IFNβ Protects Neurons from Damage in a Murine Model of HIV-1 Associated Brain Injury

Infection with human immunodeficiency virus-1 (HIV-1) causes brain injury. Type I interferons (IFN alpha/beta) are critical mediators of any anti-viral immune response and IFN beta has been implicated in the temporary control of lentiviral infection in the brain. Here we show that transgenic mice expressing HIV-1 envelope glycoprotein 120 in their central nervous system (HIVgp120tg) mount a transient IFN beta response and provide evidence that IFN beta confers neuronal protection against HIVgp120 toxicity. In cerebrocortical cell cultures, neuroprotection by IFN beta against gp120 toxicity is dependent on IFN alpha receptor 1 (IFNAR1) and the beta-chemokine CCL4, as IFNAR1 deficiency and neutralizing antibodies against CCL4, respectively, abolish the neuroprotective effects. We find in vivo that IFN beta mRNA is significantly increased in HIVgp120tg brains at 1.5, but not 3 or 6 months of age. However, a four-week intranasal IFN alpha treatment of HIVgp120tg mice starting at 3.5 months of age increases expression of CCL4 and concomitantly protects neuronal dendrites and pre-synaptic terminals in cortex and hippocampus from gp120-induced damage. Moreover, in vivo and in vitro data suggests astrocytes are a major source of IFN beta-induced CCL4. Altogether, our results suggest exogenous IFN beta as a neuroprotective factor that has potential to ameliorate in vivo HIVgp120-induced brain injury.