpressed [146]. Thereby, the dysregulation of innate immunity could contribute both to the numerical depletion of CD4 T cells and to the progressive loss of functional responsiveness of lymphocytes.

Concluding Remarks

ROS are important molecules that regulate many signal-transduction pathways and play critical roles in cell survival, death, and immune defenses, their overproduction leads to oxidative stress, directly associated with toxic effects on different cells and tissues. ROS and oxidative stress have been connected with chronic IA during HIV infection and diseases progression.

Several pathways have been involved in ROS/oxidative stress during HIV/ AIDS; however the molecular mechanism of ROS/HIV modulation is currently under study. Demonstrating protein-protein association between HIV proteins and elements involved in ROS production (for instance the association between p-22phox and Nef, which affects superoxide production) could unmask potential targets for therapeutic intervention. Further studies may contribute to develop specific therapeutic strategies, which combined with antiretroviral therapy, would improve life expectancy and quality of infected patients.

References

  1. Simon V, Ho DD, Abdool Karim Q (2006) HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet 368: 489-504.
  2. Ford ES, Puronen CE, Sereti I (2009) Immunopathogenesis of asymptomatic chronic HIV Infection: the calm before the storm. Curr Opin HIV AIDS 4: 206-214.
  3. Finkel TH, Tudor-Williams G, Banda NK, Cotton MF, Curiel T, et al. (1995) Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med 1: 129-134
  4. Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, et al. (2005) Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 434: 1093-1097.
  5. Kalayjian RC, Landay A, Pollard RB, Taub DD, Gross BH, et al. (2003) Age-related immune dysfunction in health and in human immunodeficiency virus (HIV) disease: association of age and HIV infection with naive CD8+ cell depletion, reduced expression of CD28 on CD8+ cells, and reduced thymic volumes. J Infect Dis 187: 1924-1933.
  6. Sauce D, Larsen M, Fastenackels S, Pauchard M, Ait-Mohand H, et al. (2011) HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis. Blood 117: 5142-5151.
  7. Hazenberg MD, Hamann D, Schuitemaker H, Miedema F (2000 ) T cell depletion in HIV-1 infection: how CD4+ T cells go out of stock. Nat Immunol 1: 285-289.
  8. Huang KH, Goedhals D, Carlson JM, Brockman MA, Mishra S, et al. (2011) Progression to AIDS in South Africa Is Associated with both Reverting and Compensatory Viral Mutations. PloS One 6: e19018.
  9. Aquaro S, Muscoli C, Ranazzi A, Pollicita M, Granato T, et al. (2007) The contribution of peroxynitrite generation in HIV replication in human primary macrophages. Retrovirology 4: 76.
  10. Rada B, Hably C, Meczner A, Timár C, Lakatos G, et al. (2008) Role of Nox2 in elimination of microorganisms. Semin Immunopathol 30: 237-253.
  11. Lam GY, Huang J, Brumell JH (2010) The many roles of NOX2 NADPH oxidase-derived ROS in immunity. Semin Immunopathol 32: 415-430.
  12. Santos CX, Tanaka LY, Wosniak J, Laurindo FR (2009) Mechanisms and implications of reactive oxygen species generation during the unfolded protein response: roles of endoplasmic reticulum oxidoreductases, mitochondrial electron transport, and NADPH oxidase
  13. Bartosz G (2009) Reactive oxygen species: destroyers or messengers? Biochem Pharmacol 77: 1303-1315.
  14. Biswas S, Chida AS, Rahman I (2006) Redox modifications of protein-thiols: emerging roles in cell signaling. Biochem Pharmacol 71: 551-564.
  15. Lam GY, Huang J, Brumell JH (2010) The many roles of NOX2 NADPH oxidase-derived ROS in immunity. Semin Immunopathol 32: 415-430.
  16. Huang J, Lam GY, Brumell JH (2011) Autophagy signaling through reactive oxygen species. Antioxid Redox Signal 14: 2215-2231.
  17. Nauseef WM (2004) Assembly of the phagocyte NADPH oxidase. Histochem Cell Biol 122: 277-291.
  18. Drummond GR, Selemidis S, Griendling KK, Sobey CG (2011) Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov 10: 453-471.
  19. Lassègue B, Griendling KK (2010) NADPH oxidases: functions and pathologies in the vasculature. Arterioscler Thromb Vasc Biol 30: 653-661.
  20. Infanger DW, Sharma RV, Davisson RL (2006) NADPH oxidases of the brain: distribution, regulation, and function. Antioxid Redox Signal 8: 1583-1596.
  21. Kiessling MK, Linke B, Brechmann M, Süss D, Krammer P H, et al. (2010) Inhibition of NF-?B induces a switch from CD95L-dependent to CD95L-independent and JNK-mediated apoptosis in T cells. FEBS Lett 584: 4679-4688.
  22. Mantegazza AR, Savina A, Vermeulen M, Pérez L, Geffner J, et al. (2008) NADPH oxidase controls phagosomal pH and antigen cross-presentation in human dendritic cells. Blood 112: 4712-4722.
  23. Saito Y, Nishio K, Ogawa Y, Kimata J, Kinumi T, et al. (2006) Turning point in apoptosis/necrosis induced by hydrogen peroxide. Free Radic Res 40: 619-630.
  24. Morgan MJ, Liu ZG (2010) Reactive oxygen species in TNFalpha-induced signaling and cell death. Mol Cells 30: 1-12.
  25. Morgan MJ, Liu ZG ( 2011) Crosstalk of reactive oxygen species and NF-?B signaling. Cell Res 21: 103-115.
  26. Urao N, Inomata H, Razvi M, Kim HW, Wary K, et al. (2008) Role of nox2-based NADPH oxidase in bone marrow and progenitor cell function involved in neovascularization induced by hindlimb ischemia. Circ Res103: 212-220.
  27. Saccani A, Saccani S, Orlando S, Sironi M, Bernasconi S, et al. (2000) Redox regulation of chemokine receptor expression. Proc Natl Acad Sci U S A 97: 2761-2766.
  28. Li S, Deng Y, Feng J, Ye W (2009) Oxidative preconditioning promotes bone marrow mesenchymal stem cells migration and prevents apoptosis. Cell Biol Int 33: 411-418.
  29. Tang H, Cao W, Kasturi SP, Ravindran R, Nakaya HI, et al. (2010) The T helper type 2 response to cysteine proteases requires dendritic cell-basophil cooperation via ROS-mediated signaling. Nat Immunol 11: 608-617.
  30. Kraaij MD, Savage ND, van der Kooij SW, Koekkoek K, Wang J, et al. (2010) Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species. Proc Natl Acad Sci U S A. 107: 17686-17691.
  31. Lee K, Won HY, Bae MA, Hong JH, Hwang ES (2011) Spontaneous and aging-dependent development of arthritis in NADPH oxidase 2 deficiency through altered differentiation of CD11b+ and Th/Treg cells. Proc Natl Acad Sci U S A 108: 9548-9553.
  32. Jones DP (2008) Radical-free biology of oxidative stress. Am J Physiol Cell Physiol 295: C849-868.
  33. Diebold I, Petry A, Burger M, Hess J, Görlach A (2011) NOX4 mediates activation of FoxO3a and matrix metalloproteinase-2 expression by urotensin-II. Mol Biol Cell 22: 4424-4434.
  34. Martinon F (2010) Signaling by ROS drives inflammasome activation. Eur J Immunol 40: 616-619.
  35. Sacktor N, Haughey N, Cutler R, Tamara A, Turchan J, et al. (2004) Novel markers of oxidative stress in actively progressive HIV dementia. J Neuroimmunol 157: 176-184.
  36. Cai J, Jones DP (1999) Mitochondrial redox signaling during apoptosis. J Bioenerg Biomembr 31: 327-334.
  37. Simon HU, Haj-Yehia A, Levi-Schaffer F (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5: 415-418.
  38. Alvarado-Kristensson M, Melander F, Leandersson K, Ronnstrand L, Wernstedt C, et al. (2004) p38-MAPK signals survival by phosphorylation of caspase-8 and caspase-3 in human neutrophils. J Exp Med 199: 449-458.
  39. Cimino F, Esposito F, Ammendola R, Russo T (1997) Gene regulation by reactive oxygen species. Curr Top Cell Regul 35: 123-148.
  40. Gardai S, Whitlock BB, Helgason C, Ambruso D, Fadok V, et al. (2002) Activation of SHIP by NADPH oxidase-stimulated Lyn leads to enhanced apoptosis in neutrophils. J Biol Chem 277: 5236-5246.
  41. Norell H, Martins da Palma T, Lesher A, Kaur N, Mehrotra M, et al. (2009) Inhibition of superoxide generation upon T-cell receptor engagement rescues Mart-1(27-35)-reactive T cells from activation-induced cell death. Cancer Res 69: 6282-6289.
  42. Purushothaman D, Sarin A (2009) Cytokine-dependent regulation of NADPH oxidase activity and the consequences for activated T cell homeostasis. J Exp Med 206: 1515-1523.
  43. Ziech D, Franco R, Pappa A, Panayiotidis MI (2011) Reactive Oxygen Species (ROS)--Induced genetic and epigenetic alterations in human carcinogenesis. Mutat Res 711: 167-173.
  44. Lovell MA, Markesbery WR (2007) Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer's disease. Nucleic Acids Res 35: 7497-7504.
  45. Dobmeyer TS, Findhammer S, Dobmeyer JM, Klein SA, Raffel B, et al. (1997) Ex vivo induction of apoptosis in lymphocytes is mediated by oxidative stress: role for lymphocyte loss in HIV infection. Free Radic Biol Med 22: 775-785.
  46. Munoz JF, Salmen S, Berrueta LR, Carlos MP, Cova JA, et al. (1999) Effect of human immunodeficiency virus type 1 on intracellular activation and superoxide production by neutrophils. J Infect Dis 180: 206-210.
  47. Elbim C, Pillet S, Prevost M, Preira A, Girard P, et al. (2001) The role of phagocytes in HIV-related oxidative stress. J Clin Virol 20: 99-109.
  48. Elbim C, Pillet S, Prevost M, Preira A, Girard P, et al. (1999) Redox and Activation Status of Monocytes from Human Immunodeficiency Virus-Infected Patients: Relationship with Viral Load. J Virol 73: 4561-4566.
  49. Sánchez-Pozo C, Rodriguez-Baño J, Domínguez-Castellano A, Muniain MA, Goberna R, et al. (2003) Leptin stimulates the oxidative burst in control monocytes but attenuates the oxidative burst in monocytes from HIV-infected patients. Clin Exp Immunol 134: 46
  50. Olivetta E, Pietraforte D, Schiavoni I, Minetti M, Federico M, et al. (2005) HIV-1 Nef regulates the release of superoxide anions from human macrophages. Biochem J 390: 591-602.
  51. Wang X, Viswanath R, Zhao J, Tang S, Hewlett I (2010) Changes in the level of apoptosis-related proteins in Jurkat cells infected with HIV-1 versus HIV-2. Mol Cell Biochem 337: 175-183.
  52. Masanetz S, Lehmann MH (2011) HIV-1 Nef increases astrocyte sensitivity towards exogenous hydrogen peroxide. Virol J 8: 35.
  53. Sahaf B, Heydari K, Herzenberg LA, Herzenberg LA (2005) The extracellular microenvironment plays a key role in regulating the redox status of cell surface proteins in HIV-infected subjects. Arch Biochem Biophys 434: 26-32.
  54. Perl A, Banki K (2000) Genetic and metabolic control of the mitochondrial transmembrane potential and reactive oxygen intermediate production in HIV disease. Antioxid Redox Signal 2: 551-573.
  55. Zhu DM, Shi J, Liu S, Liu Y, Zheng D (2011) HIV infection enhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactive oxygen species. PLoS One 6: e18291.
  56. Salmen S, Montes H, Soyano A, Hernández D, Berrueta L (2007) Mechanisms of neutrophil death in human immunodeficiency virus-infected patients: role of reactive oxygen species, caspases and map kinase pathways. Clin Exp Immunol 150: 539-545.
  57. Yang HC, Xing S, Shan L, O'Connell K, Dinoso J, et al. (2009) Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation. J Clin Invest 119: 3473-3486.
  58. Pyo CW, Yang YL, Yoo NK, Choi SY (2008) Reactive oxygen species activate HIV long terminal repeat via post-translational control of NF-kB. Biochem Biophys Res Comm 376: 180-185.
  59. de Martino M, Chiarelli F, Moriondo M, Torello M, Azzari C, et al. ( 2001) Restored antioxidant capacity parallels the immunologic and virologic improvement in children with perinatal human immunodeficiency virus infection receiving highly active antiretroviral therapy. Clin Immunol 100: 82-86.
  60. Banerjee A, Zhang X, Manda KR, Banks WA, Ercal N (2010) HIV proteins (gp120 and Tat) and methamphetamine in oxidative stress-induced damage in the brain: potential role of the thiol antioxidant N-acetylcysteine amide. Free Radic Biol Med 48: 1388-1398.
  61. Wu X, Sun L, Zha W, Studer E, Gurley E, et al. (2010) HIV protease inhibitors induce endoplasmic reticulum stress and disrupt barrier integrity in intestinal epithelial cells. Gastroenterology 138: 197-209.
  62. Lei B, Zha W, Wang Y, Wen C, Studer EJ, et al. (2010) Development of a novel self-microemulsifying drug delivery system for reducing HIV protease inhibitor-induced intestinal epithelial barrier dysfunction. Mol Pharm 7: 844-853.
  63. Gülow K, Kaminski M, Darvas K, Süss D, Li-Weber M, et al. (2005) HIV-1 trans-activator of transcription substitutes for oxidative signaling in activation-induced T cell death. J Immunol 174: 5249-5260.
  64. Cummins NW, Badley AD (2010) Mechanisms of HIV-associated lymphocyte apoptosis: 2010. Cell Death Dis 1: e99.
  65. Amarnath S, Dong L, Li J, Wu Y, Chen W, (2007) Endogenous TGF-beta activation by reactive oxygen species is key to Foxp3 induction in TCR-stimulated and HIV-1-infected human CD4+CD25- T cells. Retrovirology 4: 57.
  66. Antons AK, Wang R, Oswald-Richter K, Tseng M, Arendt CW, et al. (2008) Naive precursors of human regulatory T cells require FoxP3 for suppression and are susceptible to HIV infection. J Immunol 180: 764-773.
  67. Pollicita M, Muscoli C, Sgura A, Biasin A, Granato T, et al. (2009) Apoptosis and telomeres shortening related to HIV-1 induced oxidative stress in an astrocytoma cell line. BMC Neurosci 10: 51.
  68. Buhl R, Jaffe H, Holroyd K, Wells F, Mastrangeli A, et al. (1990) Glutathione deficiency and HIV. Lancet 335: 546.
  69. Zhu DM, Shi J, Liu S, Liu Y, Zheng D, (2011) HIV Infection Enhances TRAIL-Induced Cell Death in Macrophage by Down-Regulating Decoy Receptor Expression and Generation of Reactive Oxygen Species. PloS One 6: e18291.
  70. Saeki K, Kobayashi N, Inazawa Y, Zhang H, Nishitoh H, et al. (2002) Oxidation-triggered c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways for apoptosis in human leukaemic cells stimulated by epigallocatechin-3-gallate (EGCG): a distinct pathway from those of chemically induced and receptor-mediated apoptosis. Biochem J 368: 705-720.
  71. Jahoor F, Jackson A, Gazzard B, Philips G, Sharpstone D, et al. (1999) Erythrocyte glutathione deficiency in symptom-free HIV infection is associated with decreased synthesis rate. Am J Physiol Endocrinol Metab 276: 205-211.
  72. Elbim C, Prevot MH, Bouscarat F, Franzini E, Chollet-Martin S, et al. (1994) Polymorphonuclear neutrophils from human immunodeficiency virus-infected patients show enhanced activation, diminished fMLP-induced L-selectin shedding, and an impaired oxidative burst after cytokine priming. Blood 84: 2759-2766.
  73. Pitrak D (1999) Neutrophil deficiency and dysfunction in HIV-infected patients. Am J Health Syst Pharm 56: S9-16.
  74. Pitrak DL, Tsai HC, Mullane KM, Sutton SH, Stevens P (1996) Accelerated Neutrophil Apoptosis in the Acquired Immunodeficiency Syndrome. J Clin Invest 98: 2714 - 2719.
  75. Salmen S, Terán G, Borges L, Goncalves L, Albarrán B, et al. (2004) Increased Fas-mediated apoptosis in polymorphonuclear cells from HIV-infected patients. Clin Exp Immunol 137: 166-172.
  76. Jang JY, Shao RX, Lin W, Weinberg E, Chung WJ, Tsai WL, et al. (2011) HIV infection increases HCV-induced hepatocyte apoptosis. J Hepatol 54: 612-620.
  77. Bruno R, Galastri S, Sacchi P, Cima S, Caligiuri A, et al. (2010) gp120 modulates the biology of human hepatic stellate cells: a link between HIV infection and liver fibrogenesis. Gut 59: 513-520.
  78. Rotman Y, Liang TJ (2009) Coinfection with hepatitis C virus and human immunodeficiency virus: virological, immunological, and clinical outcomes. J Virol 83: 7366-7374.
  79. Macías J, Berenguer J, Japón MA, Girón JA, Rivero A, et al. (2009) Fast fibrosis progression between repeated liver biopsies in patients coinfected with human immunodeficiency virus/hepatitis C virus. Hepatology 50: 1056-1063.
  80. Lin W, Wu G, Li S, Weinberg EM, Kumthip K, et al. (2011) HIV and HCV Cooperatively Promote Hepatic Fibrogenesis via Induction of Reactive Oxygen Species and NFkB. J Biol Chem 286: 2665-2674.
  81. Mermis J, Gu H, Xue B, Li F, Tawfik O, et al. (2011) Hypoxia-Inducible Factor-1 alpha/Platelet Derived Growth Factor Axis in HIV-associated Pulmonary Vascular Remodeling. Respir Res 12: 103.
  82. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, et al. (2004) CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 200: 749-759.
  83. Mehandru S, Poles MA, Tenner-Racz K, Horowitz A, Hurley A, et al. (2004) Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med 200: 761-770.
  84. Li Q, Estes JD, Schlievert PM, Duan L, Brosnahan AJ, et al. (2009) Glycerol monolaurate prevents mucosal SIV transmission. Nature 458: 1034-1038.
  85. Shacklett BL (2010) Immune responses to HIV and SIV in mucosal tissues: 'location, location, location'. Curr Opin HIV AIDS 5: 128-134.
  86. Guadalupe M, Reay E, Sankaran S, Prindiville T, Flamm J, et al. (2003) Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol 77: 11708-11717.
  87. Haase AT (2010) Targeting early infection to prevent HIV-1 mucosal transmission. Nature 464: 217-223.
  88. Kotler DP, Gaetz HP, Lange M, Klein EB, Holt PR (1984) Enteropathy associated with the acquired immunodeficiency syndrome. Ann Intern Med 101: 421-428.
  89. Li Q, Estes JD, Duan L, Jessurun J, Pambuccian S, et al. (2008) Simian immunodeficiency virus-induced intestinal cell apoptosis is the underlying mechanism of the regenerative enteropathy of early infection. J Infect Dis 197: 420-429.
  90. Estes JD, Li Q, Reynolds MR, Wietgrefe S, Duan L, et al. (2006) Premature induction of an immunosuppressive regulatory T cell response during acute simian immunodeficiency virus infection. J Infect Dis 193: 703-712.
  91. Mukojima K, Mishima S, Oda J, Homma H, Sasaki H, et al. (2009) Protective effects of free radical scavenger edaravone against xanthine oxidase-mediated permeability increases in human intestinal epithelial cell monolayer. J Burn Care Res 30: 335-340.
  92. Forsyth CB, Banan A, Farhadi A, Fields JZ, Tang Y, et al. (2007) Regulation of oxidant-induced intestinal permeability by metalloprotease-dependent epidermal growth factor receptor signaling. J Pharmacol Exp Ther 321: 84-97.
  93. Brenchley JM, Paiardini M, Knox KS, Asher AI, Cervasi B, et al. (2008) Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 112: 2826-2835.
  94. Lackner AA, Mohan M, Veazey RS (2009) The gastrointestinal tract and AIDS pathogenesis. Gastroenterology 136: 1965-1978.
  95. Douek DC, Roederer M, Koup RA (2009) Emerging concepts in the immunopathogenesis of AIDS. Annu Rev Med 60: 471-484.
  96. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, et al. (2006) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12: 1365-1371.
  97. Sandler NG, Wand H, Roque A, Law M, Nason MC, et al. (2011) Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis 203: 780-790.
  98. Won HY, Sohn JH, Min HJ, Lee K, Woo HA, et al. (2010) Glutathione peroxidase 1 deficiency attenuates allergen-induced airway inflammation by suppressing Th2 and Th17 cell development. Antioxid Redox Signal 13: 575-587.
  99. Fausther-Bovendo H, Vieillard V, Sagan S, Bismuth G, Debré P (2010) HIV gp41 engages gC1qR on CD4+ T cells to induce the expression of an NK ligand through the PIP3/H2O2 pathway. PLoS Pathog e1000975.
  100. Nimnual AS, Taylor LJ, Bar-Sagi D (2003) Redox-dependent downregulation of Rho by Rac. Nat Cell Biol 5: 236-241.
  101. Salmen S, Colmenares M, Peterson DL, Reyes E, Rosales JD et al. (2010) HIV-1 Nef associates with p22-phox, a component of the NADPH oxidase protein complex. Cell Immunol 263: 87-99.
  102. Husain M, Meggs LG, Vashistha H, Simoes S, Griffiths KO, et al. (2009) Inhibition of p66ShcA longevity gene rescues podocytes from HIV-1-induced oxidative stress and apoptosis. J Biol Chem 284: 16648-16658.
  103. Zhang HS, Sang WW, Ruan Z, Wang YO (2011) Akt/Nox2/NF-?B signaling pathway is involved in Tat-induced HIV-1 long terminal repeat (LTR) transactivation. Arch Biochem Biophys 505: 266-272.
  104. Wu RF, Ma Z, Myers DP, Terada LS (2007) HIV-1 Tat activates dual Nox pathways leading to independent activation of ERK and JNK MAP kinases. J Biol Chem 282: 37412-37419.
  105. Olivetta E, Mallozzi C, Ruggieri V, Pietraforte D, Federico M, et al. (2009) HIV-1 Nef induces p47(phox) phosphorylation leading to a rapid superoxide anion release from the U937 human monoblastic cell line. J Cell Biochem. 106: 812-822.
  106. Vilhardt F, Plastre O, Sawada M, Suzuki K, Wiznerowicz M, et al. (2002) The HIV-1 Nef Protein and Phagocyte NADPH Oxidase Activation. J Biol Chem 277: 42136 - 42143.
  107. Deshmane SL, Mukerjee R, Fan S, Valle LD, Michiels C, et al. (2009) Activation of the oxidative stress pathway by HIV-1 Vpr leads to induction of hypoxia-inducible factor 1a expression. J Biol Chem 284: 11364-11373.
  108. Agrawala L, Louboutina JP, Marusicha E, Reyes BAS, Van Bockstaeleb EJ, et al. (2010) Dopaminergic neurotoxicity of HIV-1 gp120: Reactive oxygen species as signaling intermediates. Brain Res 1306: 116 - 130.
  109. Song HY, Ju SM, Lee JA, Kwon HJ, Eum WS, et al. (2007) Suppression of HIV-1 Tat-induced monocyte adhesiveness by a cell-permeable superoxide dismutase in astrocytes. Exp Mol Med 39: 778-786.
  110. Westendorp MO, Shatrov VA, Schulze-Osthoff K, Frank R, Kraft M, et al. (1995) HIV-1 Tat potentiates TNF-induced NF-kappa B activation and cytotoxicity by altering the cellular redox state. EMBO J 14: 546-554.
  111. Zhang HS, Li HY, Zhou Y, Wu MR, Zhou HS (2009) Nrf2 is involved in inhibiting Tat-induced HIV-1 long terminal repeat transactivation. Free Radic Biol Med 47: 261-268.
  112. D'Aversa, TG, Yu KO, Berman JW (2004) Expression of chemokines by human fetal microglia after treatment with the human immunodeficiency virus type 1 protein Tat. J Neurovirol 10: 86-97.
  113. Pu H, Tian J, Flora G, Lee YW, Nath A, et al. (2003) HIV-1 Tat protein upregulates inflammatory mediators and induces monocyte invasion into the brain. Mol Cell Neurosci 24: 224-237.
  114. Song HY, Ryu J, Ju SM, Park LJ, Lee JA, et al. (2007) Extracellular HIV-1 Tat enhances monocyte adhesion by up-regulation of ICAM-1 and VCAM-1 gene expression via ROS-dependent NF-kappaB activation in astrocytes. Exp Mol Med 39: 27-37.
  115. Turchan-Cholewo J, Dimayuga VM, Gupta S, Gorospe RM, Keller JN, et al. (2009) NADPH oxidase drives cytokine and neurotoxin release from microglia and macrophages in response to HIV-Tat. Antioxid Redox Signal 11: 193-204.
  116. Williams R, Yao H, Peng F, Yang Y, Bethel-Brown C, et al. (2010 ) Cooperative induction of CXCL10 involves NADPH oxidase: Implications for HIV dementia. Glia 58: 611-621.
  117. Mordelet E, Kissa K, Cressant A, Gray F, Ozden S, et al. (2004) Histopathological and cognitive defects induced by Nef in the brain. FASEB J 18: 1851-1861.
  118. Acheampong EA, Roschel C, Mukhtar M, Srinivasan A, Rafi M, et al. (2009) Combined effects of hyperglycemic conditions and HIV-1 Nef: a potential model for induced HIV neuropathogenesis. Virol J 6: 183.
  119. Masanetz S, Lehmann MH (2011) HIV-1 Nef increases astrocyte sensitivity towards exogenous hydrogen peroxide. Virol J 8: 35.
  120. Feeney CJ, Frantseva MV, Carlen PL, Pennefather PS, Shulyakova, N, et al. (2008) Vulnerability of glial cells to hydrogen peroxide in cultured hippocampal slices. Brain Res 1198: 1-15.
  121. Robb SJ, Connor JR (1998) An in vitro model for analysis of oxidative death in primary mouse astrocytes. Brain Res 788: 125-132.
  122. Roc AC, Ances BM, Chawla S, Korczykowski M, Wolf RL, et al. (2007) Detection of human immunodeficiency virus induced inflammation and oxidative stress in lenticular nuclei with magnetic resonance spectroscopy despite antiretroviral therapy. Arch Neurol 64: 1249-1257.
  123. Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, et al. (2008) Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 133: 235-249.
  124. Hoshino S, Konishi M, Mori M, Shimura M, Nishitani C, et al. (2010) HIV-1 Vpr induces TLR4/MyD88-mediated IL-6 production and reactivates viral production from latency. J Leukoc Biol 87: 1133-1143.
  125. Jacotot E, Ravagnan L, Loeffler M, Ferri KF, Vieira HL, et al. (2000) The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore. J Exp Med 191: 33-46.
  126. Kitayama H, Miura Y, Ando Y, Hoshino S, Ishizaka Y, et al. (2008) Human immunodeficiency virus type 1 Vpr inhibits axonal outgrowth through induction of mitochondrial dysfunction. J Virol 82: 2528-2542.
  127. Haas A, Zimmermann K, Oxenius A (2011) Antigen-dependent and -independent mechanisms of T and B cell hyperactivation during chronic HIV-1 infection. J Virol 85: 12102-12113.
  128. Catalfamo M, Wilhelm C, Tcheung L, Proschan M, Friesen T, et al. (2011) CD4 and CD8 T cell immune activation during chronic HIV infection: roles of homeostasis, HIV, type I IFN, and IL-7. J Immunol 186: 2106-2116.
  129. Shaw JM, Hunt PW, Critchfield JW, McConnell DH, Garcia JC, et al. (2011) Increased Frequency of Regulatory T Cells Accompanies Increased Immune Activation in Rectal Mucosae of HIV-Positive Noncontrollers. J Virol 85: 11422-11434.
  130. Brenchley JM, Silvestri G, Douek DC (2010) Nonprogressive and progressive primate immunodeficiency lentivirus infections. Immunity 32: 737-742.
  131. Altfeld M, Fadda L, Frleta D, Bhardwaj N (2011) DCs and NK cells: critical effectors in the immune response to HIV-1. Nat Rev Immunol 11: 176-186.
  132. Collini P, Noursadeghi M, Sabroe I, Miller RF, Dockrell DH (2010) Monocyte and macrophage dysfunction as a cause of HIV-1 induced dysfunction of innate immunity. Curr Mol Med 10: 727-740.
  133. Valdez H, Lederman MM (1997) Cytokines and cytokine therapies in HIV infection. AIDS Clin Rev 1998: 187-228.
  134. Mollace V, Nottet HS, Clayette P, Turco MC, Muscoli C, et al. (2001) Oxidative stress and neuroAIDS: triggers, modulators and novel antioxidants. Trends Neurosci 24: 411-416.
  135. Toborek M, Lee YW, Pu H, Malecki A, Flora G, et al. (2003) HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium. J Neurochem 84: 169-179.
  136. Anderson KE, Chessa TA, Davidson K, Henderson RB, Walker S, et al. (2010) PtdIns3P and Rac direct the assembly of the NADPH oxidase on a novel, pre-phagosomal compartment during FcR-mediated phagocytosis in primary mouse neutrophils. Blood 116: 4978-4989.
  137. Cerutti PA (1985) Prooxidant states and tumor promotion. Science 227, 375-381.
  138. Fridovich I (1998 ) Oxygen toxicity: a radical explanation. J Exp Biol 201: 1203-1209.
  139. Schroecksnadel K, Zangerle R, Bellmann-Weiler R, Garimorth K, Weiss G, et al. (2007) Indoleamine-2, 3-dioxygenase and other interferon-gamma-mediated pathways in patients with human immunodeficiency virus infection. Curr Drug Metab 8: 225-236.
  140. Rodriguez B, Bazdar DA, Funderburg N, Asaad R, Luciano AA, et al. (2011) Frequencies of FoxP3+ naive T cells are related to both viral load and naive T cell proliferation responses in HIV disease. J Leukoc Biol 90: 621-628.
  141. Song HY, Ju SM, Seo WY, Goh AR, Lee JK, et al. (2011) Nox2-based NADPH oxidase mediates HIV-1 Tat-induced up-regulation of VCAM-1/ICAM-1 and subsequent monocyte adhesion in human astrocytes. Free Radic Biol Med 50: 576-584.
  142. Kalebic T, Kinter A, Pol G, Anderson ME, Meister A, et al. (1991) Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine. Proc Natl Acad Sci USA 88: 986-990.
  143. Roederer MF, Staal JT, Anderson M, Rabin R, Raju PA, et al. (1993) Dysregulation of leukocyte glutathione in AIDS. Ann NY Acad Sci 677: 113-125.
  144. Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, et al. (2010) Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med 16: 452-459.
  145. Boasso A, Shearer GM (2008) Chronic innate immune activation as a cause of HIV-1 immunopathogenesis. Clin Immunol 126: 235-242.
  146. Grossman Z, Meier-Schellersheim M, Sousa AE, Victorino RM, Paul WE (2002) CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat Med 8: 319-323
  147. Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, et al. (2003) T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis 187: 1534-1543.
  148. Roederer M, Dubs JG, Anderson MT, Raju PA, Herzenberg LA, et al. (1995) CD8 naive T cell counts decrease progressively in HIV-infected adults. J Clin Invest 95: 2061-2066.
  149. Hellerstein M, Hanley MB, Cesar D, Siler S, Papageorgopoulos C, et al. (1999) Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med 5: 83-89.
  150. Freguja R, Gianesin K, Mosconi I, Zanchetta M, Carmona F, et al. (2011) Regulatory T cells and chronic immune activation in human immunodeficiency virus 1 (HIV-1)-infected children. Clin Exp Immunol 164: 373-380.
  151. Lane HC, Masur H, Edgar LC, Whalen G, Rook AH, et al. (1983) Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 309: 453-458.
  152. Sachdeva M, Fischl MA, Pahwa R, Sachdeva N, Pahwa S (2010) Immune exhaustion occurs concomitantly with immune activation and decrease in regulatory T cells in viremic chronically HIV-1-infected patients. J Acquir Immune Defic Syndr 54: 447-454.
  153. Aandahl EM, Aukrust P, Skålhegg BS, Müller F, Frøland SS, et al. (1998) Protein kinase A type I antagonist restores immune responses of T cells from HIV-infected patients. FASEB J 12: 855-862.
  154. Vang T, Torgersen KM, Sundvold V, Saxena M, Levy FO, et al. (2001) Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. J Exp Med 193: 497-507.
  155. Mahic M, Yaqub S, Johansson CC, Taskén K, Aandahl EM (2006) FOXP3+CD4+CD25+ adaptive regulatory T cells express cyclooxygenase-2 and suppress effector T cells by a prostaglandin E2-dependent mechanism. J Immunol 177: 246-254.
  156. Pettersen FO, Torheim EA, Dahm AE, Aaberge IS, Lind A, et al. (2011) An exploratory trial of cyclooxygenase type 2 inhibitor in HIV-1 infection: downregulated immune activation and improved T cell-dependent vaccine responses. J Virol 85: 6557-6566.
  157. Fonteneau JF, Larsson M, Beignon AS, McKenna K, Dasilva I, et al. (2004) Human immunodeficiency virus type 1 activates plasmacytoid dendritic cells and concomitantly induces the bystander maturation of myeloid dendritic cells. J Virol 78: 5223-5232.
  158. Taylor EW (2010) The oxidative stress-induced niacin sink (OSINS) model for HIV pathogenesis. Toxicology 278: 124-130.
  159. Boasso A, Herbeuval JP, Hardy AW, Anderson SA, Dolan MJ, et al. (2007) HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells. Blood 109: 3351-3359.
Citation: Salmen S, Berrueta L (2012) Immune Modulators of HIV Infection: The Role of Reactive Oxygen Species. J Clin Cell Immunol 3:121.

Copyright: © 2012 Salmen S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Top