HIV-1 gp120 stimulates the production of beta-chemokines in human peripheral blood monocytes through a CD4-independent mechanism.
The present study was designed to evaluate the effect of the HIV-1 envelope glycoprotein gp120 on the expression of beta-chemokines in cultured monocytes/macrophages. Treatment of either freshly isolated 1-day-cultured monocytes or 7-day-cultured monocyte-derived macrophages (MDM) with recombinant gp120-IIIB resulted in a specific and dose-dependent enhancement of secretion of monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta, and RANTES as well as a clear-cut increase in transcript accumulation. The expression of these mRNA was increased, but not superinduced, in the presence of cycloheximide. beta-Chemokine secretion was also induced after exposure of monocyte cultures to gp120-JRFL and aldrithiol-2-inactivated R5 and X4 HIV-1 strains, retaining conformational and functional integrity of envelope proteins. In contrast, no beta-chemokine secretion was triggered by X4 and R5 gp120 or aldrithiol-2-inactivated virus treatment of monocytoid cell lines that were fully responsive to LPS. The gp120-mediated effect was independent of its interaction with CD4, as preincubation with soluble CD4 did not abrogate beta-chemokine induction. Moreover, triggering of CD4 receptor by a specific Ab did not result in any beta-chemokine secretion. Interestingly, engagement of CCR5 and CXCR4 receptors by specific Abs as well as treatment with CCR5 and CXCR4 ligands induced beta-chemokine secretion. On the whole, these results indicate that HIV-1 stimulates monocytes/macrophages to produce beta-chemokines by a specific interaction of gp120 with HIV-1 coreceptors on the cell membrane. The expression of these related polypeptides may represent an important cellular response for regulating both the extent of viral infection and the recruitment of immune cells.
Fantuzzi
L
L
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.
Canini
I
I
Belardelli
F
F
Gessani
S
S
D000293:Adolescent; D000328:Adult; D000956:Antigens, Viral / Q000494:pharmacology; D015704:CD4 Antigens / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D012333:RNA, Messenger / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000502:physiology; D013045:Species Specificity; D014158:Transcription, Genetic / Q000276:immunology; D020298:U937 Cells; D015854:Up-Regulation / Q000276:immunology
D000956:Antigens, Viral; D015704:CD4 Antigens; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D015699:HIV Envelope Protein gp120; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D019707:Receptors, Chemokine