Fig. 2.

Co-receptor signaling mediated by HIV envelope. The viral envelope glycoprotein gp120 can interact with both CCR5 and CXCR4 during the attachment and entry process, initiating both G-protein dependent and independent signaling. Pathways activated through CCR5-gp120 interactions are shown here as representatives. Activation of both G_αi and G_αq has been reported in response to gp120. Signaling through G_αq mediates activation of PLCβ, calcium release, and downstream activation of small GTPases, which are critical for viral entry, replication, and changes in actin dynamics. Signaling through G_βγ can also activate PLCβ, as well as PI3K, both of which are linked to the activation of MAPKs. The most prominent MAPK shown to be involved in these processes is p38 MAPK, although other MAPK are also involved. The activation of MAPKs regulates a large number of downstream pathways, including but not limited to, the activation of STATS, activation of GTPases, the activation of MMPs, and the release of chemokines and cytokines. G_αi and G-protein independent interactions with β-arrestins can also activate the Src family of kinases, which are also linked to PI3K and MAPK activation. Activation of all of these pathways can mediate a number of deleterious processes during HIV infection of the CNS, including neuroinflammation, blood–brain barrier dysfunction and increased migration of infected cells to the CNS, increased viral replication, and neurotoxicity. Many of these pathways overlap, meaning that gp120-coreceptor interactions can influence these pathogenic processes through several different, interacting pathways depending on the cell type and system in which they are being studied. Solid arrows represent defined, published pathways while dashed lines indicate pathways that have not been directly demonstrated, but are presumed to occur based on what is known in the literature