Neuroprotection by IFN-beta in AIDS

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 DESCRIPTION (provided by applicant): 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 (MΦ) in the brain and impairment of neurogenesis. HIV-1 also triggers an innate immune response that includes production of interferons (IFNs). IFNβ 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 IFNβ 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.) IFNβ treatment starting at 3.5 months of age completely prevented neuronal damage in HIV/gp120tg mice. Third, IFNβ 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 IFNα/β receptor 1 (IFNAR1) and IFN-stimulated genes (ISGs) in neuroprotection by IFNβ against toxicity of HIV-1 or gp120. We hypothesize that IFNβ 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 IFNβ affects neuronal damage in a HIV/gp120 transgenic mouse model and the animals' response to intranasal IFNβ treatment. (2) To examine in vivo whether the interferon α/β receptor 1 (IFNAR1) of microglia or astrocytes or neurons are necessary for neuroprotection by IFNβ against toxicity of HIV/gp120. (3) To assess whether a continuous supply of exogenous IFNβ can restrict HIV-1 infection and the associated neurotoxicity of MΦ via induction of a subset of anti-viral ISGs. For Specific Aims 1 and 2, IFNβ 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 IFNβ- versus vehicle-treated HIV/gp120-transgenic mice lacking endogenous IFNβ or its receptor IFNAR1. We will also assess which neural cell type(s) are required to interact with IFNβ 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 MΦ using RNA-sequencing and will test the premise that exogenous IFNβ can overcome the down- regulation of antiviral factors and production of neurotoxins by HIV-1. All three Specific Aims will test the premise that IFNβ induces neuroprotective β-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 MΦ.