Cellular Determinants of Anti-rebound to Malaria in HIV-Exposed Children Discontinuing Chemoprophylaxis
Parent Project: UCSF-Gladstone Center for AIDS Research (CFAR)
Antimalarial chemoprevention is an emerging modality to prevent deaths and morbidity from malaria in children living in highly endemic areas, but there are concerns that it will delay the natural acquisition of antimalarial immunity. Recent studies in mice and humans have challenged this paradigm, and suggest that selective blockade of blood stage infection with antimalarial drugs may paradoxically enhance the development of sterilizing antimalarial immunity, but this has not been tested in field settings. Preliminary findings from an ongoing trial of trimethoprim-sulfamethoxazole (TS) prophylaxis in HIV-exposed Ugandan children support this hypothesis, but the immunologic correlates that mediate this protection are unclear. Leveraging samples from this trial, we will test the central hypothesis that prolonged chemoprevention with TS allows for the development of polyfunctional malaria-specific T cell responses and suppresses the generation of IL-10 mediated counterregulatory mechanisms. Specifically, we will perform a cross sectional study to compare malaria-specific T cell responses to whole parasite antigens using multiparameter flow cytometry (Aim 1) and IL-10 production by CD4+ T cells and in plasma (Aim 2) in children randomized to receive TS through the cessation of breastfeeding vs. children randomized to receive TS through 4 years of age. Analyses will be performed using cryopreserved peripheral blood mononuclear cells obtained at 4 years of age from 35 children in each group, and differences between groups will be compared using chi2 and Mann Whitney U tests. Results from these studies should significantly advance our understanding of the mechanisms of protective immunity to malaria, and assist with the design of vaccines and other immunomodulatory interventions for malaria.