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HIV-1 infection and CD4 T cell depletion in the humanized Rag2(-/-)γc(-/- )(RAG-hu) mouse model
BACKGROUND: The currently well-established humanized mouse models, namely the hu-PBL-SCID and SCID-hu systems played an important role in HIV pathogenesis studies. However, despite many notable successes, several limitations still exist. They lack multi-lineage human hematopoiesis and a functional h...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2006
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1635423/ https://www.ncbi.nlm.nih.gov/pubmed/17078891 http://dx.doi.org/10.1186/1742-4690-3-76 |
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author | Berges, Bradford K Wheat, William H Palmer, Brent E Connick, Elizabeth Akkina, Ramesh |
author_facet | Berges, Bradford K Wheat, William H Palmer, Brent E Connick, Elizabeth Akkina, Ramesh |
author_sort | Berges, Bradford K |
collection | PubMed |
description | BACKGROUND: The currently well-established humanized mouse models, namely the hu-PBL-SCID and SCID-hu systems played an important role in HIV pathogenesis studies. However, despite many notable successes, several limitations still exist. They lack multi-lineage human hematopoiesis and a functional human immune system. These models primarily reflect an acute HIV infection with rapid CD4 T cell loss thus limiting pathogenesis studies to a short-term period. The new humanized Rag2(-/-)γc(-/- )mouse model (RAG-hu) created by intrahepatic injection of CD34 hematopoietic stem cells sustains long-term multi-lineage human hematopoiesis and is capable of mounting immune responses. Thus, this model shows considerable promise to study long-term in vivo HIV infection and pathogenesis. RESULTS: Here we demonstrate that RAG-hu mice produce human cell types permissive to HIV-1 infection and that they can be productively infected by HIV-1 ex vivo. To assess the capacity of these mice to sustain long-term infection in vivo, they were infected by either X4-tropic or R5-tropic HIV-1. Viral infection was assessed by PCR, co-culture, and in situ hybridization. Our results show that both X4 and R5 viruses are capable of infecting RAG-hu mice and that viremia lasts for at least 30 weeks. Moreover, HIV-1 infection leads to CD4 T cell depletion in peripheral blood and thymus, thus mimicking key aspects of HIV-1 pathogenesis. Additionally, a chimeric HIV-1 NL4-3 virus expressing a GFP reporter, although capable of causing viremia, failed to show CD4 T cell depletion possibly due to attenuation. CONCLUSION: The humanized RAG-hu mouse model, characterized by its capacity for sustained multi-lineage human hematopoiesis and immune response, can support productive HIV-1 infection. Both T cell and macrophage tropic HIV-1 strains can cause persistent infection of RAG-hu mice resulting in CD4 T cell loss. Prolonged viremia in the context of CD4 T cell depletion seen in this model mirrors the main features of HIV infection in the human. Thus, the RAG-hu mouse model of HIV-1 infection shows great promise for future in vivo pathogenesis studies, evaluation of new drug treatments, vaccines and novel gene therapy strategies. |
format | Text |
id | pubmed-1635423 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2006 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-16354232006-11-09 HIV-1 infection and CD4 T cell depletion in the humanized Rag2(-/-)γc(-/- )(RAG-hu) mouse model Berges, Bradford K Wheat, William H Palmer, Brent E Connick, Elizabeth Akkina, Ramesh Retrovirology Research BACKGROUND: The currently well-established humanized mouse models, namely the hu-PBL-SCID and SCID-hu systems played an important role in HIV pathogenesis studies. However, despite many notable successes, several limitations still exist. They lack multi-lineage human hematopoiesis and a functional human immune system. These models primarily reflect an acute HIV infection with rapid CD4 T cell loss thus limiting pathogenesis studies to a short-term period. The new humanized Rag2(-/-)γc(-/- )mouse model (RAG-hu) created by intrahepatic injection of CD34 hematopoietic stem cells sustains long-term multi-lineage human hematopoiesis and is capable of mounting immune responses. Thus, this model shows considerable promise to study long-term in vivo HIV infection and pathogenesis. RESULTS: Here we demonstrate that RAG-hu mice produce human cell types permissive to HIV-1 infection and that they can be productively infected by HIV-1 ex vivo. To assess the capacity of these mice to sustain long-term infection in vivo, they were infected by either X4-tropic or R5-tropic HIV-1. Viral infection was assessed by PCR, co-culture, and in situ hybridization. Our results show that both X4 and R5 viruses are capable of infecting RAG-hu mice and that viremia lasts for at least 30 weeks. Moreover, HIV-1 infection leads to CD4 T cell depletion in peripheral blood and thymus, thus mimicking key aspects of HIV-1 pathogenesis. Additionally, a chimeric HIV-1 NL4-3 virus expressing a GFP reporter, although capable of causing viremia, failed to show CD4 T cell depletion possibly due to attenuation. CONCLUSION: The humanized RAG-hu mouse model, characterized by its capacity for sustained multi-lineage human hematopoiesis and immune response, can support productive HIV-1 infection. Both T cell and macrophage tropic HIV-1 strains can cause persistent infection of RAG-hu mice resulting in CD4 T cell loss. Prolonged viremia in the context of CD4 T cell depletion seen in this model mirrors the main features of HIV infection in the human. Thus, the RAG-hu mouse model of HIV-1 infection shows great promise for future in vivo pathogenesis studies, evaluation of new drug treatments, vaccines and novel gene therapy strategies. BioMed Central 2006-11-01 /pmc/articles/PMC1635423/ /pubmed/17078891 http://dx.doi.org/10.1186/1742-4690-3-76 Text en Copyright © 2006 Berges et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Berges, Bradford K Wheat, William H Palmer, Brent E Connick, Elizabeth Akkina, Ramesh HIV-1 infection and CD4 T cell depletion in the humanized Rag2(-/-)γc(-/- )(RAG-hu) mouse model |
title | HIV-1 infection and CD4 T cell depletion in the humanized Rag2(-/-)γc(-/- )(RAG-hu) mouse model |
title_full | HIV-1 infection and CD4 T cell depletion in the humanized Rag2(-/-)γc(-/- )(RAG-hu) mouse model |
title_fullStr | HIV-1 infection and CD4 T cell depletion in the humanized Rag2(-/-)γc(-/- )(RAG-hu) mouse model |
title_full_unstemmed | HIV-1 infection and CD4 T cell depletion in the humanized Rag2(-/-)γc(-/- )(RAG-hu) mouse model |
title_short | HIV-1 infection and CD4 T cell depletion in the humanized Rag2(-/-)γc(-/- )(RAG-hu) mouse model |
title_sort | hiv-1 infection and cd4 t cell depletion in the humanized rag2(-/-)γc(-/- )(rag-hu) mouse model |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1635423/ https://www.ncbi.nlm.nih.gov/pubmed/17078891 http://dx.doi.org/10.1186/1742-4690-3-76 |
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