HIV-1 gp120Bal down-Regulates Phosphorylated NMDA Receptor Subunit 1 in Cortical Neurons via Activation of Glutamate and Chemokine Receptors

Abstract

HIV-1 envelope glycoprotein gp120 (gp120) is a major virulence protein implicated in the pathogenesis of HIV-associated neurocognitive disorders (HAND). Although gp120 has been suggested to cause synaptic and neuronal injuries by disrupting NMDA receptor (NMDAR) function, the underlying mechanism is unclear. Here, we show that gp120Bal down-regulates the phosphorylation of the NMDAR subunit 1 NR1 (at Ser896 and Ser897), which is essential for NMDAR function. This effect of gp120Bal is blocked by specific antagonists of both NMDA and AMPA receptors, indicating a critical role of synaptic activation. Furthermore, AMD3100 and maraviroc, antagonists of CCR5 and CXCR4 chemokine receptors, respectively, inhibit the effect of gp120Bal on NR1, suggesting that CXCR4 and CCR5 activation are involved. These findings may provide mechanistic insights into the synaptopathogenesis caused by HIV-1 infection.

Microglia Mediate HIV-1 gp120-Induced Synaptic Degeneration in Spinal Pain Neural Circuits

“…It is known that gp120 can directly activate NMDARs by binding to their glycine binding sites (Fontana et al, 1997;Pattarini et al, 1998). Gp120 also can indirectly affect the activity of NMDARs after binding to its coreceptor, which triggers a series of signaling cascades as well as cytokine/chemokine release, thus facilitating NMDAR activation (Catani et al, 2000;Kaul et al, 2001;Nicolai et al, 2010;Marchionni et al, 2012;Maung et al, 2014;Ru and Tang, 2016). We observed that coreceptors CCR5 and CXCR4 were mainly located on the postsynapse, and blockage of CCR5 abolished gp120-induced synaptic degeneration ( Fig.…”

“…Immunofluorescent staining and quantification. For cultured cells, immunofluorescent staining was conducted as previously described (Ru and Tang, 2016). Briefly, the cultured cells were fixed in 4% paraformaldehyde (PFA) for 20 min and then incubated in blocking buffer (5% BSA and 0.3% Triton X-100 in 0.1 M PBS) for 1 h at room temperature.…”

HIV-1 gp120 Upregulates Brain-Derived Neurotrophic Factor (BDNF) Expression in BV2 Cells via the Wnt/β-Catenin Signaling Pathway

“…However, the mechanisms and extent of neurotoxicity induced by M-tropic gp120 (such as gp120Bal) differed from that of T-tropic gp120(such as gp120IIIB) (Bachis et al 2010). Gp120Bal is M-tropic, which interacts with the CD4 receptor and the co-receptor chemokine receptor CCR5 (Bashir et al 2015; Carrillo et al 2015) (rather than CXCR4 for T-tropic gp120), and modulates various cellular processes (Pierson et al 2004; Ru and Tang 2016). Because this study focused on the gp120 effect on microglia, the M-tropic gp120Bal was chosen.…”

The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs

“…The T-cell-tropic gp120 promotes the trafficking and surface clustering of NMDAR, and this process was associated with the phosphorylation of the NMDA subunit NR1 at C terminal Ser896 and Ser897 (Xu et al, 2011 ). On the other hand, the M-tropic gp120 transiently decreased the level of pSer896 and pSer897 of the NR1 subunit, having the opposite effect on the T-tropic gp120 (Ru and Tang, 2016 ). Treatment with NMDAR and AMPAR antagonists prevents the effect of M-tropic gp120 on NR1 down-regulation, suggesting that phosphorylation of NR1 is dependent on synaptic activity and NMDAR activation (Ru and Tang, 2016 ).…”

“…On the other hand, the M-tropic gp120 transiently decreased the level of pSer896 and pSer897 of the NR1 subunit, having the opposite effect on the T-tropic gp120 (Ru and Tang, 2016 ). Treatment with NMDAR and AMPAR antagonists prevents the effect of M-tropic gp120 on NR1 down-regulation, suggesting that phosphorylation of NR1 is dependent on synaptic activity and NMDAR activation (Ru and Tang, 2016 ). Moreover, both gp120 tropic forms present different neuropathological profiles—M-tropic gp120 has a weaker toxic property than T-tropic.…”