Osteopontin (OPN) also known by its official gene designation secreted phosphoprotein‐1 (SPP1) is a fascinating, multifunctional protein expressed in a number of cell types that functions not only in intercellular communication, but also in the extracellular matrix (ECM). OPN/SPP1 possesses cytokine, chemokine, and signal transduction functions by virtue of modular structural motifs that provide interaction surfaces for integrins and CD44‐variant receptors. In humans, there are three experimentally verified splice variants of OPN/SPP1 and CD44’s ten exons are also alternatively spiced in a cell/tissue‐specific manner, although very little is known about how this is regulated in the central nervous system (CNS). Post‐translational modifications of phosphorylation, glycosylation, and localized cleavage by specific proteases in the cells and tissues where OPN/SPP1 functions, provides additional layers of specificity. However, the former make elucidating the exact molecular mechanisms of OPN/SPP1 function more complex. Flexibility in OPN/SPP1 structure and its engagement with integrins having the ability to transmit signals in inside‐out and outside‐in direction, is likely why OPN/SPP1 can serve as an early detector of inflammation and ongoing tissue damage in response to cancer, stroke, traumatic brain injury, pathogenic infection, and neurodegeneration, processes that impair tissue homeostasis. This review will focus on what is currently known about OPN/SPP1 function in the brain.

Macrophages are recognized as a putative reservoir for HIV-1, but whether HIV can establish latent infection in this cell type is not known. An in vitro model using long-term cultured primary human monocyte-derived macrophages (MDM) infected with an M-tropic, enhanced green fluorescent protein (EGFP) tagged reporter virus was developed to test the hypothesis that HIV can establish a latent infection of this cell type. The EGFP-IRES-Nef cassette allowed detection of early gene transcription. The expression of GFP+ MDM was followed with time and the GFP- population was purified and analyzed for evidence of latent infection. Interestingly, in MDM cultures propagated for over two months, distinct subpopulations of infected GFP+ cells were observed and quantitated. In particular, infected MDM that displayed a high level of transcription, characterized as the GFP hi group, yet produced low levels of the late viral gene product, p24, increased with time and represented 10% of the GFP+ population in long-term cultures. The high level production of early genes such as Nef, a protein that can facilitate viral immune escape, but low level of structural proteins such as p24 in the GFP hi population suggests that a subset of infected MDM can exhibit an alternative mode of replication. The GFP- MDM population obtained by a two-step purification protocol using flow cytometry and laser ablation contained integrated provirus as assessed by Alu-LTR real-time PCR analyses. A subset of these, were replication competent as shown by their ability to express GFP and/or p24 antigen after reactivation with IL-4.

Osteopontin (OPN) is a pro-inflammatory cytokine that can be secreted from many cells including activated macrophages and T-lymphocytes. Elevated levels of osteopontin in the plasma, cerebrospinal fluid or brain of individuals with neurodegenerative diseases such as multiple sclerosis (MS), Parkinson’s and Alzheimer’s disease and more recently in HIV-associated neurocognitive disorder has been reported. However, except for the case of MS, little is known regarding the molecular mechanisms by which OPN may exacerbate disease. Alternatively, OPN through its ability to promote cell survival may in some contexts function in the brain in a protective capacity. OPN has several protein motifs that allow it to engage with several different signaling pathways involved in immunity and inflammation. A better understanding of the cellular pathways that are regulated by OPN in cells of the central nervous system is required to uncover its putative role in neuronal homeostasis.

Zika virus (ZIKV) infection during pregnancy causes significant adverse sequelae in the developing fetus, and results in long-term structural and neurologic defects. Most preventive and therapeutic efforts have focused on the development of vaccines, antivirals, and antibodies. The placental immunologic response to ZIKV, however, has been largely overlooked as a target for therapeutic intervention. The placental inflammatory response, specifically IL-1β secretion and signaling, is induced by ZIKV infection and represents an environmental factor that is known to increase the risk of perinatal developmental abnormalities. We show in a mouse model that maternally administrated IL-1 receptor antagonist (IRA; Kineret, or anakinra), following ZIKV exposure, can preserve placental function (by improving trophoblast invasion and placental vasculature), increase fetal viability, and reduce neurobehavioral deficits in the offspring. We further demonstrate that while ZIKV RNA is highly detectable in placentas, it is not correlated with fetal viability. Beyond its effects in the placenta, we show that IL-1 blockade may also directly decrease fetal neuroinflammation by mitigating fetal microglial activation in a dose-dependent manner. Our studies distinguish the role of placental inflammation during ZIKV-infected pregnancies, and demonstrate that maternal IRA may attenuate fetal neuroinflammation and improve perinatal outcomes.