PMID: 12960231, 10358771 Human immunodeficiency virus type 1 (HIV-1) entry is initiated by binding of the viral envelope (Env) glycoprotein gp120 to CD4 followed by interactions with a G protein-coupled chemokine receptor (GPCR), CCR5 or CXCR4, on the surface of target cells. PMID: 12960231, 10358771 efficient gp120?chemokine interactions typically require that gp120 first binds to CD4 to undergo conformational changes that induce the chemokine receptor binding site.

PMID: 12960231 CCR5 and CXCR4 elevate [Ca2+]i in a variety of cell types in response to chemokine stimulation. PMID: 12960231 the peak [Ca2+]i elicited by R5 gp120 was nearly twice that elicited by X4 gp120, with higher steady-state levels as well.

PMID: 12960231 In some cell types, gp120 is also known to activate the related cytoskeleton-associated focal adhesion kinase (FAK).

PMID: 12960231, 7544443 Pyk2 is often Ca2+-regulated. PMID: 12960231, 10384144, 9362541 Similar results have been reported in T cells, where Pyk2 and FAK are activated by gp120.

PMID: 12960231, 9875330 binding of R5 SIV virions (but not gp120 alone) activated JNK and p38 MAPK as well as ERK through CCR5. PMID: 12960231 Of note, R5 gp120 reliably activated these kinases, and X4 gp120 activation was inconsistent, indicating another difference between the CCR5- and CXCR4-mediated pathways.

PMID: 12960231, 9875330 binding of R5 SIV virions (but not gp120 alone) activated JNK and p38 MAPK as well as ERK through CCR5. PMID: 12960231 Of note, R5 gp120 reliably activated these kinases, and X4 gp120 activation was inconsistent, indicating another difference between the CCR5- and CXCR4-mediated pathways. PMID: 12960231, 11698270 Upon further investigation, we determined that this was dependent on the p38 MAPK pathway, as a specific p38 MAPK inhibitor (SB202190) blocked their secretion.

PMID: 12960231, 9875330 binding of R5 SIV virions (but not gp120 alone) activated JNK and p38 MAPK as well as ERK through CCR5. PMID: 12960231 Of note, R5 gp120 reliably activated these kinases, and X4 gp120 activation was inconsistent, indicating another difference between the CCR5- and CXCR4-mediated pathways.

PMID: 12960231, 9658081 Using CD4+/CXCR4+ cell lines, it was reported that binding of X4 HIV-1 gp120 activated extracellular-regulated kinase (ERK), another member of the MAPK family. However, that response was mediated by CD4, as CD4-independent X4 gp120 did not activate ERK through CXCR4, although the natural CXCR4 ligand SDF-1alpha did.

PMID: 12960231, 9658081 Using CD4+/CXCR4+ cell lines, it was reported that binding of X4 HIV-1 gp120 activated extracellular-regulated kinase (ERK), another member of the MAPK family. However, that response was mediated by CD4, as CD4-independent X4 gp120 did not activate ERK through CXCR4, although the natural CXCR4 ligand SDF-1alpha did.

PMID: 12960231, 12551992 Similar results showing that soluble and virion-associated gp120 activates PI-3K in macrophages were recently reported.

PMID: 12960231, 1548758 We also found that HIV gp120 induced macrophage TNF-alpha production. PMID: 12960231, 2789293, 1918997 It has long been known that gp120 can induce macrophages to secrete tumor necrosis factor alpha (TNF-alpha).

PMID: 12960231, 10358771 Human immunodeficiency virus type 1 (HIV-1) entry is initiated by binding of the viral envelope (Env) glycoprotein gp120 to CD4 followed by interactions with a G protein-coupled chemokine receptor (GPCR), CCR5 or CXCR4, on the surface of target cells. PMID: 12960231 Here, we will discuss our studies on the intracellular signaling pathways activated in macrophages through CCR5 and CXCR4 in response to envelope proteins from R5 or X4 viruses and contrast them with results in other cell types. PMID: 12960231, 9120386 The beta-chemokines can block virus entry by competing with gp120 for binding to chemokine receptors.

PMID: 12960231, 1548758 We also found that HIV gp120 induced macrophage TNF-alpha production.

PMID: 12960231 Although FAK and ZAP-70 were activated in resting T cells by gp120, it was not clear as to what pathways were specifically responsible for HIV up-regulation.

PMID : 12960231 confirmed pathways(Fig.2.)

PMID: 12960231 We found that macrophages exposed to gp120 produced MCP-1 and MIP-1beta, consistent with other reports. PMID: 12960231, 11698270 Upon further investigation, we determined that this was dependent on the p38 MAPK pathway, as a specific p38 MAPK inhibitor (SB202190) blocked their secretion.

PMID: 12960231 We found that macrophages exposed to gp120 produced MCP-1 and MIP-1beta, consistent with other reports. PMID: 12960231, 11698270 Upon further investigation, we determined that this was dependent on the p38 MAPK pathway, as a specific p38 MAPK inhibitor (SB202190) blocked their secretion.

PMID: 12960231 We found that macrophages exposed to gp120 produced MCP-1 and MIP-1beta, consistent with other reports. PMID: 12960231, 11698270 Upon further investigation, we determined that this was dependent on the p38 MAPK pathway, as a specific p38 MAPK inhibitor (SB202190) blocked their secretion.

PMID: 12960231 We found that macrophages exposed to gp120 produced MCP-1 and MIP-1beta, consistent with other reports. PMID: 12960231, 11698270 Upon further investigation, we determined that this was dependent on the p38 MAPK pathway, as a specific p38 MAPK inhibitor (SB202190) blocked their secretion.

PMID : 12960231 confirmed pathways(Fig.2.)

PMID : 12960231 confirmed pathways(Fig.2.)

PMID: 12960231, 9120386 The beta-chemokines can block virus entry by competing with gp120 for binding to chemokine receptors.

PMID: 12960231, 10358771 Human immunodeficiency virus type 1 (HIV-1) entry is initiated by binding of the viral envelope (Env) glycoprotein gp120 to CD4 followed by interactions with a G protein-coupled chemokine receptor (GPCR), CCR5 or CXCR4, on the surface of target cells.

PMID : 12960231 confirmed pathways(Fig.2.)

PMID: 12960231, 10358771 Human immunodeficiency virus type 1 (HIV-1) entry is initiated by binding of the viral envelope (Env) glycoprotein gp120 to CD4 followed by interactions with a G protein-coupled chemokine receptor (GPCR), CCR5 or CXCR4, on the surface of target cells. PMID: 12960231 Here, we will discuss our studies on the intracellular signaling pathways activated in macrophages through CCR5 and CXCR4 in response to envelope proteins from R5 or X4 viruses and contrast them with results in other cell types.

PMID: 12960231 macrophage-inflammatory protein-1beta (MIP-1beta; CCL4) and stromal derived factor-1alpha (SDF-1alpha; CXCL12), the natural ligands for CCR5 and CXCR4, respectively. PMIDL 12960231, 10864653 Subsequently, it was reported that HIV-1 and SIV strains with gp120 envelopes that did not elevate [Ca2+]i in macrophages failed to complete replication, and this failure could be complemented by the natural ligand MIP-1?, which converted nonproductive infection to productive infection.

PMID: 12960231 macrophage-inflammatory protein-1beta (MIP-1beta; CCL4) and stromal derived factor-1alpha (SDF-1alpha; CXCL12), the natural ligands for CCR5 and CXCR4, respectively.

PMID: 12960231 Here, we will discuss our studies on the intracellular signaling pathways activated in macrophages through CCR5 and CXCR4 in response to envelope proteins from R5 or X4 viruses and contrast them with results in other cell types. PMID: 12960231, 10358771 efficient gp120?chemokine interactions typically require that gp120 first binds to CD4 to undergo conformational changes that induce the chemokine receptor binding site.

PMID: 12960231 Here, we will discuss our studies on the intracellular signaling pathways activated in macrophages through CCR5 and CXCR4 in response to envelope proteins from R5 or X4 viruses and contrast them with results in other cell types. PMID: 12960231, 10358771 efficient gp120?chemokine interactions typically require that gp120 first binds to CD4 to undergo conformational changes that induce the chemokine receptor binding site.

PMID: 12960231 CCR5 and CXCR4 elevate [Ca2+]i in a variety of cell types in response to chemokine stimulation. PMID: 12960231 the peak [Ca2+]i elicited by R5 gp120 was nearly twice that elicited by X4 gp120, with higher steady-state levels as well.