Next Generation HSC Gene Therapy for HIV Control and Eradication

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DESCRIPTION (provided by applicant): The goal of this U19 is to develop the next generation of gene/cell therapies to treat HIV-1 and allow drug-free control of virus replication or eradication. It brings together academic and biotech partners with a strong history of collaboration and highly relevant expertise in gene engineering, virology, HSC biology and transplantation, systems biology and animal models. The program also builds on the team's extensive prior experience with HIV gene therapy, in particular with the use of zinc finger nucleases (ZFNs) to disrupt the CCR5 co-receptor, which is currently being evaluated in clinical trials. The overall approach is also informed by recent clinical findings about the nature of HIV reservoirs in HSC transplant patients such as the "Berlin Patient" and the two "Boston Patients". The contrasting outcomes for these individuals point to an essential role for HIV-resistant cells in the Boston Patient's successful eradication of HIV and highlight the urgent need to better understand the nature of the viral reservoir, including component(s) that can persist despite fully ablative transplantation regimens. Project 1 will directly address this question using a model that combines gene-marked autologous and allogeneic transplantation in pig-tail macaques. While ongoing trials based on CCR5 disruption are providing important information about the general feasibility and efficacy of gene therapy approaches for HIV, the path towards broader clinical utility must include targets beyond CCR5. In particular, this will be so as to include patients harboring dual or X4-tropic viruses. HSC-based gene therapies will also benefit from improvements in both the frequency with which appropriately engineered cells can be produced, and the contribution of such cells to subsequent hematopoiesis. Towards these goals, Projects 2, 3 and 4 will exploit recent developments in gene editing and HSC expansion technologies to develop novel approaches that will be tested in parallel in human and macaque HSC. Specifically, the teams will work synergistically to develop capabilities to: (1) maximize gene editing outcomes in human and primate HSC, (2) develop methods to expand engineered HSC ex vivo, and (3) evaluate novel anti-HIV strategies based on site-specific gene addition and editing of endogenous genes. Finally, Project 4 will use the macaque model to directly address whether methods to expand the contribution of engineered cells to engraftment can lead to a more potent anti-HIV effect using the low toxicity conditioning regimens that will be appropriate in the clinical setting. The work will be supported by three Cores, providing administrative oversight, non-human primate models of HSC transplantation, and systems biology analysis of outcomes. In summary, the individual Projects and Core in this U19 will address the major shortcomings of current anti-HIV gene/cell therapies, and thereby guide the development of future therapies with demonstrated efficacy, enhanced safety, and improved potential for practical applications in HIV-infected individuals.