A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies
| Autor: | Catherine M. Bollard, Ali Danesh, Chanson J. Brumme, Thomas Lars Andresen, Douglas S. Jones, Bruce D. Walker, Zabrina L. Brumme, Eva M. Stevenson, Thomas R Dilling, Shabnum Patel, Winnie Dong, Christiaan H. van Dorp, Adam R. Ward, Elizabeth Zale, Alan S. Perelson, R. Brad Jones, Darrell J. Irvine, Talia M. Mota, Chase D. McCann |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
CD4-Positive T-Lymphocytes
0301 basic medicine T cell medicine.medical_treatment Immunology Cell HIV Infections Viremia Disease CD8-Positive T-Lymphocytes Virus Replication Technical Advances and Resources Cell Line Infectious Disease and Host Defense Mice 03 medical and health sciences 0302 clinical medicine In vivo medicine Immunodeficiency Animals Humans Immunology and Allergy Cytotoxic T cell 030304 developmental biology Interleukin-15 0303 health sciences business.industry HEK 293 cells Immunotherapy medicine.disease 3. Good health HEK293 Cells 030104 developmental biology medicine.anatomical_structure Viral replication Cell culture 030220 oncology & carcinogenesis Mutation HIV-1 Cancer research Heterografts business CD8 |
| Zdroj: | Rockefeller University Press The Journal of Experimental Medicine |
| Popis: | McCann et al. describe the development and characterization of a new mouse model for studying HIV-specific T cell responses and testing various immunotherapeutic strategies, which they validate by demonstrating enhanced therapeutic effects of autologous HIV-specific T cells augmented with cytokine-loaded nanogels. 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. |
| Databáze: | OpenAIRE |
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