HIV-OPN/SPP1Triad II: Molecular Pathways Regulating Neuronal-Glial Inflammation in the Brain

PROJECT SUMMARY
The prevalence and incidence of neurological complications in people with HIV (PWH) remains steady
for those aging on antiretroviral therapy (ART). Eliminating the tight association between chronic
inflammation and HIV reservoirs in the periphery and CNS remain major therapeutic challenges. Elevated
osteopontin/secreted phosphoprotein-1 (OPN/SPP1) in PWH having moderate to severe neurological
complications was first reported in 2008. Since this time, the importance of high OPN/SPP1 RNA expression in
human brain and more widely in neurodegenerative microglia has emerged. However, much remains to
uncover about OPN/SPP1's fundamental basic molecular mechanism (s) of action in the brain in HIV infection.
In this regard, our investigations over the past several years using in vitro and in vivo experimental models have
begun to close the gap. A fundamental concept has emerged from our collective findings: OPN/SPP1 function
is required in the CNS for brain recovery and return to homeostasis after infection. For the first time, able
to knockdown OPN expression in vivo, we obtained a clearer view that its functional specificity is context-
dependent. OPN/SPP1 signaling supports viral replication in vivo within tissue compartments via an as yet
uncharacterized mechanism that varies with sex. In addition, OPN/SPP1 expression is strongly correlated with
the retention of immune cells in the peripheral organs. OPN/SPP1 supports increased trafficking of SIV
monocytes to the brain, but whether the same is true for human cells is not known. We discovered using micro-
PET neuroimaging, that when homeostasis is disrupted by HIV infection, OPN/SPP1 is a potent sensor and
regulator of neuroinflammation in the brain. An additional novel insight gained was the detection not only of
inflamed microglia, but of a unique subset of “activated” translocator protein (TSPO) and tyrosine hydroxylase
(TH) reactive neurons in the striatum. We hypothesize that the conservation of OPN as a sensor/regulator
of CNS homeostasis in adult mammals suggests that it plays a key central mechanistic role in
neuroprotective pathways that modulate neuroinflammation. Moreover, the molecular mechanisms are
tissue context-dependent and utilize ligand-receptor dynamics initiated by microglia and propagated by
specific neurons in the striatum. Teasing out of the mechanistic details requires a combinatorial approach
using basic biochemical and molecular tools, in vitro primary cell culture and the latest in vivo chimeric mouse
models. Importantly, we have successfully demonstrated that the mouse-human chimera represented in the
NSG-hCD34 system recapitulates key aspects of neuroinflammation similar to that seen in people with neuroHIV.
Testing of the underlying hypotheses of the integrated aims of this proposal will determine which splice variants
of OPN/SPP1 are active in the CNS, identify new mechanistic insights into why disruption of OPN/SPP1
increases neuroinflammatory signaling in microglia and specific neuronal subtypes, how these responses are
regulated and whether cognition or affective behaviors are altered.

Grant Number: 5R01NS102006-09
NIH Institute/Center: NIH
Principal Investigator: AMANDA BROWN