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Despite the success of antiretroviral therapy (ART) in reducing HIV-1–related morbidity and mortality, viral reservoirs persist in infected cells in individuals on suppressive ART. Unfortunately, very few therapeutic strategies have led to a substantial decrease in the number of these persistently infected cells, and novel approaches to eliminate or reduce HIV reservoir burden are urgently needed.1 One such high-priority strategy is the identification of cell-surface markers of either quiescent or HIV-1 transcriptionally active cells that may be targeted with therapeutics such as cytotoxic antibody-drug conjugates (ADCs).2,3 Whereas the search for targetable biomarkers on quiescent, latently infected cells has remained elusive, an alternative approach involves targeting and clearing viral reactivated cells following in vivo HIV-1 latency reversal, thereby providing the “kill” component to the “shock-and-kill” approach to achieving a functional HIV-1 cure or long-term ART-free remission.2,3 We recently reported that CD4+ T cells expressing CD30, a cell-surface membrane protein and a member of the tumor necrosis factor receptor superfamily, were enriched in HIV-1 RNA, and that CD30 and HIV-1 transcriptional activity strongly colocalized in gut tissue from ART-suppressed individuals.2 Furthermore, HIV-1–infected individuals, either viremic or on suppressive ART, had significantly higher percentages of memory CD4+ T cells that expressed CD30 compared with uninfected controls.2 Prior studies also demonstrated a link between HIV-1 plasma RNA and disease progression with soluble plasma CD30 levels.4-8 CD30 is usually expressed on tumor cells involved with Hodgkin or aggressive lymphomas, but is otherwise expressed in very few cells from healthy, HIV-1–uninfected individuals,9,10 making it an enticing target. We have also observed that ex vivo treatment of peripheral blood mononuclear cells (PBMCs) from ART-suppressed individuals with brentuximab vedotin, an anti-CD30 ADC,11 led to a decrease in HIV-1 DNA levels in samples from 4 of 7 participants tested.2 However, the direct, longitudinal impact of brentuximab vedotin therapy on measures of HIV-1 persistence in vivo is not known and proof-of-concept studies are urgently needed. Therefore, we studied the impact of 3 doses of brentuximab vedotin therapy for Hodgkin lymphoma on HIV-1 persistence and immune phenotype in a newly identified HIV-1–infected individual on long-term ART.