Summary Current HIV curative strategies have proven insufficient to eradicate viral reservoirs or prevent viral rebound after antiretroviral therapy (ART) cessation. The unifying hypothesis for the BEAT-HIV Collaboratory is that through a better mechanistic understanding of HIV latent reservoirs and host factors governing viral control and reactivation, long-term viral remission or eradication of HIV will be achieved by combination immunotherapy inclusive of bNAbs, adoptively transferred immune cells, and nanoparticle therapies. We will test this hypothesis by pursuing three highly interconnected research focus areas. The first aim will seek to understand epigenetic status of intact proviruses, extrinsic/intrinsic factors affecting proviral reactivation and expression, and novel host mechanisms for post-treatment control of HIV. The second aim will develop strategies for long-term control in the absence of ART by use of DNA-delivered anti-HIV bNAbs and eCD4Ig in combination with optimized tissue-based CD8 T-cell- and NK cell-mediated responses. The third aim will develop a combination nanotherapy and immunotherapy strategy to eradicate viral reservoirs. All aims will be supported by a clinical biorepository (blood and tissue), CD34+ or patient-derived xenograft humanized mice, non-human primate (NHP) models, and a clinical trial development group as a link to the ACTG. Community engagement will advance education and a socio-behavioral sciences and ethics focus by leveraging a >25-year relationship with the local HIV community thereby ensuring partnership with stakeholders. Central administration of resources will ensure achievement of high impact milestones, study team communications, and yearly goal- oriented resource allocation and/or redistribution as informed by advances in the field. As an established Collaboratory, we bring together diverse expertise, innovation, and industry partners to develop and test novel strategies to advance an HIV cure and/or durable viral control in the absence of ART under a single common multi-investigator, multi-industry team. Studies within the three interconnected aims together with a strong community engagement plan will lay the groundwork for future clinical trials that will integrate new knowledge gained by the BEAT HIV-1 Collaboratory to eradicate or functionally cure HIV infection.