Modulation of endogenous IL-1 beta and IL-1 receptor antagonist results in opposing effects on HIV expression in chronically infected monocytic cells.
A proportion of HIV-infected individuals experience episodes of localized or systemic bacterial infections caused by Gram-negative bacteria. Many of the clinical side effects of these infections are associated with the production of proinflammatory cytokines, which are induced primarily by LPS, a constituent of the bacterial cell wall of Gram-negative bacteria. The present study examines the mechanisms involved in LPS-mediated induction of HIV expression in U1 cells, a promonocytic cell line chronically infected with HIV. Stimulation of U1 cells by LPS alone induced minimal levels of HIV expression, which was significantly enhanced by granulocyte-macrophage colony-stimulating factor (GM-CSF). Costimulation of U1 cells with LPS plus GM-CSF resulted in the accumulation of steady-state levels of HIV RNA; however, only a weak induction of HIV long terminal repeat-driven transcription, which was not associated with the activation of the cellular transcription factor nuclear factor-kappa B, was noted. Costimulation of cells with LPS plus GM-CSF induced the production of proinflammatory cytokines, IL-8, IL-1 beta and IL-6, but not TNF-alpha. IL-1 receptor antagonist (ra) inhibited LPS enhancement of HIV expression in GM-CSF-stimulated cells, suggesting that endogenous IL-1 was involved in LPS-mediated viral production. In this regard, anti-inflammatory cytokines inhibited LPS plus GM-CSF-stimulated HIV expression, and this effect closely correlated with inhibition of IL-1 beta release and, in particular, with up-regulation of endogenous IL-1ra production. Thus, the balance between an endogenously produced viral inducer (IL-1 beta ) and an inhibitor (IL-1ra) may represent an important pathway leading to modulation of HIV expression from monocytic cells.
Goletti
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National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, USA.
Kinter
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Hardy
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Poli
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Fauci
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AS
D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006678:HIV / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016325:HIV Long Terminal Repeat / Q000502:physiology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D016328:NF-kappa B / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism* / Q000494:pharmacology*; D014775:Virus Activation / Q000187:drug effects / Q000235:genetics
D000998:Antiviral Agents; D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012367:RNA, Viral; D012795:Sialoglycoproteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor