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

Abstract

Infection with human immunodeficiency virus-1 (HIV-1) causes brain injury. Type I interferons (IFNα/β) are critical mediators of any anti-viral immune response and IFNβ 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 IFNβ response and provide evidence that IFNβ confers neuronal protection against HIVgp120 toxicity. In cerebrocortical cell cultures, neuroprotection by IFNβ against gp120 toxicity is dependent on IFNα receptor 1 (IFNAR1) and the β-chemokine CCL4, as IFNAR1 deficiency and neutralizing antibodies against CCL4, respectively, abolish the neuroprotective effects. We find in vivo that IFNβ mRNA is significantly increased in HIVgp120tg brains at 1.5, but not 3 or 6 months of age. However, a four-week intranasal IFNβ 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 IFNβ-induced CCL4. Altogether, our results suggest exogenous IFNβ as a neuroprotective factor that has potential to ameliorate in vivo HIVgp120-induced brain injury.

Transgenic mice expressing HIV-1 envelope protein gp120 in the brain as an animal model in neuroAIDS research

“…The gene expression pattern indicative of a type I IFN signature was in accordance with an earlier report of IFN-stimulated gene (ISG)-15 in the brain of HIVgp120tg mice (Wang et al , 2012). A recent follow-up study confirmed that GFAP-gp120tg mice mounted a transient IFNβ response around 1.5 months of age (Thaney et al , 2017). While the mRNA expression for IFNβ had returned to baseline in 3 and 6 months-old animals, the signature of IFN-stimulated genes remained detectable.…”

“…Moreover, a peripheral immune challenge with recombinant gp160 triggered a strong lymphocyte-mediated immune response and infiltration of the brain only in gp120tg animals, but not non-tg littermate controls or in GFAP-LacZ tg mice, thus providing indirect evidence for the presence of viral envelope protein in the CNS of gp120tg mice (Toggas and Mucke, 1998). Several subsequent studies included an additional GFAP-gp120tg founder line that expresses more easily detectable envelope protein levels and therefore is called gp120tg H igh P rotein E xpressor, (HPX) line (Garden et al , 2002; Lee et al , 2011; Maung et al , 2014; Thaney et al , 2017; Toggas and Mucke, 1996). The studies discussed here served at least one of two purposes: either improving our understanding of the neuropathological mechanism(s) of HIV infection, or exploring potential future therapies for NeuroAIDS and HAND.…”

“…In contrast, IFNβ has been implicated in the control of HIV and SIV infection in the brain (Barber et al , 2004; Kitai et al , 2000). A recent study showed that IFNβ confers neuronal protection against HIVgp120 toxicity and GFAP-gp120tg mice mount a transient IFNβ response with IFNβ mRNA significantly increased in brains at 1.5, but not 3 or 6 months of age (Thaney et al , 2017). Neuroprotection by IFNβ against toxicity of HIVgp120 required IFNα receptor 1 (IFNAR1) and the β-chemokine CCL4.…”

“…Neuroprotection by IFNβ against toxicity of HIVgp120 required IFNα receptor 1 (IFNAR1) and the β-chemokine CCL4. Moreover, a four-week intranasal IFNβ treatment of HIVgp120tg mice starting at 3.5 months of age increased expression of CCL4 and concomitantly abrogated gp120-induced damage to neuronal dendrites and pre-synaptic terminals in hippocampus and cerebral cortex (Thaney et al , 2017). Altogether, the results suggested exogenous IFNβ as a neuroprotective factor that has potential to ameliorate in vivo HIV-induced brain injury.…”

Understanding the Role of Antiviral Cytokines and Chemokines on Neural Stem/Progenitor Cell Activity and Survival

“…IFNb is induced in the CNS during many neurotropic infections, including WNV, La Crosse virus, HIV, and HSV-1 (9,33,70,130,136). IFNb signaling is crucial for viral control in the brain for WNV and HSV-1 infections, and may be neuroprotective and limit viral replication during HIV infection of the CNS (9,10,70,119,130). HSV-infected NSPCs can produce IFNb, suggesting that the NSPCs may have an autocrine response to IFNb (114).…”