Binding of human immunodeficiency virus type 1 to CD4 and CXCR4 receptors differentially regulates expression of inflammatory genes and activates the MEK/ERK signaling pathway.
We have previously shown that binding of human immunodeficiency virus type 1 (HIV-1) virions to CD4 receptors stimulates association of Lck with Raf-1 and results in the activation of Raf-1 kinase in a Ras-independent manner. In the present study, we demonstrate that HIV-1 envelope glycoproteins of both T-cell-tropic and macrophagetropic strains rapidly activate the ERK/mitogen-activated protein (MAP) kinase pathway and the binding of nuclear transcription factors (AP-1, NF-kappaB, and C/EBP) and stimulate expression of cytokine and chemokine genes. The activation of this signaling pathway requires functional CD4 receptors and is independent of binding to CXCR4. Binding of the natural ligand stromal cell-derived factor 1 (SDF-1) to CXCR4, which inhibits entry of T-cell-tropic HIV-1, activates also the ERK/MAP kinase pathway. However, SDF-1 did not affect the CD4-mediated expression of cytokine and chemokine genes. These results provide firm molecular evidence that binding of HIV-1 envelope glycoproteins to CD4 receptor initiates a signaling pathway(s) independent of the binding to the chemokine receptor that leads to the aberrant expression of inflammatory genes and may contribute significantly to HIV-1 replication as well as to deregulation of the immune system.
Popik
W
W
Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Hesselgesser
J E
JE
Pitha
P M
PM
D000911:Antibodies, Monoclonal / Q000378:metabolism; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D054407:Chemokine CCL4; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D003593:Cytoplasm; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D015967:Gene Expression Regulation, Viral; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D008264:Macrophages / Q000821:virology; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D000911:Antibodies, Monoclonal; D022762:CCAAT-Enhancer-Binding Proteins; D015704:CD4 Antigens; C515255:CXCL12 protein, human; D054407:Chemokine CCL4; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D004268:DNA-Binding Proteins; D015699:HIV Envelope Protein gp120; D019402:Macrophage Inflammatory Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D019718:Receptors, CXCR4; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases