Avaliação da produção de IFN-γ por células T expressando marcadores de exaustão em pacientes pediátricos HIV+ durante a imunização contra o meningococo C

Abstract

Due to the incidence of meningococcal disease and the prevalence of serogroup C in Brazil, the National Immunization Program has offered the conjugated vaccine to meningococcus C (anti-MenC) for HIV+ children and adolescents since 2006. However, HIV+ patients have a low seroconversion rate after immunization against MenC. The persistent activation of the immune system during HIV infection leads to T cell exhaustion, which is characterized by high expression of inhibitory receptors and progressive loss of function. Although highly relevant, cellular exhaustion is poorly studied in pediatric HIV+ patients, requiring additional studies for a better understanding of its impact on the immune response of these individuals, as well as on vaccine responsiveness. The objective of this study was to evaluate IFN-γ production by T cells expressing exhaustion markers in vertically HIV-infected children and adolescents who were immunized with anti-MenC. Blood samples from healthy volunteers (N=8) were collected before immunization (V1) and 1 to 2 months after a single dose of the vaccine (V2). For HIV+ patients (N=14), blood samples were collected between 12 to 18 months after the first dose (V3) and 1 to 2 months after the booster vaccination (V4). Peripheral blood mononuclear cells were stimulated with a leukocyte activation cocktail for 5 hours to evaluate IFN-γ production and characterize cell populations expressing exhaustion markers (PD-1 and TIGIT) by flow cytometry. Comparative analyses showed that CD4+PD-1- T cells produced more IFN-γ compared to CD4+PD-1+ T cells in the control group (at V1, P<0.05) and in the HIV+ patients (at V3 and V4, P<0.01). We also observed a higher production of IFN-γ in CD4+TIGIT- T cells compared to CD4+TIGIT+ T cells in both groups (at V1, V2, and V3, P<0.01; and at V4, P<0.001). The same was observed in CD8+PD-1- T cells compared to CD8+PD-1+ T cells (at V1 and V2, P<0.05; at V3, P<0.01; at V4, P<0.001). On the other hand, only HIV+ patients exhibited a higher frequency of IFN-γ+ in CD8+TIGIT- T cells compared to CD8+TIGIT+ T cells (at V3 and V4, P<0.01). We observed a positive and significant correlation between the frequency of CD4+PD-1-IFN-γ+ and CD4+TIGIT-IFN-γ+ T cells in HIV+ patients (r=0.748, P=0.007, at V3 and V4), as did the frequencies of CD8+PD-1-IFN-γ+ and CD8+TIGIT-IFN-γ+ T cells (r=0.636, P=0.029, at V3; r=0.756, P=0.006, at V4). An inverse and significant correlation between the frequency of CD4+TIGIT+IFN-γ+ T cells and viral load were detected at V3 (r=0.723, P=0.007). The results reveal an impaired IFN-γ production by T cells expressing PD-1 and TIGIT in HIV+ pediatric patients. These findings may help to enhance the understanding of the immune profile of HIV+ individuals.