As the most abundant glial cells population within the central nervous system (CNS), astrocytes play an important role in the CNS inflammatory reactions. However, there is emerging evidence that astrocytes participate in the CNS innate immunity, as they display an array of receptors involved in innate immunity. Astrocytes express certain members of the Toll-like receptors (TLR) family, in particular, TLR3, a major trigger of innate immune response to viral infections. In addition, astrocytes functionally express retinoic acid-inducible gene-I (RIG-I), a key mediator of antiviral immunity. Our early studies demonstrated that the activation of TLR3 in astrocytes inhibited HSV replication. We also showed that TLR3 signaling of macrophages suppress HIV replication. However, it is unclear about the role of TLR3/RIG-I signaling of astrocytes in the neuroprotection and CNS innate immunity against HIV. Also, there is little information about whether opioids impair the antiviral function of astrocytes. The overall aim of this project is to determine the anti-HIV activity and neuroprotective effect of TLR3 and RIG-I activation of astrocytes and the impact of opioids on astroglial TLR3/RIG-I signaling. We hypothesize that the astroglial TLR3/RIG-I signaling can mount an effective immunity against HIV and protect neuronal cells. Furthermore, we hypothesize that morphine compromises astrocyte-mediated antiviral immunity and facilitates HIV infection of microglia. We propose two specific aims to address these hypotheses:
Aim 1 Determine the effect of astroglial TLR3/RIG-I signaling on HIV infection of microglia (glia-glia interaction) and the impact of morphine on this astrocyte-mediated anti-HIV action.
Aim 2 Determine the effect of astroglial TLR3/RIG-I signaling on the neuronal cell protection in the context of morphine use and/or HIV. These proposed studies should for the first time provide insight of the beneficial role of astroglia TLR3/RIG- I signaling in the neuronal cell protection ad the CNS innate immunity against HIV.
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