HIV-1 Nef induces the release of inflammatory factors from human monocyte/macrophages: involvement of Nef endocytotic signals and NF-kappa B activation.
It has been recently reported that the endogenous expression of HIV-1 Nef in human monocyte/macrophages induces the release of chemokines and other as yet unidentified soluble factors leading to multiple effects of pathogenic significance, such as the recruitment and activation of quiescent lymphocytes. However, the description of underlying molecular mechanisms remained elusive. We recently demonstrated that human monocyte-derived macrophages (MDM) efficiently internalize soluble rNef, thereby inducing effects largely resembling those observed in cells endogenously expressing Nef. By exploiting the rNef/MDM model, we sought to gain more insights on the molecular mechanisms underlying the response of MDM to Nef. Array analysis for the detection of transcripts from a large number of monokines, chemokines, cytokines, and receptors thereof showed that MDM promptly responded to rNef treatment by increasing the transcription of genes for several inflammatory factors. Analysis of supernatants revealed that rNef treatment induced the release of macrophage inflammatory proteins 1alpha and 1beta, IL-1beta, IL-6, and TNF-alpha. Conversely, rNefs mutated in domains critical for the interaction with the endocytotic machinery (i.e., EE155-156QQ, and DD174-175AA) were ineffective. Interestingly, we found that the Nef-dependent release of inflammatory factors correlated with the activation of the NF-kappaB transcription factor, mainly in its p50/p50 homodimeric form, and in a de novo protein synthesis-independent manner. Our data add new hints supporting the idea that the presence of Nef is per se heavily detrimental for monocyte/macrophages and relative cross-talking cell types.
Olivetta
Eleonora
E
Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161-Rome, Italy.
Percario
Zulema
Z
Fiorucci
Gianna
G
Mattia
Gianfranco
G
Schiavoni
Ilaria
I
Dennis
Caitriona
C
Jäger
Joachim
J
Harris
Mark
M
Romeo
Gianna
G
Affabris
Elisabetta
E
Federico
Maurizio
M
D000328:Adult; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004705:Endocytosis / Q000235:genetics / Q000276:immunology*; D015693:Gene Products, nef / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D019814:Myristic Acid / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary / Q000235:genetics; D011506:Proteins / Q000037:antagonists & inhibitors; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D012995:Solubility; D014158:Transcription, Genetic / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus
D018925:Chemokines; D016207:Cytokines; D015693:Gene Products, nef; D018836:Inflammation Mediators; D016328:NF-kappa B; D010446:Peptide Fragments; D011506:Proteins; D011993:Recombinant Fusion Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; D019814:Myristic Acid; D003513:Cycloheximide