Infection with HIV-1 can induce dementia for which a treatment is currently not available. Experimental evidence from our and other laboratories strongly suggests that HIV-1 infection and neurotoxic stimulation of microglia and macrophages (M?) in the brain trigger neuronal damage and impairment of neurogenesis. We recently observed that mitogen-activated protein kinase (MAPK) p38 was required in both M?/microglia for induction of HIV/gp120 toxicity and in neurons for initiation of apoptosis by M? toxins. In follow-up studies we found that knockdown of p38? MAPK by specific siRNAs down-regulated cysteinyl leukotriene synthase (LTC4S) in M?. We also discovered that blockade of the cysteinyl-leukotriene receptor 1 (CysLTR1) protected cerebrocortical neurons against toxicity of gp120-stimulated or HIV-infected M?. Therefore, we propose to study in vivo how genetic deletion of LTC4S or blockade of CysLTR1 affects brain injury caused by HIV-1 or its envelope gp120. We hypothesize that ablation of CysLT production or CysLTR1 inhibition can prevent HIV and gp120 from inducing neuronal injury and behavioral impairment. The long-term objectives are to find new protective strategies against brain injury by HIV infection.
The specific aims (SA) are: (1) To determine in vivo whether genetic deletion of cysteinyl-leukotriene synthase (LTC4S) prevents neuronal injury and behavioral impairment in a HIV/gp120 transgenic mouse model. (2) To investigate in vivo whether pharmacological inhibition of CysLTR1 ameliorates neuronal damage in a HIV/gp120 transgenic mouse model. (3) To assess in vitro how the blockade of CysLTR1 or knockout (KO) of LTC4S enables neuronal survival in the presence of HIV-induced macrophage toxins. Transgenic mice expressing HIV/gp120 will be cross-bred with LTC4SKO animals (SA1) and Montelukast will be used to block CysLTR1 (SA2). Memory and cognition-based behavioral performance, neuronal injury and glial cell activation will be compared in LTC4SKO versus wild-type and Montelukast- versus vehicle-treated HIV/gp120-transgenic mice for SA1 and 2, respectively. For SA3, we will use pharmacological inhibition of CysLTR1 besides LTC4SKO and wild-type cerebrocortical neurons and astrocytes exposed to conditioned media of HIV-infected and un-infected, primary human M?. All three SAs will employ multi-dimensional mass spectrometry-based shotgun lipidomics to profile CysLTs in comparison to other cellular lipids and mediators in different parts of the brain (SA1 and 2) and neurons, astrocytes and M? (SA3). For all three SAs neuronal injury and death will be analyzed by deconvolution microscopy after immunolabeling for neuronal cellular and synaptic markers and staining of nuclear DNA by Hoechst dye. All three Specific Aims will test the premise that deletion of CysLT production or blockade of CysLTR1 prevents inflammatory and injurious processes in favor of neuroprotective mechanisms, such as reduced activity of p38 MAPK and Caspase 3, and increased activity of Akt,. We will also assess in vivo whether LTC4SKO and CysLTR1 blockade can preserve memory and cognition and ameliorate gliosis in the presence of HIV/gp120.

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 critical cellular signaling mechanisms and inflammatory mediators that contribute to HIV-1 induced neurodegeneration and inflammation 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH105330-03
Application #
9204433
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Rao, Vasudev
Project Start
2015-04-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$394,875
Indirect Cost
$192,375
Name
Sanford Burnham Prebys Medical Discovery Institute
Department
Type
Research Institutes
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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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