Abstract
The advent of Human Immunodeficiency Virus (HIV) antiretrovirals have reduced the severity of HIV related neurological comorbidities but they nevertheless remain prevalent. Synaptic degeneration due to the action of several viral factors released from infected brain myeloid and glia cells and inflammatory cytokines has been attributed to the manifestation of a range of cognitive and behavioral deficits. The contributions of specific pro-inflammatory factors and their interplay with viral factors in the setting of treatment and persistence are incompletely understood. Exposure of neurons to chemokine receptor-4(CXCR4)-tropic HIV-1 envelope glycoprotein (Env) can lead to post-synaptic degradation of dendritic spines. The contribution of members of the extracellular matrix (ECM) and specifically, of perineuronal nets (PNN) toward synaptic degeneration, is not fully known, even though these structures are found to be disrupted in post-mortem HIV-infected brains. Osteopontin (Opn, gene name SPP1), a cytokine-like protein, is found in abundance in the HIV-infected brain. In this study, we investigated the role of Opn and its ECM integrin receptors, β1- and β3 integrin in modifying neuronal synaptic sculpting. We found that in hippocampal neurons incubated with HIV-1 Env protein and recombinant Opn, post-synaptic-95 (PSD-95) puncta were significantly increased and distributed to dendritic spines when compared to Env-only treated neurons. This effect was mediated through β3 integrin, as silencing of this receptor abrogated the increase in post-synaptic spines. Silencing of β1 integrin, however, did not block the increase of post-synaptic spines in hippocampal cultures treated with Opn. However, a decrease in the PNN to βIII-tubulin ratio was found, indicating an increased capacity to support spine growth. From these results, we conclude that one of the mechanisms by which Opn counters the damaging impact of the HIV Env protein on hippocampal post-synaptic plasticity is through complex interactions between Opn and components of the ECM which activate downstream protective signaling pathways that help maintain the potential for effective post-synaptic plasticity.
Highlights
Neurocognitive problems due to human immunodeficiency virus type 1 (HIV-1) infection are prevalent and comprise a spectrum of impairments that cannot be fully controlled by suppressive antiretrovirals
Cells were probed with antibodies against post-synaptic protein PSD-95 (1:600, Neuromics MO50000), βIII-tubulin (Millipore MAB1637 1:100) and biotin conjugated wisteria floribunda lectin (WFA) which binds to the glycoproteins in perineuronal nets (PNN) [41] (1:50, Sigma-Aldrich, L1516-2MG) at 4 ◦ C
The number of dendritic spines reflect the status of neuronal plasticity as they protrude out of the dendrites, serving as inputs for pre-synaptic boutons extending from axons [42]
Summary
Neurocognitive problems due to human immunodeficiency virus type 1 (HIV-1) infection are prevalent and comprise a spectrum of impairments that cannot be fully controlled by suppressive antiretrovirals. Most recently PNN were shown to be degraded in the HIV-infected brain and attributed to an increased metalloproteinase (MMP) activity [23] Due to their role in synaptic remodeling we hypothesized that excess Opn, secreted during HIV infection, engages these receptors and modulates synaptic machinery. We hypothesized that Opn acts as an upstream mediator that activates integrin function leading to altered synaptic integrity by influencing post-synaptic changes In this regard, Opn might have an impact on synaptic density in the presence of dysregulated Ca2+ initiated by HIV-1 Env, since calcium signaling is pertinent in controlling plasticity related genes [39,40]. Silencing β3 integrins did not decrease the number post-synapses in the presence of both Opn and HIV-1 Env, but interestingly it did in Opn-only treated neurons This finding suggests the possibility of convergent signaling between β3 integrin and. In HIV-1 Env only treated neurons, silencing β3 integrins decreased the number of post-synapses suggesting activation of protective compensatory signaling that serves to block further damage
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
