The human IL-15 superagonist N-803 promotes migration of virus-specific CD8+ T and NK cells to B cell follicles but does not reverse latency in ART-suppressed, SHIV-infected macaques

Gabriela M. Webb, Jhomary Molden, Kathleen Busman-Sahay, Shaheed Abdulhaqq, Helen L. Wu, Whitney C. Weber, Katherine B. Bateman, Jason S. Reed, Mina Northrup, Nicholas Maier, Shiho Tanaka, Lina Gao, Brianna Davey, Benjamin L. Carpenter, Michael K. Axthelm, Jeffrey J. Stanton, Jeremy Smedley, Justin M. Greene, Jeffrey T. Safrit, Jacob D. EstesPamela J. Skinner, Jonah B. Sacha

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Despite the success of antiretroviral therapy (ART) to halt viral replication and slow disease progression, this treatment is not curative and there remains an urgent need to develop approaches to clear the latent HIV reservoir. The human IL-15 superagonist N-803 (formerly ALT-803) is a promising anti-cancer biologic with potent immunostimulatory properties that has been extended into the field of HIV as a potential “shock and kill” therapeutic for HIV cure. However, the ability of N-803 to reactivate latent virus and modulate anti-viral immunity in vivo under the cover of ART remains undefined. Here, we show that in ART-suppressed, simian-human immunodeficiency virus (SHIV)SF162P3-infected rhesus macaques, subcutaneous administration of N-803 activates and mobilizes both NK cells and SHIV-specific CD8+ T cells from the peripheral blood to lymph node B cell follicles, a sanctuary site for latent virus that normally excludes such effector cells. We observed minimal activation of memory CD4+ T cells and no increase in viral RNA content in lymph node resident CD4+ T cells post N-803 administration. Accordingly, we found no difference in the number or magnitude of plasma viremia timepoints between treated and untreated animals during the N-803 administration period, and no difference in the size of the viral DNA cell-associated reservoir post N-803 treatment. These results substantiate N-803 as a potent immunotherapeutic candidate capable of activating and directing effector CD8+ T and NK cells to the B cell follicle during full ART suppression, and suggest N-803 must be paired with a bona fide latency reversing agent in vivo to facilitate immune-mediated modulation of the latent viral reservoir.

Original languageEnglish (US)
Article numbere1008339
JournalPLoS pathogens
Volume16
Issue number3
DOIs
StatePublished - 2020

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (https://www.nih.gov/) grants R21 AI128970, R01 AI129703, and R01 AI140888 from the National Institute of Allergy and Infectious Diseases (NIAID) awarded to J.B.S.. Additionally, K01 OD026561 was awarded to J.M.G. and P51 OD011092 from the NIH Office of the Director awarded to the Oregon National Primate Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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