title: Non-mitogenic T cell activation signals are sufficient for induction of human immunodeficiency virus transcription.
abstract: The expression of human immunodeficiency virus type 1 (HIV) is enhanced after T cell activation due to the interaction of cell-encoded nuclear factors with binding sites in the viral long terminal repeats (LTR). We studied the minimal signal transduction requirements for induction of HIV transcription during T cell activation. Monoclonal antibodies (mAb) against the T cell receptor/CD3 complex induced interleukin (IL) 2 production as well as HIV-LTR-directed gene expression in Jurkat T cells. Addition of cyclosporin A or buffering of intracellular Ca2+ changes did not abolish this LTR-directed gene expression but did block IL 2 production. In contrast, interference with protein kinase C (PKC) activation did inhibit both IL 2 production and LTR-driven gene expression. Under all conditions HIV-LTR-directed gene expression correlated with gene expression induced by the NF-kB binding enhancer, but not by the NF-AT or OCT-1 binding sites. In accordance with observations by Verweij, Geerts and Aarden on the CD28 co-stimulatory activation of IL2 transcription via an NF-kB-like activity, stimulation of the CD2, CD28 and CD44 accessory molecules was tested to mimick physiological activation signals independent of T cell receptor triggering. mAb directed against CD2 and CD44 only marginally induced the LTR. Next, non-mitogenic stimulation by mAb against CD28 clearly induced the HIV-LTR- and NF-kB- but not NF-AT- and OCT-1-driven chloramphenicol acetyltransferase CAT expression, showing a direct effect on gene expression via this receptor. Taken together, this report shows that non-mitogenic T cell activation signals are sufficient to induce HIV transcription. The finding that these signals may be delivered by receptors that are not dependent on antigen-specific activation may have important implications for our understanding of HIV pathogenesis.
authors.affiliation: Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdem.
authors.forename: R A
authors.initials: RA
authors.lastname: Gruters
authors.forename: S A
authors.initials: SA
authors.lastname: Otto
authors.forename: B J
authors.initials: BJ
authors.lastname: Al
authors.forename: A J
authors.initials: AJ
authors.lastname: Verhoeven
authors.forename: C L
authors.initials: CL
authors.lastname: Verweij
authors.forename: R A
authors.initials: RA
authors.lastname: Van Lier
authors.forename: F
authors.initials: F
authors.lastname: Miedema
mesh_terms: D015703:Antigens, CD / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology; D018106:CD28 Antigens; D017252:CD3 Complex; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D004742:Enhancer Elements, Genetic; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D016325:HIV Long Terminal Repeat / Q000502:physiology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000382:microbiology / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D000001:Calcimycin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium