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To investigate the influence of CD4+ T-cell activation and regulatory populations in HIV-infected children antibody response to vaccination with a conjugate C polysaccharide vaccine.CD4+ T-cell activation was evaluated by expression of CD38, HLA-DR and CCR5 molecules. Regulatory CD4+ T cells (TReg) were characterized as FoxP3+CD127−CD25+ and inducer T cells (TInd) as CD4+FoxP3−CD25−CD39+.All patients (n = 36) were HIV-vertically infected, aged 2–17 years-old and were vaccinated with one vaccine injection. Blood samples were obtained before and after immunization to determine bactericidal antibody titers (SBA), CD4+ T-cell activation and frequency of TReg and TInd subsets (multiparametric flow cytometry).Children not-responding (n = 18) to MenC vaccine expressed higher frequency of activated CD4+ T cells (HLA-DR+CD38+CCR5+) than responders (n = 18), both before and after vaccination (P < 0.05). A significant higher frequency of TReg was detected in responders compared with nonresponders (P = 0.0001). We also detected an inverse correlation between CD4+DR+CD38+CCR5+ (P = 0.01) or CD4+DR+CD38+ (P = 0.02) T cells and TReg cell frequency after vaccination. CD4+ T-cell activation negatively correlated (P = 0.006) with postvaccination SBA titers but a positive correlation (P = 0.0001) was detected between TReg cells and SBA. TReg and TInd subsets were inversely correlated (P = 0.04).Our findings suggest that higher CD4+ T-cell activation leads to poor vaccine response in children living with HIV, which may be associated with a TReg/TInd disequilibrium.