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Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection
Humanized bone marrow-liver-thymus (HuBLT) mice are a revolutionary small-animal model that has facilitated the study of human immune function and human-restricted pathogens, including human immunodeficiency virus type 1 (HIV-1). These mice recapitulate many aspects of acute and chronic HIV-1 infect...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189152/ https://www.ncbi.nlm.nih.gov/pubmed/34122425 http://dx.doi.org/10.3389/fimmu.2021.667393 |
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author | Garcia-Beltran, Wilfredo F. Claiborne, Daniel T. Maldini, Colby R. Phelps, Meredith Vrbanac, Vladimir Karpel, Marshall E. Krupp, Katharine L. Power, Karen A. Boutwell, Christian L. Balazs, Alejandro B. Tager, Andrew M. Altfeld, Marcus Allen, Todd M. |
author_facet | Garcia-Beltran, Wilfredo F. Claiborne, Daniel T. Maldini, Colby R. Phelps, Meredith Vrbanac, Vladimir Karpel, Marshall E. Krupp, Katharine L. Power, Karen A. Boutwell, Christian L. Balazs, Alejandro B. Tager, Andrew M. Altfeld, Marcus Allen, Todd M. |
author_sort | Garcia-Beltran, Wilfredo F. |
collection | PubMed |
description | Humanized bone marrow-liver-thymus (HuBLT) mice are a revolutionary small-animal model that has facilitated the study of human immune function and human-restricted pathogens, including human immunodeficiency virus type 1 (HIV-1). These mice recapitulate many aspects of acute and chronic HIV-1 infection, but exhibit weak and variable T-cell responses when challenged with HIV-1, hindering our ability to confidently detect HIV-1–specific responses or vaccine effects. To identify the cause of this, we comprehensively analyzed T-cell development, diversity, and function in HuBLT mice. We found that virtually all HuBLT were well-reconstituted with T cells and had intact TCRβ sequence diversity, thymic development, and differentiation to memory and effector cells. However, there was poor CD4+ and CD8+ T-cell responsiveness to physiologic stimuli and decreased TH1 polarization that correlated with deficient reconstitution of innate immune cells, in particular monocytes. HIV-1 infection of HuBLT mice showed that mice with higher monocyte reconstitution exhibited greater CD8+ T cells responses and HIV-1 viral evolution within predicted HLA-restricted epitopes. Thus, T-cell responses to immune challenges are blunted in HuBLT mice due to a deficiency of innate immune cells, and future efforts to improve the model for HIV-1 immune response and vaccine studies need to be aimed at restoring innate immune reconstitution. |
format | Online Article Text |
id | pubmed-8189152 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-81891522021-06-10 Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection Garcia-Beltran, Wilfredo F. Claiborne, Daniel T. Maldini, Colby R. Phelps, Meredith Vrbanac, Vladimir Karpel, Marshall E. Krupp, Katharine L. Power, Karen A. Boutwell, Christian L. Balazs, Alejandro B. Tager, Andrew M. Altfeld, Marcus Allen, Todd M. Front Immunol Immunology Humanized bone marrow-liver-thymus (HuBLT) mice are a revolutionary small-animal model that has facilitated the study of human immune function and human-restricted pathogens, including human immunodeficiency virus type 1 (HIV-1). These mice recapitulate many aspects of acute and chronic HIV-1 infection, but exhibit weak and variable T-cell responses when challenged with HIV-1, hindering our ability to confidently detect HIV-1–specific responses or vaccine effects. To identify the cause of this, we comprehensively analyzed T-cell development, diversity, and function in HuBLT mice. We found that virtually all HuBLT were well-reconstituted with T cells and had intact TCRβ sequence diversity, thymic development, and differentiation to memory and effector cells. However, there was poor CD4+ and CD8+ T-cell responsiveness to physiologic stimuli and decreased TH1 polarization that correlated with deficient reconstitution of innate immune cells, in particular monocytes. HIV-1 infection of HuBLT mice showed that mice with higher monocyte reconstitution exhibited greater CD8+ T cells responses and HIV-1 viral evolution within predicted HLA-restricted epitopes. Thus, T-cell responses to immune challenges are blunted in HuBLT mice due to a deficiency of innate immune cells, and future efforts to improve the model for HIV-1 immune response and vaccine studies need to be aimed at restoring innate immune reconstitution. Frontiers Media S.A. 2021-05-26 /pmc/articles/PMC8189152/ /pubmed/34122425 http://dx.doi.org/10.3389/fimmu.2021.667393 Text en Copyright © 2021 Garcia-Beltran, Claiborne, Maldini, Phelps, Vrbanac, Karpel, Krupp, Power, Boutwell, Balazs, Tager, Altfeld and Allen https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Garcia-Beltran, Wilfredo F. Claiborne, Daniel T. Maldini, Colby R. Phelps, Meredith Vrbanac, Vladimir Karpel, Marshall E. Krupp, Katharine L. Power, Karen A. Boutwell, Christian L. Balazs, Alejandro B. Tager, Andrew M. Altfeld, Marcus Allen, Todd M. Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection |
title | Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection |
title_full | Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection |
title_fullStr | Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection |
title_full_unstemmed | Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection |
title_short | Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection |
title_sort | innate immune reconstitution in humanized bone marrow-liver-thymus (hublt) mice governs adaptive cellular immune function and responses to hiv-1 infection |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189152/ https://www.ncbi.nlm.nih.gov/pubmed/34122425 http://dx.doi.org/10.3389/fimmu.2021.667393 |
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