in vitro modeling of IgH-reprogrammed B cells in secondary lymphoid organoids

Scripps Research Institute, The, La Jolla CA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT The main goal of this project is to develop and test a cell therapy that supports the development of robust, boostable, and durable broadly neutralizing antibody (bnAb) responses as a functional cure for HIV. This portion of the P01 project will focus on optimizing this therapeutic strategy in immune organoids, which are derived from murine, non-human primate, and human lymphoid tissues and can recapitulate several aspects of in vivo germinal center responses. Clinical trials have shown that sufficiently high antibody titers can suppress viremia during withdrawal of conventional antiretroviral treatment. However, achieving durable bnAb responses using current techniques remains challenging due to low B cell receptor (BCR) precursor frequency. Recent advancements have demonstrated that murine B cells can be reprogrammed to express HIV bnAbs using gene- editing technologies, but significant efforts are needed to determine how to guide these cells into germinal center reactions and subsequent durable memory and long-lived plasma cell phenotypes. Our proposal seeks to optimize techniques for translating this strategy to non-human primate models and human clinical studies. Our project will address the lack of animal models that accurately replicate the human HIV-specific immune response by testing engineered B cells in lymphoid tissue organoid models across murine, non-human primate, and human systems. By integrating in vitro organoid cultures with in vivo data, we aim to predict and optimize HIV-specific B cell responses, and ultimately accelerate the translation of our strategy into the clinic. In this project, we will characterize engineered B cell behavior, identify effective immunogen pairings, and advance the development of durable and scalable bnAb therapies for HIV. Our work will use protein designs and engineered cells from the affiliated immunogen and B cell engineering cores. We will also collaborate with the ‘Last Gift’ study to validate engineered B cell responses in organoids prepared from lymphoid tissues of people living with HIV to assess preventive vs. therapeutic cell therapy strategies. Successful completion of this project will establish the predictive value of organoid models for analysis of HIV responses across murine, NHP, and human model systems, with the long-term goal of accelerating the development of B cell bnAb engineering-based therapies for HIV. Additionally, the organoid approach will enhance our understanding of B cell biology and immune response dynamics during HIV antigen stimulation and infection. By developing and refining organoid culture techniques, we hope to better mimic in vivo responses and provide a valuable tool for future research. This project not only seeks to advance therapeutic approaches but also develop and test a scalable platform for rapid optimization of engineered cells and immunogens to develop the targeted adaptive immune response, ultimately contributing to the broader field of HIV research and treatment.