A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies
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jem_20201908.pdf
Description
Published version
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7.24 MB
Format
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Checksum (MD5)
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Author(s)
McCann, Chase D
van Dorp, Christiaan H
Danesh, Ali
Ward, Adam R
Dilling, Thomas R
Mota, Talia M
Zale, Elizabeth
Stevenson, Eva M
Patel, Shabnum
Brumme, Chanson J
Date Issued
2021
Journal
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Citation
McCann, Chase D, van Dorp, Christiaan H, Danesh, Ali, Ward, Adam R, Dilling, Thomas R et al. 2021. "A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies." The Journal of Experimental Medicine, 218 (7).
Version
Final published version
Abstract
HIV-specific CD8+ T cells partially control viral replication and delay disease progression, but they rarely provide lasting protection, largely due to immune escape. Here, we show that engrafting mice with memory CD4+ T cells from HIV+ donors uniquely allows for the in vivo evaluation of autologous T cell responses while avoiding graft-versus-host disease and the need for human fetal tissues that limit other models. Treating HIV-infected mice with clinically relevant HIV-specific T cell products resulted in substantial reductions in viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an IL-15 superagonist, but it was ultimately limited by the pervasive selection of a diverse array of escape mutations, recapitulating patterns seen in humans. By applying mathematical modeling, we show that the kinetics of the CD8+ T cell response have a profound impact on the emergence and persistence of escape mutations. This “participant-derived xenograft” model of HIV provides a powerful tool for studying HIV-specific immunological responses and facilitating the development of effective cell-based therapies.
MIT Department
Ragon Institute of MGH, MIT and Harvard
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Materials Science and Engineering
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biological Engineering
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1084/jem.20201908
