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Background: HIV persistence during antiretroviral therapy (ART) is the principal obstacle to cure. Lymphoid tissue is a compartment for HIV, but mechanisms of persistence during ART and viral rebound when ART is interrupted are inadequately understood. Metabolic activity in lymphoid tissue of patients on long-term ART is relatively low, and increases when ART is stopped. Increases in metabolic activity can be detected by 18 F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and may represent sites of HIV replication or immune activation in response to HIV replication., Methods: FDG-PET imaging will be used to identify areas of high and low metabolic uptake in lymphoid tissue of individuals undergoing long-term ART. Baseline tissue samples will be collected. Participants will then be randomized 1:1 to continue or interrupt ART via analytic treatment interruption (ATI). Image-guided biopsy will be repeated 10 days after ATI initiation. After ART restart criteria are met, image-guided biopsy will be repeated once viral suppression is re-achieved. Participants who continued ART will have a second FDG-PET and biopsies 12-16 weeks after the first. Genetic characteristics of HIV populations in areas of high and low FDG uptake will be assesed. Optional assessments of non-lymphoid anatomic compartments may be performed to evaluate HIV populations in distinct anatomic compartments., Anticipated Results: We anticipate that PET standardized uptake values (SUV) will correlate with HIV viral RNA in biopsies of those regions and that lymph nodes with high SUV will have more viral RNA than those with low SUV within a patient. Individuals who undergo ATI are expected to have diverse viral populations upon viral rebound in lymphoid tissue. HIV populations in tissues may initially be phylogenetically diverse after ATI, with emergence of dominant viral species (clone) over time in plasma. Dominant viral species may represent the same HIV population seen before ATI., Discussion: This study will allow us to explore utility of PET for identification of HIV infected cells and determine whether high FDG uptake respresents areas of HIV replication, immune activation or both. We will also characterize HIV infected cell populations in different anatomic locations. The protocol will represent a platform to investigate persistence and agents that may target HIV populations., Study Protocol Registration: Identifier: NCT05419024., Competing Interests: Author BW would like to disclose the following: Licensed Patents/Royalties: Philips and NIH have a patent licensing agreement under which NIH receives royalties, a portion of which are then given to BW. NVIDIA and NIH have a licensing agreement. NIH and Canon have a licensing agreement. BW is Principal Investigator on the following Cooperative Research & Development Agreements (CRADAs), between NIH and industry: Philips (CRADA), Philips Research (CRADA), Celsion Corp (CRADA), BTG Biocompatibles/Boston Scientific (CRADA), Siemens (CRADA), NVIDIA (CRADA), XAct Robotics (CRADA). Negotiating CRADA with ProMaxo, Tempus, Galvanize, Theromics, Imactis, Varian. The following industry partners also support research in the Center for Interventional Oncology/Dr. Wood's lab via equipment, personnel, devices and/or drugs: 3T Technologies (devices), Exact Imaging (data), Angiodynamics (equipment), Astra Zeneca (pharmaceuticals, NCI CRADA), ArciTrax (devices and equipment), Imactis (Equipment), Johnson and Johnson (equipment), Medtronic (equipment), Promaxo (equipment & personnel), Theromics (Supplies), Profound (equipment and supplies), and QT Imaging (equipment and supplies). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lau, Adan, Earhart, Seamon, Nguyen, Savramis, Adams, Zipparo, Madeen, Huik, Grossman, Chimukangara, Wulan, Millo, Nath, Smith, Ortega-Villa, Proschan, Wood, Hammoud and Maldarelli.)