Activation of signal transduction and apoptosis in healthy lymphomonocytes exposed to bystander HIV-1-infected cells.
Persistent activation of the immune system is one of the hallmarks of HIV-1 infection. In this study we analysed the induction of factors involved in cytokine signal transduction, such as STAT 1 proteins and IRF-1 mRNA, in normal peripheral blood mononuclear cells (PBMC) exposed to HIV-infected cells, and the induction of apoptosis. Western blot analyses and reverse transcriptase-polymerase chain reaction results indicate that both cells infected with a X4 strain and cells infected with a R5 strain are able to increase intracellular levels of STAT 1alpha and beta proteins as well as IRF-1 mRNA. This effect was prevented by neutralizing antibodies against interferon-alpha (IFN-alpha). HIV-1-infected cells dose-dependently induced apoptotic commitment in normal PBMC, as revealed by DNA fragmentation analysis, but this was not accompanied by an increase of caspase-3 activity, even if a slight up-regulation of IL-1beta-converting enzyme mRNA was detected. Apoptosis induction could be abrogated mainly by antibodies against tumour necrosis factor-alpha (TNF-alpha) and, to a lesser extent, by antibodies against IFN-gamma. All these findings suggest that uninfected PBMC can undergo activation of signal transduction and apoptosis after exposure to bystander HIV-infected cells, subsequent to the induction of cytokines such as IFNs and TNF-alpha.
Abbate
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I
National Institute for Infectious Diseases, 'L. Spallanzani' I. R. C. C. S., Laboratory of Virology, Laboratory of Microbiology, S. Pertini Hospital, and Libera Universita Campus Biomedico, Rome, Italy.
Dianzani
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F
Capobianchi
M R
MR
D017209:Apoptosis; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha / Q000276:immunology / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000821:virology; D009500:Neutralization Tests; D010750:Phosphoproteins / Q000235:genetics; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; D010750:Phosphoproteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma