Enhanced dendritic cell-driven proliferation and anti-HIV activity of CD8(+) T cells by a new phenothiazine derivative, aminoperazine.
T cell anergy, apoptosis, and chronic activation of T lymphocytes are prevailing features of HIV infection. The inability to develop an efficient natural antiviral activity in infected patients might be the consequence of a failure of the Ag presentation by dendritic cells (DCs) in chronically activated lymphoid tissues. We have identified a new phenothiazine derivative aminoperazine (APR; 2-amino-10-[3'-(1-methyl-4-piperazinyl)propyl]phenothiazine, C(20)H(26)N(4)S; m.w. 354.51) able to increase (effective dose from 0.1 to 100 nM) the Ag-specific DC-driven proliferation and differentiation of in vitro HIV-infected and uninfected normal donor T cells and of T cells from HIV-1-infected patients. The immunomodulatory effect of APR-sensitized DCs were ascribed to soluble factors derived from DCs. APR was also capable of increasing HIV gag-p24-specific proliferation and anti-HIV cytotoxic activity of patients' CD8(+) T cells against autologous B-lymphoblastoid cell lines expressing a HIV gag gene, resulting in the suppression of both proviral DNA and supernatant viral RNA in the HIV-1-infected patients' T cell culture. This new phenothiazine derivative (APR) might be used for boosting the immune response of vaccinated individuals and for restoring the immunity of immunocompromised patients.
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Laboratory of Molecular Oncology and Virology, Necker Faculty of Medicine, Saints-Pères Biomedical Center, René Descartes University, Paris, France. louis.weilu@biomedicale.univ.paris5.fr
Achour
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Arlie
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Cao
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Andrieu
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D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D015750:Genes, gag; D016655:HIV Core Protein p24 / Q000008:administration & dosage / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D010640:Phenothiazines; D010879:Piperazines; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C439689:2-amino-10-(3'-(1-methyl-4-piperazinyl)propyl)phenothiazine; D000276:Adjuvants, Immunologic; D016655:HIV Core Protein p24; D010640:Phenothiazines; D010879:Piperazines; D013755:Tetradecanoylphorbol Acetate