Creative and Novel Ideas in HIV Research (CNIHR) Program

We have identified a super-agonist monoclonal antibody (mAb) to human IL-21 (hIL-21) by screening homemade libraries. The mAb (clone 2P2) enhances the hIL-21 bioactivity at a level ~10 fold in vitro. The anti-hIL-21 super-agonist mAb represents a novel class of immunostimulating therapeutics to boost IL-21-mediated immune enhancement to eliminate activated latently infected cells for HIV cure. We hypothesize: 1. The super-agonist mAb 2P2 boosts hIL-21 bioactivity to enhance the cytotoxicity of CD8+ T cells and NK cells to eliminate activated latently infected CD4+ T cells. 2. The super-agonist mAb 2P2 doesn?t induce spontaneous activation and proliferation of CD4+ T cells. 3. The hIL-21/2P2 complex surpasses hIL-21 alone to enhance cytotoxic immune responses in vivo. Specific aims to test these hypotheses: 1. To investigate how the hIL-21/2P2 complex enhances cytotoxicity of CD8+ T cells and NK cells from HIV-infected patients to kill activated latently infected CD4+ T cells. 2. To evaluate the effect of the hIL-21/2P2 complex on CD4+ T cell activation and proliferation. 3. To evaluate the potential of the hIL-21/2P2 complex to boost in vivo cytotoxicity using human IL-21 receptor knock-in (hIL-21RKI) mice.