A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies

• Main Authors: McCann, Chase D (Author), van Dorp, Christiaan H (Author), Danesh, Ali (Author), Ward, Adam R (Author), Dilling, Thomas R (Author), Mota, Talia M (Author), Zale, Elizabeth (Author), Stevenson, Eva M (Author), Patel, Shabnum (Author), Brumme, Chanson J (Author), Dong, Winnie (Author), Jones, Douglas S (Author), Andresen, Thomas L (Author), Walker, Bruce D (Author), Brumme, Zabrina L (Author), Bollard, Catherine M (Author), Perelson, Alan S (Author), Irvine, Darrell J (Author), Jones, R Brad (Author)
• Format: Article
• Language: English
• Published: Rockefeller University Press, 2021-10-25T18:31:21Z.
• Subjects: Article
• Online Access: Get fulltext

 <jats:p>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.</jats:p>