Understanding of T cell responses during infections will be vital to rational vaccine design. Malaria and AIDS represent two leading causes of death from infectious diseases worldwide, and their high geographic overlap means coinfection is prevalent. It remains unknown whether distinct immune responses during malaria/HIV coinfection dictate clinical outcomes. We tested this hypothesis by employing macaque models of malaria/simian-human immunodeficiency virus (SHIV) coinfection. P. fragile malaria coinfection of acutely-SHIV-infected macaques induced hyper-immune-activation and remarkable expansion of CD4+ and CD8+ T effector cells producing IFNγ or TNFα de novo. Malaria-driven cellular hyper-activation/expansion and high-level Th1-cytokines enhanced SHIV disease characterized by enhancing CD4+ T-cell depletion, profound lymphoid depletion/destruction and even necrosis in lymph nodes and spleens. Importantly, malaria/SHIV-mediated lymphoid depletion, destruction and necrosis in lymphoid tissues led to bursting parasite replication and fatal virus-associated malaria. Surprisingly, chronically-SHIV-infected macaques without AIDS employed different defense mechanisms during malaria coinfection, and mounted unique ~200-fold expansion of IL-17+/IL-22+ T-effectors with profound Th1 suppression. Such remarkable expansion of Th17/Th22 cells and inhibition of Th1 response coincided with development of immunity against fatal virus-associated malaria without accelerating SHIV disease. These novel findings suggest that virus infection status and selected Th1 or Th17/Th22 responses after malaria/AIDS virus coinfection contribute to distinct outcomes of virus infection and malaria. In addition, Vγ2Vδ2 T cells were not expanded during malaria infection of macaques, despite being expanded in human malaria infection. Vγ2Vδ2 T cells were expanded during L. monocytogenes infection, and exhibited various effector functions, including production of cytokines and the ability to directly lyse infected cells. By determining how T cells are activated during infection and what protective immune functions are, we can aid rational vaccine design against a variety of pathogens
