Neurologic disease in feline immunodeficiency virus infection: disease mechanisms and therapeutic interventions for NeuroAIDS

Feline immunodeficiency virus (FIV) is a lentivirus that causes immunosuppression through virus-mediated CD4+ T cell depletion in feline species. FIV infection is complicated by virus-induced disease in the nervous system. FIV enters the brain soon after primary infection and is detected as FIV-encoded RNA, DNA, and proteins in microglia, macrophages, and astrocytes. FIV infection activates neuroinflammatory pathways including cytokines, chemokines, proteases, and ROS with accompanying neuronal injury and loss. Neurobehavioral deficits during FIV infection are manifested as impaired motor and cognitive functions. Several treatment strategies have emerged from studies of FIV neuropathogenesis including the therapeutic benefits of antiretroviral therapies, other protease inhibitors, anti-inflammatory, and neurotrophic compounds. Recently, insulin's antiviral, anti-inflammatory, and neuroprotective effects were investigated in models of lentivirus brain infection. Insulin suppressed HIV-1 replication in human microglia as well as FIV replication of lymphocytes. Insulin treatment diminished cytokine and chemokine activation in HIV-infected microglia while also protecting neurons from HIV-1 Vpr protein-mediated neurotoxicity. Intranasal (IN) insulin delivery for 6 weeks suppressed FIV expression in the brains of treated cats. IN insulin also reduced neuroinflammation and protected neurons in the hippocampus, striatum, and neocortex of FIV-infected animals. These morphological and molecular effects of IN insulin were confirmed by neurobehavioral studies that showed IN insulin-treated FIV-infected animals displayed improved motor and cognitive performance compared to sham-treated FIV-infected animals. Thus, FIV infection of the nervous system provides a valuable comparative in vivo model for discovering and evaluating disease mechanisms as well as developing therapeutic strategies for NeuroAIDS in humans.