| Title: |
A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies |
| Authors: |
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; Dong, Winnie; Jones, Douglas S; Andresen, Thomas L; Walker, Bruce D; Brumme, Zabrina L; Bollard, Catherine M; Perelson, Alan S; Irvine, Darrell J; Jones, R Brad |
| Contributors: |
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 |
| Source: |
Rockefeller University Press |
| Publisher Information: |
Rockefeller University Press |
| Publication Year: |
2021 |
| Collection: |
DSpace@MIT (Massachusetts Institute of Technology) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
The Journal of Experimental Medicine; https://hdl.handle.net/1721.1/133106 |
| Availability: |
https://hdl.handle.net/1721.1/133106 |
| Rights: |
Creative Commons Attribution-Noncommercial-Share Alike ; http://creativecommons.org/licenses/by-nc-sa/4.0/ |
| Accession Number: |
edsbas.CF5E87B3 |
| Database: |
BASE |