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.
A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies
Disclosures: D.S. Jones reported "other" from Repertoire Immune Medicines and "other" from Bristol Myers Squibb outside the submitted work; in addition, D.S. Jones had a patent to PCT/US2019/061837 pending and a patent to PCT/US2017/037249 pending. T.L. Andresen reported being a co-founder of Repertoire Immune Medicine. C.M. Bollard reported "other" from Mana Therapeutics outside the submitted work; in addition, C.M. Bollard had a patent number 9,885,021 licensed to Mana Therapeutics. C.M. Bollard also reported being on the board of directors of Cabaletta Bio, being a co-founder of Mana Therapeutics and Catamaran Bio, and having stock ownership in Repertoire Immune Medicines and Neximmune. D.J. Irvine reported “other” from Repertoire Immune Medicines during the conduct of the study; in addition, D.J. Irvine had a patent to Cell Surface Coupling of Nanoparticles with royalties paid for Repertoire Immune Medicine. No other disclosures were reported.
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Chase D. McCann, Christiaan H. van Dorp, Ali Danesh, Adam R. Ward, Thomas R. Dilling, Talia M. Mota, Elizabeth Zale, Eva M. Stevenson, Shabnum Patel, Chanson J. Brumme, Winnie Dong, Douglas S. Jones, Thomas L. Andresen, Bruce D. Walker, Zabrina L. Brumme, Catherine M. Bollard, Alan S. Perelson, Darrell J. Irvine, R. Brad Jones; A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies. J Exp Med 5 July 2021; 218 (7): e20201908. doi: https://doi.org/10.1084/jem.20201908
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