Interferon downregulates CXCR4 (fusin) gene expression in peripheral blood mononuclear cells.
OBJECTIVE
Cytokines modulate human immunodeficiency virus type 1 (HIV-1) replication at multiple stages of its life cycle. We examined the effects of several HIV-1-stimulatory and HIV-1-inhibitory cytokines on CXCR4 (fusin) gene expression in lymphoid cells.


METHODS
Peripheral blood mononuclear cells (PBMCs) were treated with various cytokines, and CXCR4 gene expression was assessed by Northern blot analysis. Cell-cell fusion was assessed using HeLa-MAGI cells expressing T-cell-tropic HIV-1 (i.e., LAV strain) envelope glycoproteins and U937 cells expressing HIV-1 tat.


RESULTS
Although treatment of PBMCs with interferon-alpha (IFN-alpha) and IFN-gamma led to a significant repression of CXCR4 gene expression, interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) had no significant effect on CXCR4 gene expression in PBMCs. IFN-alpha and IFN-gamma also inhibited CXCR4 gene expression in the promyelocytic cell line U937, and this inhibition led to a decrease in cell-cell fusion between U937 cells and HeLa-MAGI cells. In U937 cells, TNF-alpha and phorbol myristate acetate (PMA) stimulated CXCR4 gene transcription; this effect was reversed with prior treatment of cells with IFN-gamma.


CONCLUSIONS
IFN-alpha and IFN-gamma effectively downmodulate fusin gene expression in lymphoid cells, indicating that IFNs modulate HIV-1 replication at postentry levels as well as at the level of HIV-1 entry.
Shirazi
Y
Y
Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Pitha
P M
PM
D015152:Blotting, Northern; D002459:Cell Fusion; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation; D015967:Gene Expression Regulation, Viral; D015686:Gene Products, env; D015696:Gene Products, tat; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D054322:tat Gene Products, Human Immunodeficiency Virus
D016207:Cytokines; D015686:Gene Products, env; D015696:Gene Products, tat; D016898:Interferon-alpha; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D054322:tat Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma