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Enhanced Dendritic Cell-Driven Proliferation and Anti-HIV Activity of CD8⁺ T Cells by a New Phenothiazine Derivative, Aminoperazine¹

Wei Lu^*,, Amar Achour^*, Marine Arlie, Li Cao^* and Jean-Marie Andrieu^*,

^* Laboratory of Molecular Oncology and Virology, Necker Faculty of Medicine, Saints-Pères Biomedical Center, René Descartes University, Paris, France; and Department of Medical Oncology, Georges Pompidou European Hospital, Paris, France

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, C₂₀H₂₆N₄S; 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.