UC Riverside

Human immunodeficiency virus-1 (HIV-1) is a retrovirus that can infiltrate and infect the central nervous system (CNS) leading to HIV-associated neurocognitive disorders (HAND). HAND is a condition behaviorally characterized by cognitive and neurological impairments, and pathologically characterized by rampant inflammation and loss of synaptic integrity. Although therapeutics exist to increase the lifespan of people living with HIV, the overall prevalence of HAND and the presence of HIV induced neuronal damage remains unchanged. Understanding the mechanisms underlying the neuropathology in HIV will guide the development of more efficacious therapeutics.One hallmark response to HIV is the type I interferon antiviral response. HIV-1, and an HIVgp120 transgenic (HIVgp120tg) mouse model, both activate the innate immune system, including the production of type 1 interferons (IFNs) α and β, and induction of IFN-stimulated genes (ISG). In this dissertation, we characterize IFNβ’s role in HIVgp120tg induced neuroHIV using an IFNβKO mouse model. The neuropathology observed in HIVgp120tg is only moderately affected by the KO of IFNβ but in a sex-dependent fashion. Notably, IFNβKO results in an amelioration of neuronal presynaptic terminal damage but no protection of neuronal dendrites in the hippocampal CA1 region of HIVgp120tg mice. Additionally, female IFNβ-deficient HIVgp120tg mice display diminished microglial activation in the cortex and hippocampus. IFNβKO abrogates or diminishes the induction of type I interferon related genes including MX1, DDX58, IRF7, and IRF9 in HIVgp120tg brains. Additionally, the effects of IFNβKO on MAPK activities with a pronounced reduction of active ERK1/2 and active p38 in the HIVgp120tg brain. In summary, these findings show that IFNβ’s absence in the presence of HIVgp120, is partially protective when assessing hippocampal pre-synaptic terminals and microglial counts, but partially damaging based on cortical dendritic assessment. Moreover, IFNβ plays a vital role in mediating the gp120 induced type I interferon response, expression of pro-inflammatory markers, and MAPK signaling. Additionally, we highlight the activation of ephrin-B/EphB in the CNS of people living with HIV driven, at least in part, by gp120 viral envelope protein and type I interferon, IFNβ. Furthermore, EphB2 mediated ephrin-B reverse signaling onto microglia induces a prominent pro-inflammatory and antiviral signature with the capacity for this microglial specific pro-inflammatory secretome profile to induce non-contact dependent neurotoxicity. Finally, knockdown of microglial ephrin-B1, a binding partner for EphB2, shows a partial alleviation of the microglial pro-inflammatory signature and resulting neurotoxicity. Elevated EphB2 and its signaling onto microglia may present as a novel mechanism of neuroinflammation, and mediator of neurotoxicity, seen in the context of neuroHIV and potentially other neurodegenerative diseases.