Early activation events render T cells susceptible to HIV-1-induced syncytia formation. Role of protein kinase C.
In human immunodeficiency virus-1 (HIV-1)-infected cell cultures, cell-to-cell fusion and the formation of multinucleated giant cells (syncytia) are induced as a consequence of interactions between the viral envelope glycoprotein on infected cells and cell surface CD4 molecules on uninfected cells. Although activated CD4+ T cells rapidly form syncytia when cultured with HIV-1 envelope glycoprotein expressing (env+) cells, freshly isolated, unstimulated CD4+ T cells do so more slowly. In these studies, we sought to explore the role of T cell activation in rendering CD4+ T cells susceptible to HIV-1-mediated syncytia formation. Our results indicate that within 2 h of exposure to immunologic stimuli, CD4+ T cells acquire the ability to form syncytia with HIV-1 env+ cells. Both cholera toxin, an inhibitor of protein kinase C (PKC) through its effects on inositol triphosphate and diacylglycerol production, and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride, a noncompetitive inhibitor (with respect to ATP) of PKC, prevented unstimulated but not previously stimulated CD4+ T cells from forming syncytia with HIV-1 env+ cells. 1-Oleoyl-2-acetyl glycerol, an analog of the PKC activator, diacylglycerol, enhanced syncytia formation whereas ionomycin, a calcium ionophore, had no effect. These results suggest that activation of PKC is essential for previously unstimulated CD4+ T cells to become fusogenic.
Mohagheghpour
N
N
Stanford Blood Center, Palo Alto, California 94304.
Chakrabarti
R
R
Stein
B S
BS
Gowda
S D
SD
Engleman
E G
EG
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D017252:CD3 Complex; D015704:CD4 Antigens / Q000276:immunology; D002118:Calcium / Q000494:pharmacology; D002459:Cell Fusion; D002772:Cholera Toxin / Q000494:pharmacology; D015726:Giant Cells / Q000276:immunology* / Q000502:physiology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008213:Lymphocyte Activation; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000502:physiology
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D015704:CD4 Antigens; D007546:Isoquinolines; D010879:Piperazines; D011948:Receptors, Antigen, T-Cell; D015759:Ionomycin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002772:Cholera Toxin; D011493:Protein Kinase C; D002118:Calcium