Project Abstract 37 million people worldwide are diagnosed with Human Immunodeficiency Virus (HIV). Of these 37 million, an estimated 15-55% of people living with HIV develop HIV-associated neurocognitive disorder (HAND). Previous work in ours and other labs identifies a transient increase of interferon beta (IFNβ), and antiviral type 1 interferon, preceding any behavioral or neuropathological signs in the HIVgp120 transgenic mouse and SIV models, suggesting a neuroprotective role for IFNβ in early HIV infection. We have previously shown that exogenous intranasal exposure of HIVgp120tg animals with IFNβ is sufficient to confer neuroprotection. Preliminary data from our lab describes the ability of HIVgp120 viral protein and IFNβ to regulate an important cell surface transmembrane ligand, ephrin-B1, in the CNS. Neuronal ephrin-B1 has been well studied and implicated in neuronal development, recruitment of NMDA receptors and synaptic plasticity mainly through its signaling with EphB receptors. However, ephrin-B1’s functional role in HIV, particularly microglial specific ephrin-B1, has not been well characterized at all. Our preliminary data identifies a statistically significant upregulation in EphB2 mRNA (one of the main receptors of ephrin-B1) in the cortex of HIV+ Patients with brain pathology. In addition, we describe significant inverse correlations between ephrin-B1 mRNA in the cortex of HIV+ Patients with both neurocognitive domain scores and inhibitory neuronal gene expression. In a transgenic NeuroHIV mouse in vivo model, we show in the cortex and hippocampus that the presence of gp120 upregulates ephrin-B1 protein expression in a cell-specific manner, including microglia. Treatment with IFNβ marginally reduces ephrin-B1 expression but significantly reduces ephrin-B1 off the surface of microglia. We believe that enhanced signaling between EphB2 and ephrin-B1 in the CNS of HIV+ Patients may lead to enhanced inflammatory response as well as unwanted synaptic pruning, and ablation of microglial ephrin-B1 will, in part, mitigate inflammation and synaptic pruning. This proposal seeks to identify the functional consequences of regulating microglial ephrin-B1 on microglial state and neuronal health in the context of HIV.