Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways

Abstract

Macrophages are major targets for infection by human immunodeficiency virus type 1 (HIV-1). In addition to their role as productive viral reservoirs, inappropriate activation of infected and uninfected macrophages appears to contribute to pathogenesis. HIV-1 infection requires initial interactions between the viral envelope surface glycoprotein gp120, the cell-surface protein CD4, and a chemokine receptor CCR5 or CXCR4. Besides their role in HIV-1 entry, CCR5 and CXCR4 are G protein-coupled receptors that can activate multiple intracellular signaling pathways. HIV-1 gp120 has been shown to activate signaling pathways through the chemokine receptors in several cell types including lymphocytes, neurons, and astrocytes. In some cell types, these consequences may cause cellular injury. In this review, we highlight our data demonstrating diverse signaling events that occur in primary human macrophages in response to gp120/chemokine receptor interactions. These responses include K+, Cl-, and nonselective cation currents, intracellular Ca2+ increases, and activation of several kinases including the focal adhesion-related tyrosine kinase Pyk2, mitogen-activated protein kinases (MAPK), and phosphoinositol-3 kinase. Activation of the MAPK leads to gp120-induced expression of chemokines such as monocyte chemoattractant protein-1 and macrophage-inflammatory protein-1beta and the proinflammatory cytokine tumor necrosis factor alpha. These responses establish a complex cytokine network, which may enhance or suppress HIV-1 replication. In addition, dysregulation of macrophage function by gp120/chemokine receptor signaling may contribute to local inflammation and injury and further recruit additional inflammatory and/or target cells. Targeting these cellular signaling pathways may have benefit in controlling inflammatory sequelae of HIV infection such as in neurological disease.

CXCR4-Tropic HIV-1 Envelope Glycoprotein Functions as a Viral Chemokine in Unstimulated Primary CD4+ T Lymphocytes

“…Because signaling through the TCR inhibits CXCR4-mediated signaling (52), it is possible that prior activation of CD4 ϩ T cells contributes to these differences. Dendritic cells and macrophages are other cell types in which X4 gp120 signals inefficiently and is defective for chemotaxis (23,25,31). One contributing factor is limiting CXCR4 expression in immature dendritic cells (53), and possibly in macrophages (54).…”

“…In contrast, the natural ligand of CXCR4, the chemokine stromal cellderived factor 1 (SDF-1) 4 (CXCL12), induced the Erk-1/2 pathway in both stimulated and unstimulated CD4 ϩ T cells (30). Other studies in activated T cells or macrophages showed a defective or limited capacity of gp120 from X4 strains to induce calcium flux and chemotactic responses as compared with gp120 from CCR5-tropic (R5) strains, raising the possibility that gp120 induced an incomplete or aberrant set of signals through CXCR4 (22)(23)(24)31).…”

Macrophages and HIV-1: dangerous liaisons

“…In macrophages, early activation is due both to gp120 signalling through CD4 and CCR5 molecules at viral entry and to activation of innate defence mechanisms (cytokines, chemokines, proteases) Lee et al, 2003;Wahl et al, 2003). After a quiescent phase of a few days, viral replication results in further changes in gene expression (Wahl et al, 2003).…”

Dendritic Cell Differentiation and Maturation in the Presence of HIV Type 2 Envelope

“…In addition to direct human immunodeficiency virus (HIV) type 1 infection of these professional antigen-presenting cells, viral envelope (Env) proteins per se are able to induce a significant impairment of DC function [2][3][4][5][6][7]. The HIV-1 surface glycoprotein, gp 120, is readily shed from the cell surface due to its noncovalent association with the transmembrane Env gp41, exerting modulatory effects on bystander cells through binding to CD4, chemokine receptors or other molecules expressed by DC, such as lectins [8][9][10]. HIV-1 Env proteins were shown to functionally impair isolated primary DC [2,3,11], as well as the in vitro development and maturation of monocyte-derived DC [4][5][6][7].…”