Abstract Since its inception in 2011, the Martin Delaney Collaboratory program has made important advances towards a cure for HIV. In response to the Martin Delaney Collaboratories (MDC) for HIV Cure Research RFA, we seek to continue to advance the field by discovery of successful modalities to cure HIV infection. We will expand our expertise and work toward a better understanding of persistent HIV infection, the discovery of novel approaches to disrupt latency, methods to clear the HIV reservoir, and identification of strategies to control viral rebound. By building on the significant advances that we have made to develop, implement, and execute a suite of pre-clinical experiments that represent the most advanced and novel concepts, we will continue to pursue our central unifying hypothesis that reversing HIV latency such that viral proteins are expressed, in parallel with interventions that speed the clearance of cells emerging from latent infection, will ultimately lead to eradication of persistent HIV infection. In parallel to the efforts to clear the infection, we will pursue interventions to prevent rebound of viremia after ART interruption. We will leverage a broad portfolio of tools from both academic and industry partners, and apply new discoveries, demonstrating proof-of-concept for clinical initiatives. We will engage academic scientists and clinicians, industry investigators, and the community to a) define novel targets to destabilize proviral genomes that persist despite antiretroviral therapy (ART) b) define novel approaches to block proviral establishment c) develop and deploy novel effectors to clear viral reservoirs, d) delineate effective strategies to prevent rebound viremia that might emanate from such reservoirs after ART is discontinued and e) create bridges to the community to improve the understanding of and access to HIV cure research and clinical trials. Our initial efforts will focus on biology discovery to illuminate new host targets for latency reversal, and the validation of the novel biological concept of latency prevention. Universal strategies for proviral control or clearance will be developed and tested, including those based on HLA-E targeting, eCD4, and CD4 mimetics. Our major recent advance in latency reversal via NF-kB signaling will be further developed in both non-human primate and humanize mice models, in combination with candidates to clear infected cells. We envision an iterative process with insights gained in ex vivo and pre-clinical studies, carried forward to enhance the next step in clinical development and, importantly, fed back to scientists to validate assays or hypotheses, and explore new directions. As we have done in the past, we will develop human clinical trials to address questions and test concepts developed in our work through funding mechanisms distinct from CARE. We are dedicated to working together in a nimble program, with our research direction following our discoveries. Together...