Interferon-α Causes Neuronal Dysfunction in Encephalitis

Interferon-alpha (IFN alpha) is a pleomorphic cytokine produced by nucleated cells in response to viral infection. In patients, treatment with IFN alpha has side effects including cognitive impairment resembling subcortical dementia, which is a hallmark of human immunodeficiency virus (HIV)-associated dementia (HAD). IFN alpha is increased in the CSF of HAD patients compared with HIV patients without dementia. In this study, blocking IFN alpha in a HIV encephalitis (HIVE) mouse model with intraperitoneal injections of IFN alpha neutralizing antibodies (NAbs) significantly improved cognitive function compared with untreated or control antibody-treated HIVE mice during water radial arm maze behavioral testing. Treatment with IFN alpha NAbs significantly decreased microgliosis and prevented loss of dendritic arborization in the brains of HIVE mice. Furthermore, treatment of primary neuron cultures with IFN alpha resulted in dose-dependent loss of dendritic arborization that was blocked with IFN alpha NAb treatment and partially blocked with NMDA antagonists [AP5 and MK801 (dizocilpine maleate)] indicating glutamate signaling is involved in IFN alpha-mediated neuronal damage. These results show that IFN alpha has a major role in the pathogenesis of HIVE in mice and is likely important in the development neurocognitive dysfunction in humans with HIV. Blocking IFN alpha could be important in improving cognitive and pathological developments in HAD patients and may be clinically important in other neuroinflammatory diseases as well.