In vitro effects of the CCR5 inhibitor maraviroc on human T cell function

Abstract

Background: Several potential immunological benefits have been observed during treatment with the CC chemokine receptor 5 (CCR5) antagonist maraviroc, in addition to its antiviral effect. Our objective was to analyse the in vitro effects of CCR5 blockade on T lymphocyte function and homeostasis.

Methods: Peripheral blood mononuclear cells (PBMCs) from both HIV-negative (n=28) and treated HIV-positive (n=27) individuals were exposed in vitro to different concentrations of maraviroc (0.1-100 μM). Effects on T cell activation were analysed by measuring the expression of the CD69, CD38, HLA-DR and CD25 receptors as well as CCR5 density using flow cytometry. Spontaneous and chemokine-induced chemotaxis were measured by transwell migration assays, and polyclonal-induced proliferation was assessed by a lymphoproliferation assay and carboxyfluorescein succinimidyl ester staining.

Results: Maraviroc increases CCR5 surface expression on activated T cells, even at low doses (0.1 μM). Slight differences were detected in the frequency and mean fluorescence intensity of activation markers at high concentrations of maraviroc. Expression of CD25, CD38 and HLA-DR tended to decrease in both CD4+ and CD8+ T lymphocytes, whereas expression of CD69 tended to increase. Maraviroc clearly inhibits T cell migration induced by chemokines in a dose-dependent manner. Moreover, at 100 μM, maraviroc tends to inhibit T cell proliferation.

Conclusions: These data showed that in vitro exposure to maraviroc decreases some activation expression markers on T lymphocytes and also migration towards chemoattractants. These results support the additional immunological effects of CCR5 blockade and suggest that maraviroc might have potential capacity to inhibit HIV-associated chronic inflammation and activation, both by directly affecting T cell activation and by reducing entrapment of lymphocytes in lymph nodes.