Jialin C. Zheng, M.D. - US grants

DESCRIPTION (Provided by applicant): Increased numbers of activated brain MP (perivascular and brain macrophages and resident microglia) remain the principal histologic correlate for dementia in late-stage HIV- disease. We hypothesize that in HAD HIV-1-infected and immune-activated MP secrete soluble toxins that damage neural tissue, ultimately causing cognitive and motor dysfunction. Two aspects of this hypothesis remain poorly understood. First, mechanisms underlying brain MP activation in HAD are not known. Recently, we demonstrated increased expression of the immune molecule CD40 ligand (CD40L) on peripheral blood mononuclear cells from late-stage HIV-1 patients. Further, we showed that CD40L activates primary human macrophages in vitro, an effect that is potentiated by HIV-1 infection. Second, mechanisms linking MP activation to neuronal dysfunction are not well defined. Two important classes of molecules, chemokines and excitatory neurotoxins, are secreted by HIV-1-infected, immune-activated macrophages and may alter neuronal function through receptor-mediated or non-specific mechanisms. Indeed, human neurons express receptors for both chemokines and glutamate. In toto,we believe that CD40Lstimulation of virus-infected brain MP induces the production of chemokines and glutamate, which ultimately lead to neuronal compromise. Using primary human macrophage and neuronal culture systems, we propose to study mechanisms that underlie macrophage activation in HAD and link macrophage activation to neuronal dysfunction. This proposal integrates disciplines of virology, immunology, and receptor pharmacology in a mechanistic study of HAD.

Brain mononuclear phagocyte (MP; macrophage and microglia) activation and neuronal injury are central features of HIV-1 encephalitis (HIVE), the pathological correlate of HIV-1-associated dementia (HAD). However, the pathways through which brain MP activation occurs and elicits neuronal dysfunction remains poorly understood. Recently, others and we demonstrated that neural injury can directly affect MP activation, through production of neuronal chemokines such as fractalkine (FKN). FKN is constitutively expressed on neurons and can be released in a soluble form. FKN can activate MP and induce cytokine secretion. Further, CSF levels of FKN are higher in HAD patients than in infected subjects without neurological disease. Thus, we hypothesize that MP recruitment and activation in HAD is regulated, in part, by FKN. While it is acknowledged that MP secrete both neurotrophic and toxic factors following viral infection and activation, the signaling pathways which selectively regulate these processes remain to be elucidated. To this end, we propose that FKN-stimulation and HIV-1 infection of brain MP leads to the activation of multiple protein kinase pathways, such as the MAP kinases. Activation of these pathways result in neurotrophic and toxic factor dysregulation and ultimately neuronal compromise. Primary human macrophage, microglia and neuronal culture systems, combined with "state-of-the-art" human gene microarray technology, will be used to study how FKN mediates MP activation, affects intracellular signaling pathways, and regulates both neurotrophic and neurotoxic factor production. The determination of mechanisms involved in FKN-mediated MP activation and secretory factor production may assist in identification of potential targets for therapeutic intervention. This project unites with others in the program in seeking to determine how MP immunity affects the neurodegenerative process associated with HAD.

AIDS /HIV neuropathy; human immunodeficiency virus 1; virus cytopathogenic effect; clinical research;

DESCRIPTION (provided by applicant): Brain inflammation underlies the neuropathogenesis of HIV-1 infection. What triggers neuronal death and the inflammatory mechanism driving neurological disease affects multiple neurodegenerative disorders including HIV-1-associated dementia (HAD). One important and newly discovered inflammatory mediator implicated in the pathogenesis of HAD is TRAIL. TRAIL, a member of the TNF superfamily, mediates immunoregulatory and inflammatory responses through its interaction with TRAIL receptor one (R1) and two (R2), decoy receptors (R3 and R4), and a soluble receptor, osteoprotegerin (OPG). Recently, we demonstrated that TRAIL is upregulated on HIV-infected, immune-activated macrophages. Importantly, TRAIL induces neuronal cell death by binding to neuronal death receptors. Of further importance to HAD are the described links between glutamate and TRAIL. HIV-1 infection of macrophage leads to the upregulation of glutaminase C (the GAC isoform of the glutaminase gene) and consequently increased glutamate production. Recombinant TRAIL enhances HIV-1 infected macrophage death leading to the significant increase of glutamate production that affects macrophage mediated neuronal injury. Based on these preliminary results, this competitive renewal proposal will examine the hypothesis that an important inflammatory event in HAD is the upregulation of TRAIL expression. We argue that this is a significant pathogenic event that triggers macrophage-neuron and macrophage-macrophage interactions engaging death receptors and affecting signaling events eventually leading to generalized cell death. Moreover, we hypothesize that a specific consequence of TRAIL mediated MP death is glutaminase release, increasing drain glutamate levels and leading to secondary neuronal death. This project will develop assays that mimic brain macrophage activation, neuronal injury and apoptotic signaling that occur in HAD. The elucidation of the mechanisms by which TRAIL-TRAIL receptors and glutaminase interact during MP mediated neuronal injury may open up new therapeutic ideas for disease treatment or prevention.

DESCRIPTION (provided by applicant): HIV-1 clade C is currently responsible for more than 50% of new HIV infections and is now the most commonly transmitted subtype worldwide. While HIV-1-associated dementia (HAD) continues to be a major neuropathological manifestation of AIDS among clade B-infected individuals in the US and Europe, the incidence of HAD in regions like India and sub-Saharan Africa, where clade C infection is prevalent, appears to be lower. Whether the low apparent prevalence of neuroAIDS is due to underlying differences in HIV-clade pathogenesis or simply an artifact of confounding variables such as data sampling, clinical diagnosis or opportunistic infections is unclear. Potential differences in clade B and C neurovirulence and the mechanism by which HIV-1 infected brain mononuclear phagocytes (MP;perivascular macrophages and microglia) mediate pathogenesis have yet to be investigated. Our recent preliminary data indicates clade B viral strains may produce more neurotoxins, such as glutamate, during HIV-1 infection than clade C viral strains. We have shown previously that HIV-1 clade B infection of MP leads to enhanced glutamate production through the enzyme glutaminase. In this R21 application, we hypothesize that neurotoxicity is mediated through brain inflammation and the dysregulation of glutaminase in HIV-1-infected macrophages. In comparison to HIV clade B, we hypothesize clade C isolates will demonstrate decreased infection efficiency, altered cytokine/chemokine profiles, and decreased glutamate production by infected MP, providing mechanistic insight into differences between clade B and C infection of the brain. We will apply human monocyte-derived macrophage (MDM) infected by a panel of HIV-1 strains (HIV-1 laboratory clade B strains, primary clade B strains and primary clade C strains), to a severe combined immune deficient (SCID) HIV-1 encephalitis (HIVE) mouse model, thus modeling macrophage driven HAD in vivo. This approach will utilize laboratory assays that mimic HIV-1 infection and immune activation of brain MP to investigate the effects of the CNS immune response on production of inflammatory factors and neurotoxins as well as neuronal injury as it occurs during HAD. This application will establish a foundation of work detailing the differences between viral clades and the potential implications for HIV-induced brain inflammation and dementia. Determining the mechanisms by which HIV-1 infected MP and cytokines influence neuronal injury may identify new therapeutic strategies for treating HAD and other neurodegenerative disorders. HIV-1 viral strain clade C is currently responsible for more than 50% of new HIV infections and is now the most commonly transmitted subtype worldwide. While HIV-1-associated dementia continues to be a major neurological complication of AIDS among HIV-1 clade B-infected individuals in the US and Europe, the incidence of HIV-1-associated dementia in regions like India and sub-Saharan Africa, where clade C infection is prevalent, appears to be lower. This application will establish a foundation of work detailing the differences between viral clade B and C and the potential implications for HIV-induced dementia. It is our hope that determining the mechanisms by which HIV-1 influence neuronal injury may identify new therapeutic strategies for treating HIV-1-associated dementia and other neurodegenerative disorders.

5-BrdU; 5-Bromo-2'-deoxyuridine; 5-Bromodeoxyuridine; 5-Bromouracil deoxyriboside; 5-Bromouracil-2-deoxyriboside; 5-Budr; 72-kDa Gelatinase; 72-kDa Type IV Collagenase; 72kD type IV Collagenase; AIDS Dementia; AIDS Dementia Complex; AIDS Virus; AIDS with dementia; AIDS-related dementia; Acquired Immune Deficiency Syndrome related dementia; Affect; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers disease; Amentia; Amino Acids; Ammon Horn; Animal Model; Animal Models and Related Studies; Animals; Area; Assay; Astrocytes; Astrocytus; Astroglia; Attenuated; Autopsy; BHLH Protein; BUdR; Basal Ganglia; Basal Nuclei; Basic HLH Protein; Basic Helix-Loop-Helix Protein; Basic Helix-Loop-Helix Transcription Factors; Bioassay; Biologic Assays; Biological Assay; Blood monocyte; Blotting, Western; Body Tissues; Brain; Brain Diseases, Metabolic; BrdU; Bromodeoxyuridine; Bromodeoxyuridine (BUDR); Bromouracil Deoxyriboside; Broxuridine; C-X-C Chemokine Receptor Type 4; CD184 Antigen; CXC-R4; CXCL12 protein; CXCR-4; CXCR4; CXCR4 Receptors; CXCR4 gene; Cachectin; Cachectin-Tumor Necrosis Factor; Cathepsin G; Cell Communication and Signaling; Cell Culture System; Cell Function; Cell Growth in Number; Cell Locomotion; Cell Migration; Cell Mobility; Cell Movement; Cell Multiplication; Cell Process; Cell Proliferation; Cell Signaling; Cell physiology; Cell/Tissue, Immunohistochemistry; Cells; Cellular Function; Cellular Migration; Cellular Mobility; Cellular Physiology; Cellular Process; Cellular Proliferation; Central Nervous System Viral Diseases; Cerebrospinal Fluid; Chemokine (C-X-C Motif) Ligand 12; Chemokine (C-X-C Motif) Receptor 4; Chemokine, CXC Motif, Receptor 4; Chemotaxis; Class; Cleaved cell; Co-culture; Cocultivation; Coculture; Coculture Techniques; Collaborations; Confocal Microscopy; Consequences of HIV; Cornu Ammonis; Cytokine Receptors; Cytokines, Chemotactic; D2S201E; Data; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Dementia; Dementia Complex, AIDS-Related; Dementia Complex, Acquired Immune Deficiency Syndrome; Dementia Due to HIV Disease; Dementia associated with AIDS; Dementia in human immunodeficiency virus (HIV) disease; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Disease; Disease Progression; Disorder; EC 2.7.2-; Encephalitis; Encephalon; Encephalons; Encephalopathies, Metabolic; Envelope Glycoprotein gp120, HIV; Environment; Enzymes; Event; Extracellular Signal-Regulated Kinases; FB22; Figs; Figs - dietary; Foundations; Fusin; GFAC; GFP; Gelatinase A; Gelatinase Neutrophil; Gene Action Regulation; Gene Expression Regulation; Gene Inactivation; Gene Products, RNA; Gene Regulation; Gene Regulation Process; Gene Silencing; Genes; Glia; Glial Cells; Goals; Granulocyte Elastase; Green Fluorescent Proteins; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; HIV Dementia; HIV Envelope Protein gp120; HIV Infections; HIV associated dementia; HIV-1; HIV-1 associated dementia; HIV-1 dementia; HIV-Associated Cognitive Motor Complex; HIV-I; HIV-related dementia; HIV1; HM89; HSY3RR; HTLV-III Infections; HTLV-III gp120; HTLV-III-LAV Infections; Harvest; Hippocampus; Hippocampus (Brain); Homologous Chemotactic Cytokines; Hortega cell; Human; Human immunodeficiency virus 1; Human, General; IHC; IL-1; IL-1 beta; IL-1-b; IL1; IL1 Receptors; IL1-Beta; IL1B Protein; IL1F2; INFLM; Idiopathic Parkinson Disease; Image Analyses; Image Analysis; Immune; Immune response; Immunity; Immunodeficiency Virus Type 1, Human; Immunohistochemistry; Immunohistochemistry Staining Method; Impairment; In Vitro; Individual; Infection; Infections, Viral CNS; Inflammation; Inflammation, Brain; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injections; Intercrines; Interleukin 1, Beta Proprotein; Interleukin 1beta; Interleukin I; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Interleukins; Intracellular Communication and Signaling; Investigation; Kinetic; Kinetics; Knockout Mice; Kolliker's reticulum; LAP3; LC/MS; LCR1; LESTR; LPS; LPS-Associated Protein 3; Label; Laboratories; Leukocyte Elastase; Leukocyte-Derived Seven-Transmembrane Domain Receptor; Lewy Body Parkinson Disease; Life; Ligands; Link; Lipopolysaccharide-Associated Protein 3; Lipopolysaccharides; Lymphocyte-Stimulating Hormone; Lysosomal Elastase; MAP kinase; MAPK; MMP-2; MMP2; MMPs; MS (Multiple Sclerosis); Macrophage Activation; Macrophage Cell Factor; Mammals, Mice; Man (Taxonomy); Man, Modern; Marrow monocyte; Matrix Metalloproteinase-2; Matrix Metalloproteinases; Measurement; Mediating; Medical Imaging, Single Photon Emission Computed Tomography; Metabolic Brain Diseases; Metabolic Brain Syndromes; Metabolic Disorders, Brain; Methods; Mice; Mice, Knock-out; Mice, Knockout; Microglia; Microscopy, Confocal; Mitogen-Activated Protein Kinases; Modality; Modeling; Modification; Monitor; Mononuclear; Motility; Motility, Cellular; Multiple Sclerosis; 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TNF-binding protein I, human; TNFR55 protein, human; TNFRSF1A; TNFRSF1A protein, human; TNFalpha receptor; Testing; Therapeutic; Therapeutic Intervention; Thinking; Thinking, function; Thymidin; Thymidine; Time; Tissues; Tomography, Emission-Computed, Single-Photon; Transcript; Tumor Necrosis Factor; Tumor Necrosis Factor Binding Protein 1; Tumor Necrosis Factor Receptor Superfamily, Member 1A; Tumor Necrosis Factor Receptor Type 1; Tumor Necrosis Factor-Alpha Receptor; Tumor Necrosis Factor-alpha; Uridine, 5-bromo-2'-deoxy-; Viral Gene Products; Viral Gene Proteins; Viral Infections, Central Nervous System; Viral Proteins; Western Blotting; Western Blottings; Western Immunoblotting; Work; Wound Healing; Wound Repair; amebocyte; aminoacid; base; biological signal transduction; brain tissue; cell motility; chemoattractant cytokine; chemokine; chemokine receptor; cleaved; cytokine; day; dementia of the Alzheimer type; disease/disorder; env Protein gp120, HIV; experiment; experimental research; experimental study; gene product; gitter cell; gliogenesis; gp120; gp120 ENV Glycoprotein; gp120(HIV); hIRH; hippocampal; host response; human T cell leukemia virus III; human T lymphotropic virus III; human TNFRSF1A protein; human disease; image evaluation; immunoresponse; in vivo; in vivo Model; injured; injury and repair; insular sclerosis; intervention therapy; liquid chromatography mass spectrometry; lymphocyte activating factor; macrophage; mesoglia; microglial cell; microgliocyte; migration; model organism; monocyte; mouse model; necropsy; nerve cement; nerve stem cell; neural; neural progenitor cells; neurodegenerative illness; neurogenesis; neuron injury; neuronal; neuronal progenitor; neuronal progenitor cells; new therapeutics; next generation therapeutics; novel; novel therapeutics; pathway; perivascular glial cell; postmortem; prevent; preventing; primary degenerative dementia; programs; protein blotting; receptor; recruit; relating to nervous system; release factor; repair; repaired; research study; response; senile dementia of the Alzheimer type; siRNA; social role; spinal fluid; stromal cell-derived factor-1alpha; tissue repair; transcription factor; tumor necrosis factor alpha receptor; tumor necrosis factor binding protein 1, human; tumor necrosis factor receptor 1 (55kD) protein, human; tumor necrosis factor receptor superfamily, member 1A protein, human; unspecified interleukin; virus protein

DESCRIPTION (provided by applicant): Neural progenitor cells (NPC) are present throughout life and replenish neurons and glia (astrocytes and oligodendrocytes) through neurogenesis, a process that requires proper migration, proliferation and differentiation of NPC. Neurogenesis appears to be dysfunctional in neurodegenerative disorders including HIV-1 associated dementia (HAD), Alzheimer's and Parkinson's diseases, where dead or injured neurons are not replaced. HAD is a neurodegenerative disorder where HIV-1-infected and activated brain mononuclear phagocytes (MP;perivascular macrophages and microglia) mediate inflammatory conditions that alter brain homeostasis. We recently demonstrated that HIV-1-infected and activated macrophages inhibit neurogenesis but enhance gliogenesis. We propose this gliogenesis is mediated through brain inflammation attributable to the dysregulation of stromal cell-derived factor 1 (SDF-1). SDF-1 is an endogenous ligand for the chemokine receptor, CXCR4, which is highly expressed on human NPC and mediates NPC migration. Improper SDF-1 and CXCR4 function can affect neural repair by impairing NPC migration. SDF-1 is released in response to glial activation, mediated by inflammatory cytokines from HIV-1-infected and activated MP such as Interleukin one beta (IL-12). SDF-1 is elevated in the cerebrospinal fluid of HAD patients. Activated matrix metalloproteinase-2 (MMP-2) is produced by HIV-1 infected and activated MP and cleaves SDF-1 resulting in a neurotoxic fragment. This proposal will examine the role of HIV-1-infected and activated macrophage in brain inflammation and their effects on neurogenesis. We hypothesize HIV-1-infected and immune- activated MP inhibit neuronal differentiation and promote gliogenesis. Specifically, we propose this shift in neurogenesis is dependent upon SDF-1 produced by activated astrocytes. This gliogenesis may be a consequence of modification/degradation of SDF-1 by factors released from HIV-1-infected MP leading to impairment of normal SDF-1/CXCR4 mediated NPC migration, survival, proliferation and differentiation, generating an environment detrimental to CNS repair. Using our human NPC culture system in a severe combined immune deficient (SCID) HIV-1 encephalitis (HIVE) mouse model, this project will mimic HIV-1-infection and immune-activation of brain MP and investigate the effect of CNS inflammation on neurogenesis. Elucidating the mechanisms of SDF-1/CXCR4 influence on neurogenesis may identify new therapeutic strategies for treating HAD and other neurodegenerative disorders. PUBLIC HEALTH RELEVANCE Globally, about 40 million people are infected with HIV. 10-20% of these individuals will eventually develop HIV-associated dementia (HAD). This work will elucidate mechanisms through which neurogenesis is affected by HAD, which could identify new therapeutic strategies for treating HAD and other neurodegenerative disorders.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Phosphorylation/dephosphorylation is the most crucial chemical reaction taking place in living organisms, which is the basis for the regulatory control of many diverse biological events triggered by extracellular effectors. Our project involves the determination of the crystal structures of two protein kinases, AceK (also a protein phosphatase) and Etk, and a protein phosphatase, calcineurin. For AceK, which possesses both kinase and phosphatase activities, the kinase and phosphatase conformations of AceK, as well as AceK-ICDH complex structures will be solved for investigating the AceK activity switch and regulatory mechanism. The structures of full length membrane Etk, its mutants, and its complex with substrate Ugd will be determined. For calcineurin, which is a calmodulin-activated central controller of signaling in eukaryotes, we have created a fusion construct (known as CBA) to facilitate the structure determination of calmodulin-calcineurin complex, which would represent a structure of calmodulin in complex with an intact substrate.

DESCRIPTION (provided by applicant): Brain inflammation underlies the neuropathogenesis of HIV-1 infection. The inflammatory mechanism driving neurological disease and neuronal injury affects multiple neurodegenerative disorders including HIV-1-associated dementia (HAD). One important and newly discovered inflammatory and neurotoxic mediator implicated in the pathogenesis of HAD is glutaminase. Glutaminase catalyzes the deamination of glutamine to glutamate and is generally localized to the inner membrane of the mitochondria. Recently, we demonstrated that glutamate is upregulated by HIV-infected, immune-activated monocyte derived macrophages (MDM) and this neurotoxic increase in glutamate represents a major contribution to macrophage-mediated neurotoxicity. Importantly, glutaminase activity is required for glutamate production, and glutaminase-specific siRNA and small-molecule glutaminase inhibitors effectively prevent excess glutamate production. Moreover, the glutaminase isoform glutaminase C (GAC) is upregulated in HIV-1-infected MDM, and GAC release may be involved in increased glutamate production. HIV-1 infection also decreases the levels of expression of microRNA-23a/b, a glutaminase-targeting member of non- coding RNAs, in HIV-1 infected MDM. Further, cytokines such as TNF-1 and IFN-1, produced by HIV-1-infected and immune-activated macrophages increase glutaminase isoform kidney type glutaminase (KGA) expression in neurons, which could potentiate macrophage mediated neurotoxicity during HIV-1 infection. Based on these preliminary results, this competitive renewal proposal will examine the hypothesis that an important event in HAD is the increase of glutaminase expression and release, mediated by inflammation and mitochondria stress during HIV- 1 infection. We argue that this is a significant pathogenic event that triggers macrophage-neuron interactions and affects signaling events eventually leading to increased brain glutamate levels and excitotoxic neuronal damage. This project will develop assays that investigate brain macrophage activation, miRNA23a/b regulation, mitochondrial stress and neuronal injury that occur in HAD. A drug delivery system including a copolymer conjugated with glutaminase and mitochondrial stress inhibitors will be examined in a severe combined immune deficient HIV-1 encephalitis mouse model. The elucidation of the mechanisms by which glutaminase mediates neuronal injury during HIV-1 infection will aid in developing potential new therapeutic agents and drug delivery systems for the treatment of HAD. PUBLIC HEALTH RELEVANCE: Globally, about 40 million people are infected with HIV. 10-20% of these individuals will eventually develop HIV-1 associated neurocognitive disorders (HAND). This work will elucidate mechanisms through which glutaminase play in neuronal injury during HAND, which could identify new therapeutic strategies for treating HAND and other neurodegenerative disorders.

? DESCRIPTION (provided by applicant): Despite the effectiveness of antiretroviral therapy, HIV-associated neurocognitive disorders (HAND) that affect HIV infected individuals continue to increase. The prevalence of HAND and incomplete reversal of neurocognitive dysfunctions after antiretroviral therapy has called for novel therapeutic approaches. Among the various pathophysiology of HAND, synaptic dysfunction likely underlies cognitive impairments. Interestingly, brain-specific HIV protein Tat expression in mice mimics key aspects of HAND pathology in the post-cART era, suggesting that Tat may be responsible for the sustained CNS complications in patients receiving cART. Tat is known to cause neuronal injury via excitotoxic mechanisms. Furthermore, HIV-1-infected patients have significantly higher concentrations of glutamate in their plasma and cerebrospinal fluid compared to uninfected controls. Elevated levels of glutamate disrupt normal neural transmission in the brain, contributing to the neuropathogenesis of HIV-1 infection. In the past decade we have established that blocking the activity of glutaminase (GLS), a primary enzyme for the production of glutamate, could alleviate macrophages/microglia (MP) neuroinflammatory and neurotoxic response. We have demonstrated causal effects of innate immune activation and proinflammatory on the GLS function in MP and neurons, respectively. Furthermore, we have observed an intriguing release of GLS by MP and neurons, through unidentified mechanism(s) that could cause neuronal injury. Therefore, in the current proposal, we hypothesize that release of GLS-containing MVs is a critical pathogenic event in HIV-1-mediated neuronal injury and synaptic dysfunction in the hippocampus. Moreover, we hypothesize that blocking aberrantly upregulated/released GLS through GLS inhibitors could have therapeutic effects in HAND. Information will be provided as whether brain-specific overexpression of GLS is sufficient to induce brain inflammation, impair synaptic integrity and cognition in mice, and whether conditional knockout of GLS gene could protect neuronal function in a Tat transgenic mouse model of HAND. Furthermore, novel water-soluble GLS inhibitors will be evaluated for their therapeutic potentials in HAND relevant animal models. The elucidation of the GLS dysregulation and its contribution to pathophysiology of HAND will aid in developing potential novel agents for the treatment of HAND and other neurodegenerative disorders.