Infection with Human Immunodeficiency virus (HIV)-1 can induce dementia for which currently no treatment is available. Several lines of evidence strongly suggest that neurodegeneration occurs as a consequence of HIV-1 infection and neurotoxic immune stimulation of microglia and macrophages (M?) in the brain and impairment of neurogenesis. HIV-1 also triggers an innate immune response that includes production of interferons (IFNs). IFN? has been implicated in the control of HIV infection in the brain and has pronounced anti-inflammatory effects. In the previous funding period we found: First, a CNS gene expression analysis of HIV/gp120 transgenic (tg) mice revealed a limited IFN response. HIV/gp120tg brains transiently expressed IFN? at 1.5 but not 3 or 6 months of age when neuropathology and behavioral impairment developed. Second, we found that a four-week intranasal (i.n.) IFN? treatment starting at 3.5 months of age completely prevented neuronal damage in HIV/gp120tg mice. Third, IFN? protected neurons in vitro against neurotoxicity of HIV/gp120 by early induction of CCL3, which occurred most efficiently in the presence of microglia. In this renewal application we propose to characterize i) the contribution of the endogenous IFN response and ii) the cell type-specific role of IFN?/? receptor 1 (IFNAR1) and IFN-stimulated genes (ISGs) in neuroprotection by IFN? against toxicity of HIV-1 or gp120. We hypothesize that IFN? can protect neurons from HIV-1/gp120 induced toxicity and preserve behavioral performance by a mechanisms, comprising induction of neuroprotective IFN-stimulated genes (ISG) such as IRF1 and CCL3 and inhibition of inflammation.
The specific aims are: (1) To study in vivo how endogenous IFN? affects neuronal damage in a HIV/gp120 transgenic mouse model and the animals' response to intranasal IFN? treatment. (2) To examine in vivo whether the interferon ?/? receptor 1 (IFNAR1) of microglia or astrocytes or neurons are necessary for neuroprotection by IFN? against toxicity of HIV/gp120. (3) To assess whether a continuous supply of exogenous IFN? can restrict HIV-1 infection and the associated neurotoxicity of M? via induction of a subset of anti-viral ISGs.
For Specific Aims 1 and 2, IFN? will be administered via an intranasal route, which allows bypassing the blood brain barrier while delivering the drug to the brain. Memory and cognition-based behavioral performance, neuronal injury and gliosis will be compared in IFN?- versus vehicle-treated HIV/gp120-transgenic mice lacking endogenous IFN? or its receptor IFNAR1. We will also assess which neural cell type(s) are required to interact with IFN? in order to preserve memory and cognition and to reduce gliosis in the presence of HIV/gp120.
Specific Aim 3 will define an RNA signature of neurotoxic HIV-1 infected M? using RNA-sequencing and will test the premise that exogenous IFN? can overcome the down- regulation of antiviral factors and production of neurotoxins by HIV-1. All three Specific Aims will test the premise that IFN? induces neuroprotective ?-chemokines, increases activity of Akt and reduces activity of p38 MAPK, and thus protects neurons and their dendrites and synapses from HIV or gp120-induced toxicity of microglia and M?.

Public Health Relevance

HIV infection, AIDS and HIV-associated dementia remain a substantial public health concern and the proposed research aims at finding improved treatments by better understanding the disease process. Characterization of the neuroprotective potential of anti-viral cytokines, such as interferon-?, versus the neurotoxic mechanisms in neural cell type(s) and macrophages involved in HIV-1 induced neurodegeneration may provide the basis for future therapeutic strategies aimed at preventing neuronal injury and death observed in brains of children and adults infected with HIV-1. The scientific long-term objectives are to find future therapeutic targets and thus new potential treatments for HIV-associated dementia via the analysis of intercellular and intracellular signaling mechanisms affected by HIV-1 and cytokines.

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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Colosi, Deborah
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Sanford Burnham Prebys Medical Discovery Institute
La Jolla
United States
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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:
Thaney, Victoria E; O'Neill, Alan M; Hoefer, Melanie M et al. (2017) IFN? Protects Neurons from Damage in a Murine Model of HIV-1 Associated Brain Injury. Sci Rep 7:46514
Kaul, Marcus (2017) The 23rd Scientific Conference of the Society on Neuroimmune Pharmacology. J Neuroimmune Pharmacol 12:1-2
Thaney, Victoria E; Sanchez, Ana B; Fields, Jerel A et al. (2017) Transgenic mice expressing HIV-1 envelope protein gp120 in the brain as an animal model in neuroAIDS research. J Neurovirol :
Noel, Richard J; Kaul, Marcus (2016) The 22nd Scientific Conference of the Society on Neuroimmune Pharmacology. J Neuroimmune Pharmacol 11 Suppl 1:S1-2
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