Mentored Scientist Award

Human immunodeficiency virus (HIV) continues to be a significant global health issue, affecting millions worldwide. While antiretroviral therapy (ART) can suppress viral replication, it does not cure HIV, highlighting the need for strategies that promote long-term viral control without continuous ART. CD8+ T cells play a crucial role in eliminating HIV-infected cells, but these cells often become exhausted after ART cessation. Enhancing T cell-based therapies that restore the function of HIV-specific CD8+ T cells is essential for potential cure strategies. Interleukin-2 (IL-2)-based therapies have shown promise in improving CD8+ T cell survival, proliferation, and cytotoxicity in chronic viral infections, but their clinical application is limited by severe toxicities. Engineered IL-2 variants (IL-2Vs) have been developed to selectively activate effector T cells while reducing off-target effects. However, their safety and efficacy in restoring HIV-specific CD8+ T cell function without inadvertently activating the HIV reservoir remain unclear. This study aims to evaluate the effects of four IL-2Vs—NKTR-214, THOR-707, RO7284755, and AB248—on HIV-specific CD8+ T cell responses. In Aim 1, the regenerative potential, activation, expansion, differentiation, and cytotoxic activity of IL-2Vs will be assessed, while in Aim 2, their potential to activate the HIV reservoir by promoting viral reactivation in CD4+ T cells will be investigated. This project will advance HIV cure research by developing therapies that selectively boost HIV-specific CD8+ T cell responses while minimizing activation of other immune subsets. Using cutting-edge technologies, such as spectral flow cytometry and digital droplet PCR, the study will provide valuable insights into IL-2V-treated CD8+ T cells and their impact on HIV reservoirs, paving theway for safer and more effective HIV cure strategies.