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

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.

Comparison of T-cell subsets' reconstitution after 12 months of highly active antiretroviral therapy initiated during early versus advanced states of HIV disease.

UNLABELLED: This research comprised a pilot open prospective clinical study comparing T-cell subset reconstitution in antiretroviral-naive patients, after 12 months of HAART when treatment was initiated in early stages (ES; n = 18) of infection versus advanced stages (AS; n = 20). CONTROL GROUP: 10 healthy HIV-negative individuals. Immunophenotypic markers were evaluated before and after 6-and 12-months' therapy. Functional assays were performed in one subset. RESULTS: Viral load (VL) was < 200 copies/ml in all patients. Median percentages of CD4+ pretherapy were 33% and 6%, respectively, in the ES and AS groups, increment after 12 months of therapy was +15% and +13% respectively. Only the ES group achieved normal values. Declines of CD8+ percentage were significantly higher in the ES (-18%) than in the AS group (-2%). CD4+ memory and naive cells in the ES group were similar to those of controls before treatment and did not change after therapy. In contrast, CD4+ memory and naive cells in the AS group did not reach normal levels despite treatment. In the ES group, there was a significant increment in CD8+ naive cells (+8%) and a decrement in CD8+CD38+ cells (-17%), both populations reached values close to normal, whereas these subsets remained far from normal in the AS group. Improvement of lymphoproliferative response after therapy was observed in both groups. One patient in the ES group showed positive LPR against p24 after treatment. After 12 months' highly active antiretroviral therapy, only those who began such therapy in ES disease reached values within the range of healthy controls. To achieve a more complete immunologic reconstitution, early initiation of potent antiretroviral therapy should be recommended.

Immunological benefits of antiretroviral therapy in very early stages of asymptomatic chronic HIV-1 infection.

OBJECTIVES: To assess whether an almost complete restoration of immune system can be achieved when antiretroviral therapy is initiated at very early stages of asymptomatic chronic HIV-1 infection. DESIGN: T cell subsets and cell-mediated responses were analysed at baseline and after 12 months of either a double or a triple antiretroviral therapy in 26 asymptomatic HIV-1-infected patients with CD4 T cell counts > 500 x 10(6) cells/l and a baseline plasma viral load > 10000 copies/ml. RESULTS: Triple therapy was significantly more effective in reducing plasma HIV RNA to undetectable levels, in returning CD4:CD8 ratio to nearly normal levels, in reducing activated cells (CD38) and in increasing naive (CD45RA+CD45RO-) and memory (CD45RA-CD45RO+) CD4 cells. Both double and triple therapies caused a clear decrease in memory (CD45RA-CD45RO+) CD8 cells as well as a significant increase in the CD28 subset of CD8 cells. At baseline, there was an important increase in cells producing interferon-gamma (IFNgamma) with no significant abnormalities in T lymphocytes producing interleukin 2 (IL-2), tumour necrosis factor alpha and interleukin 4. Both types of therapy reduced IFNgamma- and IL2-producing CD4 T lymphocytes while IFNgamma-producing CD8 cells remained increased. Even before therapy, these HIV-1-positive patients lacked significant abnormalities in the T cell responsiveness to polyclonal stimuli as well as in the secretion of CCR5 chemokines by peripheral blood mononuclear cells. CONCLUSIONS: Initiating highly active antiretroviral therapy at very early stages of chronic HIV-1 infection allows rapid and almost complete normalization of T cell subsets and preservation of T cell functions. These early-treated patients could be excellent candidates for receiving additional HIV-specific immune-based therapies, which might be essential for the control of HIV infection.