An hematopoietic stem-cell-based approach to treat HIV employing CAR T cells and anti-HIV broadly neutralizing antibodies.

Our project aimed to develop a groundbreaking therapy for HIV that could eliminate the need for lifelong antiretroviral medications. Current treatments suppress the virus but cannot eradicate it, requiring patients to stay on medication indefinitely. We sought to create a new treatment approach that both targets and destroys HIV-infected cells and neutralizes free-floating viruses. We engineered immune cells with a dual function: expressing chimeric antigen receptors (CARs) derived from broadly neutralizing antibodies against HIV to recognize and kill virus-producing cells, and simultaneously producing and secreting functional antibodies to neutralize circulating HIV particles. We designed a library of genetic constructs combining these functions into a "universal" system, allowing easy optimization. In laboratory studies, the engineered cells effectively produced both CARs and neutralizing antibodies, demonstrating the ability to kill HIV-infected cells and neutralize a diverse range of HIV strains, indicating broad-spectrum activity. We also optimized methods for introducing these genetic changes into immune cells, improving efficiency and viability—crucial steps for developing an effective therapy. Building on these results, the next phase involves testing the most effective engineered cells in animal models to assess their safety and effectiveness. We aim to refine delivery methods to ensure these cells can persist and function long-term in the body. Ultimately, we plan to advance this therapy toward clinical trials, collaborating with regulatory agencies to ensure its safety and efficacy. We believe this dual-action approach could transform HIV treatment by providing a one-time therapy that eliminates infection and offers ongoing protection, greatly improving patients' quality of life.

This project aimed to develop a new type of cell-based therapy to treat HIV that could potentially eliminate the need for lifelong antiretroviral drugs. The approach used engineered immune cells derived from blood-forming or personalized stem cells called iPSCs. These cells are modified to carry special receptors—called CARs—based on powerful anti-HIV antibodies. The engineered cells are designed to do two things: directly kill HIV-infected cells and release antibodies that block the virus from spreading. During this award, we successfully designed, generated, and tested various genetic tools to deliver these anti-HIV functions to immune cells, including T, NK, and HSCs. We also demonstrated that engineered molecules released from human iPSCs can recognize HIV-infected cells and neutralize a broad spectrum of HIV strains in lab-based models. Next steps will include further testing these engineered cells in preclinical animal models to evaluate safety and long-term effectiveness. If successful, this work will lay the foundation for future clinical trials aimed at developing a durable and potentially curative therapy for HIV patients.