Infection with Human Immunodeficiency virus (HIV)-1 injures the brain and compromises memory and cognition. Our and other laboratories have found consistent evidence that HIV-1 infection and neurotoxic immune stimulation of microglia and macrophages (MF) in the brain trigger neuronal damage and impairment of neurogenesis. Recently, we found in a transgenic (tg) model of HIV-associated brain injury induced by a CXCR4-utilizing viral envelope gp120 that the genetic knockout (KO) of CCR5 prevented microglial activation and neuronal damage. The CCR5KO also protected gp120tg mice from impairment of spatial learning and memory. Thus CCR5 critically contributed to brain injury by a CXCR4-utilizing gp120. In additional studies we identified lipocalin-2 (LCN2), an acute phase protein, as a novel potentially cytotoxic player in HIVgp120- associated neuronal injury as well as reduction of microglial cell numbers in the CCR5KO. However, the extent to which LCN2 contributes to HIV/gp120-associated brain injury in vivo and the molecular mechanisms of the interaction between LCN2 and CCR5 are unknown and will be studied here using in vivo and in vitro models. We hypothesize that genetic deletion of LCN2 can ameliorate or prevent neuronal damage and behavioral impairment induced by HIV and gp120. The long-term objectives are to find new therapeutic targets for prevention of HIV-associated brain injury.
The specific aims (SA) are: (1) To study in vivo whether genetic deletion of lipocalin-2 prevents neuronal damage and astrocytosis in a HIV/gp120 transgenic mouse model. (2) To investigate whether deletion or knockdown of lipocalin-2 in microglia or MF ameliorates the cells' neurotoxicity induced by HIV-infection or viral gp120. (3) To assess whether deletion of lipocalin-2 in neurons and astrocytes suffices to protect the cells against HIV-1 or gp120-induced neurotoxicity of microglia and MF. We have already generated LCN2-deficient HIVgp120tg animals of both CCR5WT and CCR5KO genotypes proving viability. We will assess performance in behavioral tasks of memory and cognition, and analyze neuronal injury and gliosis in comparison with control animals in SA1. For SA2 and 3, we will use neurons, astrocytes and microglia of LCN2KO, CCR5KO and WT in mixed genotype cerebrocortical cell cultures in combination with HIV-infected human macrophages to analyze the contribution of the distinct cell types to neurotoxicity of HIV-1, gp120 and LCN2. For all three Specific Aims cellular injury and death will be analyzed by deconvolution microscopy after immunolabeling for neuronal cellular and synaptic markers and fluorescence staining of intact and fragmented nuclear DNA. Biochemical, molecular biology and imaging techniques will be employed to monitor and study the involvement of LCN2 and its receptors, iron-regulatory proteins, signaling factors, cell death-related proteins, markers of astrocyte and microglia/MF activation and HIV/gp120 receptors. In addition, time course experiments and bioinformatic tools will be used to identify and characterize mechanistically involved biological networks and pathways.

Public Health Relevance

HIV infection, AIDS and HIV-associated disorders, including dementia, remain a substantial public health concern and the proposed research aims at improving our understanding of the disease process and mediating the development of treatments. Characterization of the contribution to HIV-1 induced neurodegeneration and inflammation of critical components of the innate immune system, such as acute phase proteins, may provide the basis for future therapeutic strategies. The scientific long-term objectives are to find future therapeutic targets and thus new potential treatments for HIV-associated brain injury.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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NeuroAIDS and other End-Organ Diseases Study Section (NAED)
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Joseph, Jeymohan
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Sanford Burnham Prebys Medical Discovery Institute
La Jolla
United States
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Thaney, Victoria E; Kaul, Marcus (2018) Type I Interferons in NeuroHIV. Viral Immunol :
Thaney, Victoria E; Sanchez, Ana B; Fields, Jerel A et al. (2018) Transgenic mice expressing HIV-1 envelope protein gp120 in the brain as an animal model in neuroAIDS research. J Neurovirol 24:156-167
Sanchez, Ana B; Kaul, Marcus (2017) Neuronal Stress and Injury Caused by HIV-1, cART and Drug Abuse: Converging Contributions to HAND. Brain Sci 7:
Noel, Richard J; Kaul, Marcus (2016) The 22nd Scientific Conference of the Society on Neuroimmune Pharmacology. J Neuroimmune Pharmacol 11 Suppl 1:S1-2
Sanchez, Ana B; Varano, Giuseppe P; de Rozieres, Cyrus M et al. (2016) Antiretrovirals, Methamphetamine, and HIV-1 Envelope Protein gp120 Compromise Neuronal Energy Homeostasis in Association with Various Degrees of Synaptic and Neuritic Damage. Antimicrob Agents Chemother 60:168-79
Sanchez, Ana B; Medders, Kathryn E; Maung, Ricky et al. (2016) CXCL12-induced neurotoxicity critically depends on NMDA receptor-gated and L-type Ca(2+) channels upstream of p38 MAPK. J Neuroinflammation 13:252