Abstract 37 million people worldwide are diagnosed with Human Immunodeficiency Virus (HIV). An estimated 15–55% of these individuals develop HIV-associated neurocognitive disorder (HAND). Previous studies, including work in our lab identifies a transient increase of interferon beta (IFNβ), an anti-inflammatory and anti-viral type 1 interferon, preceding any behavioral or neuropathological signs in the HIVgp120 transgenic mouse and Simian Immunodeficiency Virus (SIV) models, suggesting a neuroprotective role for IFNβ in early HIV infection. We have previously shown that exogenous intranasal IFNβ treatment is sufficient to confer neuronal protection in HIVgp120 transgenic mice. However, the mechanism by which IFNβ mediates neuroprotection remains unclear. Here we focus primarily on the microglial contribution to IFNβ mediated neuroprotection, as HIV productively infects macrophage/microglia in the CNS. In this study, we show that abrogating IFNβ down regulates expression of viral sensor, RIG-I, as well as interferon regulatory factors, IRF9, and most robustly IRF7 in the cortex of IFNβ KO HIVgp120tg mice. In addition, using the HMC3 human microglial cell line we show a robust dose dependent increase in innate immune anti-viral genes including IRF7, IFIT1, GBP1 and GBP4. Beyond its anti-viral effects, IFNβ treated microglia are potent inducers of the neuroprotective beta chemokines MIP-1a (CCL3), MIP-1b (CCL4) and RANTES (CCL5). Taken together, this data suggests that IFNβ may be conferring neuroprotection through microglial specific induction of anti-viral genes and neuroprotective beta chemokines CCL3, -4 and -5.

Elucidating the mechanism of Interferon Beta (IFNβ) mediated neuroprotection in HIV associated neurocognitive disorder (HAND)