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 (IFNß), and antiviral type 1 interferon,
preceding any behavioral or neuropathological signs in the HIVgp120 transgenic mouse and SIV models,
suggesting a neuroprotective role for IFNß in early HIV infection. We have previously shown that exogenous
intranasal exposure of HIVgp120tg animals with IFNß is sufficient to confer neuroprotection. Preliminary data
from our lab describes the ability of HIVgp120 viral protein and IFNß 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 IFNß 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.
