Microarray analysis reveals CCL24/eotaxin-2 as an effector of the pathogenetic effects induced by HIV-1 Nef.
Human immunodeficiency virus (HIV)-1 Nef is a regulatory protein critically involved in AIDS pathogenesis. We previously demonstrated that extracellular Nef is efficiently internalized by human primary monocyte-derived macrophages (MDMs), thereby activating a number of transcription factors including STATs, MAPKs, IRF-3, and NF-kappaB. Such an activation state leads to the release of inflammatory factors whose paracrine effects deserve deep consideration. Here, we demonstrate that quiescent CD4 lymphocytes undergo cell activation when cultivated in supernatants from autologous MDMs treated with extracellular wt Nef but not with its counterpart mutated in the (72)PxxP(75) polyproline domain. Of a pathogenetic relevance, this effect coupled with the sensitization of quiescent CD4 lymphocytes to HIV-1 infection. By microarray assay, we found that the CCL24/eotaxin-2 gene was up-regulated in MDMs treated with wt Nef but not with the (72)AxxA(75) mutant. In addition, the higher transcription activity correlated with a significant increase of the CCL24/Eotaxin-2 release. Finally, we observed that anti-CCL24/eotaxin-2 antibodies efficiently neutralized the stimulatory effect on CD4 lymphocytes of supernatants from MDMs treated with extracellular Nef. Overall, these data support the idea that CCL24/eotaxin-2 is part of the mechanism of CD4 lymphocyte activation paracrinally induced by Nef.
Fiorucci
Gianna
G
Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy.
Olivetta
Eleonora
E
Chiantore
Maria Vincenza
MV
Federico
Maurizio
M
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D054423:Chemokine CCL24; D019742:Chemokines, CC / Q000096:biosynthesis / Q000502:physiology*; D015693:Gene Products, nef / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D008297:Male; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D019899:Paracrine Communication; D010455:Peptides / Q000235:genetics; D014158:Transcription, Genetic; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus
C515484:CCL24 protein, human; D054423:Chemokine CCL24; D019742:Chemokines, CC; D015693:Gene Products, nef; D010455:Peptides; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; C011083:polyproline