Osteopontin and Integrin Mediated Modulation of Post-Synapses in HIV Envelope Glycoprotein Exposed Hippocampal Neurons

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.

Osteopontin/secreted phosphoprotein‐1 harnesses glial‐, immune‐, and neuronal cell ligand‐receptor interactions to sense and regulate acute and chronic neuroinflammation

“…Interestingly, suppression of OPN/SPP1 in uninfected control mice did not change basal neuroinflammation 115 . These results demonstrate that OPN/SPP1, by mechanisms that remain to be defined, (1) senses pathologic changes in brain homeostatic states and (2) regulates the neuroinflammatory response 68 . Interestingly, in HIV‐infected mice, a specific region of the brain known as the striatum, a region necessary for cognitive function, decision‐making, and reward, showed intense labeling for TSPO 115 .…”

“…The disruption of homeostatic plasticity likely underlies several neurological and neuropsychiatric disorders, given the direct evidence for alterations in integrin expression and positive associations with specific allelic variants 36 . We found that changes in PNN density were regulated in a differential fashion by signaling through β1‐ or β3‐integrins in the presence of HIV Env and OPN/SPP1 68 . Based on what is currently known about the contributions of PNN to signal propagation, we suggest that OPN/SPP1, in its role as an extracellular matrix protein, facilitates proper signal transmission.…”

“…The neurochemical messenger dopamine regulates reward responses and is impaired in untreated HIV infection and those experiencing long‐term neurologic complications 71,82 . We found that OPN/SPP1 protected against HIV Env induced decreases in dendritic spine density that depended on β1 integrin expression on rat hippocampal neuronal cultures devoid of glial cells 68 . Moreover, through the engagement of β3‐integrin signaling, OPN/SPP1 alone increased spine density 68 .…”

“…Therefore, we hypothesized that increased OPN/SPP1 expression in the brain would enhance HIV replication and exacerbate viral‐mediated damage to neuronal integrity. However, using primary cultures of rat cortical neurons, we found that, instead, OPN/SPP1 protected these cells from the damaging effects of HIV envelope protein on axonal and dendritic spine integrity 67,68 …”

Both Full-Length and Protease-Cleaved Products of Osteopontin Are Elevated in Infectious Diseases

“…In postmortem examination, the levels were also elevated in brain tissue of patients with HAND [129]. Similarly, in postmortem brain tissue, perineuronal nets (PNNs)-degrading enzyme was increased in HAND and OPN was abundant in the HIV-infected brain [130,131].…”