| 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: |
National Institute of Allergy and Infectious Diseases; National Institutes of Health; National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institutes of Health Office of the Director; National Center for Advancing Translational Sciences; District of Columbia Developmental Center for AIDS Research; National Cancer Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute; National Institute on Aging; Fogarty International Center; National Institute of General Medical Sciences; National Institute of Diabetes and Digestive and Kidney Diseases; Office of AIDS Research; Canadian Institutes of Health Research; Michael Smith Foundation for Health Research; U.S. Department of Energy |
| Source: |
Journal of Experimental Medicine ; volume 218, issue 7 ; ISSN 0022-1007 1540-9538 |
| Publisher Information: |
Rockefeller University Press |
| Publication Year: |
2021 |
| 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 |
| Language: |
English |
| DOI: |
10.1084/jem.20201908 |
| DOI: |
10.1084/jem.20201908/1781699/jem_20201908.pdf |
| Availability: |
https://doi.org/10.1084/jem.20201908; https://rupress.org/jem/article-pdf/doi/10.1084/jem.20201908/1781699/jem_20201908.pdf |
| Rights: |
http://www.rupress.org/terms/ ; https://creativecommons.org/licenses/by-nc-sa/4.0/ |
| Accession Number: |
edsbas.C643D359 |
| Database: |
BASE |