HIV gp120 upregulates tonic inhibition through α5-containing GABAARs

Abstract

HIV-Associated Neurocognitive disorder (HAND) affects nearly half of infected patients. The HIV envelope protein gp120 is shed by infected cells and is a potent neurotoxin in vitro that reproduces many aspects of HAND when expressed in vivo. Here, we show that HIV gp120 increases the amplitude of a tonic current mediated by γ-aminobutyric acid type-A receptors (GABA A Rs). Treating rat hippocampal cultures with 600 pM gp120 IIIB for 4 h increased a tonic bicucullinesensitive current, which remained elevated for 24 h. The increased current resulted from upregulation of extrasynaptic α5-containing GABA A Rs, as indicated by inhibition with the selective inverse agonist basmisanil. Treatment with gp120 increased α5-GABA A R immunoreactivity on the cell surface without new protein synthesis. The increase in tonic inhibition was prevented by a C-X-C chemokine receptor type 4 (CXCR4) antagonist or elimination of microglia from the culture. Treatment with interleukin-1β (IL-1β) increased the tonic current and an IL-1 receptor antagonist blocked the gp120-evoked response. Pharmacological or genetic inhibition of p38 mitogen-activated protein kinase (MAPK) prevented the gp120-evoked increase in tonic current and direct activation of a mutant form of p38 MAPK expressed in neurons increased the current.

Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain

“…The mainly neuronal location of CXCR3 confirms and explains why intrathecally administered CXCR3 ligands induce fast and strong pain-like behaviors in naive mice [28]. The binding of ligands to CXCR3 is associated with an increase in the intracellular Ca 2+ concentration and the activation of MAPKs and NF-κB, which, as is well known, contributes to the development of hypersensitivity [296][297][298][299]. Therefore, the single and repeated intrathecal administration of a potent and selective CXCR3 antagonist ((±)-NBI-74330) attenuates neuropathic pain symptoms.…”

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

“…For example, we have recently shown that exposure to gp120 IIIB leads to dendritic spine deficits in cultured cortical neurons in a process that requires secretion of interleukin-1β (IL-1β) from co-cultured glial cells, suggesting that IL-1β is an important contributor to HIV-induced spine deficits in the cortex [ 90 ]. Other studies in rat hippocampal cultures have shown that gp120 IIIB increased inhibitory synapses and tonic inhibition, which also required gp120-induced secretion of IL-1β from microglia in the same cultures [ 114 , 115 ]. Since IL-1β indirectly activated NMDA receptors in these neurons [ 114 ], the shift toward inhibitory input may represent an adaptive mechanism that could at least partially explain why hippocampal neurons are not as hyper-excitable as other types of neurons in animal models of HAND.…”

“…Two recent studies have identified mechanistic insights on how this occurs in gp120-treated hippocampal neurons. In the first, a 4-h treatment with gp120 IIIB increased inhibitory currents by enhancing the surface expression of neuronal α5 subunit-containing GABA A receptors, and these outcomes were mediated by gp120-induced secretion of IL-1β from microglia and activation of neuronal p38 mitogen-activated protein kinase [ 115 ]. In the second study, a 24-h treatment with gp120 IIIB increased the number of gephyrin-labeled inhibitory synapses, which also involved IL-1β activation of p38 in addition to NMDA receptor and Src kinase-mediated protein synthesis [ 114 ].…”

Chemical Nature of Metals and Metal-Based Materials in Inactivation of Viruses

“…HIV-1 has a lipid envelope and its surface-attached glycoprotein gp120 can bind to the CD4 receptor on host cells, which is a key step in HIV infection of host cells ( Figure 4 A) [ 61 , 62 , 63 ]. That is, gp120 glycoprotein is a potential target for the binding of Ag NPs.…”