Safety and virologic impact of the IL-15 superagonist N-803 in people living with HIV: a phase 1 trial

Jeffrey S. Miller, Zachary B. Davis, Erika Helgeson, Cavan Reilly, Ann Thorkelson, Jodi Anderson, Noemia S. Lima, Siri Jorstad, Geoffrey T. Hart, John H. Lee, Jeffrey T. Safrit, Hing Wong, Sarah Cooley, Lavina Gharu, Hyunsoo Chung, Patrick Soon-Shiong, Curtis Dobrowolski, Courtney V. Fletcher, Jonathan Karn, Daniel C. DouekTimothy W. Schacker

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


There is no cure for HIV infection, and lifelong antiretroviral therapy (ART) is required. N-803 is an IL-15 superagonist comprised of an N72D mutant IL-15 molecule attached to its alpha receptor and a human IgG1 fragment designed to increase IL-15 activity. Preclinical studies with both HIV and SIV suggest that the drug has potential to reduce virus reservoirs by activating virus from latency and enhancing effector function. We conducted a phase 1 study of N-803 (NCT02191098) in people living with HIV, the primary objective of which was to assess the safety and tolerability of the drug, with an exploratory objective of assessing the impact on peripheral virus reservoirs. ART-suppressed individuals were enrolled into a dose-escalation study of N-803 in four different cohorts (0.3, 1.0, 3.0 and 6.0 mcg kg−1). Each cohort received three doses total, separated by at least 1 week. We enrolled 16 individuals, of whom 11 completed all three doses. The maximum tolerated dose was 6.0 mcg kg−1. The primary clinical adverse events (AEs) reported were injection site rash and adenopathy, and four participants experienced a grade 1 or grade 2 QTc prolongation. No significant laboratory AEs attributable to N-803 were observed. In exploratory analyses, N-803 was associated with proliferation and/or activation of CD4+ and CD8+ T cells and natural killer cells that peaked at 4 d after dosing. IFN-γ, IP-10, MCP-1 and IL-15 increased during treatment. HIV transcription in memory CD4 T cells and intact proviral DNA initially increased after N-803 treatment; however, there was a small but significant decrease in the frequency of peripheral blood mononuclear cells with an inducible HIV provirus that persisted for up to 6 months after therapy. These data suggest that N-803 administration in ART-suppressed people living with HIV is safe and that larger clinical trials are needed to further investigate the effects of N-803 on HIV reservoirs.

Original languageEnglish (US)
Pages (from-to)392-400
Number of pages9
JournalNature Medicine
Issue number2
StatePublished - Feb 2022

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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