Ragon Institute of MGH, MIT and Harvard; Howard Hughes Medical Institute (HHMI) - Chevy Chase; Massachusetts Institute of Technology (MIT) - Institute for Medical Engineering and Science
Government of the United States of America - Theoretical Biology and Biophysics; Government of the United States of America - Los Alamos National Laboratory
HIV-specific CD8 + T-cells partially control viral replication and delay disease progression, but rarely provide lasting protection – largely due to immune escape. 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, which were augmented by engineering with IL-15 superagonist-containing nanogels. Ultimately, in vivo activity was limited by the selection of diverse 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.
McCann, Chase and van Dorp, Christiaan and Ward, Adam R. and Danesh, Ali and Dilling, Thomas and Mota, Talia and Zale, Elizabeth and Patel, Shabnum and Brumme, Chanson and Dong, Winnie and Jones, Douglas S. and Andresen, Thomas L. and Walker, Bruce D. and Brumme, Zabrina and Bollard, Catherine and Perelson, Alan and Irvine, Darrell and Jones, R. Brad, A Participant-Derived Xenograft Model of HIV Enables Long-Term Evaluation of Autologous Immunotherapies. Available at SSRN: https://ssrn.com/abstract=3596601 or http://dx.doi.org/10.2139/ssrn.3596601
This version of the paper has not been formally peer reviewed.
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