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Humanized Mice Engrafted With Human HSC Only or HSC and Thymus Support Comparable HIV-1 Replication, Immunopathology, and Responses to ART and Immune Therapy.

ABSTRACT: Immunodeficient mice reconstituted with human immune tissues and cells (humanized mice) are relevant and robust models for the study of HIV-1 infection, immunopathogenesis, and therapy. In this study, we performed a comprehensive comparison of human immune reconstitution and HIV-1 infection, immunopathogenesis and therapy between immunodeficient NOD/Rag2-/-/γc-/- (NRG) mice transplanted with human HSCs (NRG-hu HSC) and mice transplanted with HSCs and thymus fragments (NRG-hu Thy/HSC) from the same donors. We found that similar human lymphoid and myeloid lineages were reconstituted in NRG-hu HSC and NRG-hu Thy/HSC mice, with human T cells more predominantly reconstituted in NRG-hu Thy/HSC mice, while NRG-hu HSC mice supported more human B cells and myeloid cells reconstitution. HIV-1 replicated similarly and induced similar T cell depletion, immune activation, and dysfunction in NRG-hu HSC and NRG-hu Thy/HSC mice. Moreover, combined antiretroviral therapy (cART) inhibited HIV-1 replication efficiently with similar persistent HIV-1 reservoirs in both models. Finally, we found that blocking type-I interferon signaling under cART treatment transiently activated HIV-1 reservoirs, enhanced T cell recovery and reduced HIV-1 reservoirs in both HIV-1 infected NRG-hu HSC and NRG-hu Thy/HSC mice. In summary, we report that NRG-hu Thy/HSC and NRG-hu HSC mice support similar HIV-1 infection and similar HIV-1 immunopathology; and HIV-1 replication responds similarly to cART and IFNAR blockade therapies. The NRG-hu HSC mouse model reconstituted with human HSC only is sufficient for the study of HIV-1 infection, pathogenesis, and therapy.

SUBMITTER: Cheng L

PROVIDER: S-EPMC5916969 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Human liver chimeric mice are useful models of human hepatitis virus infection, including hepatitis B and C virus infections. Independently, immunodeficient mice reconstituted with CD34(+) hematopoietic stem cells (HSC) derived from fetal liver reliably develop human T and B lymphocytes. Combining these systems has long been hampered by inefficient liver reconstitution of human fetal hepatoblasts. Our study aimed to enhance hepatoblast engraftment in order to create a mouse model with syngeneic human liver and immune cells.The effects of human oncostatin-M administration on fetal hepatoblast engraftment into immunodeficient fah(-/-) mice was tested. Mice were then transplanted with syngeneic human hepatoblasts and HSC after which human leukocyte chimerism and functionality were analyzed by flow cytometry, and mice were challenged with HBV.Addition of human oncostatin-M enhanced human hepatoblast engraftment in immunodeficient fah(-/-) mice by 5-100 fold. In contrast to mice singly engrafted with HSC, which predominantly developed human T and B lymphocytes, mice co-transplanted with syngeneic hepatoblasts also contained physiological levels of human monocytes and natural killer cells. Upon infection with HBV, these mice displayed rapid and sustained viremia.Our study provides a new mouse model with improved human fetal hepatoblast engraftment and an expanded human immune cell repertoire. With further improvements, this model may become useful for studying human immunity against viral hepatitis.Important human pathogens such as hepatitis B virus, hepatitis C virus and human immunodeficiency virus only infect human cells which complicates the development of mouse models for the study of these pathogens. One way to make mice permissive for human pathogens is the transplantation of human cells into immune-compromised mice. For instance, the transplantation of human liver cells will allow the infection of these so-called "liver chimeric mice" with hepatitis B virus and hepatitis C virus. The co-transplantation of human immune cells into liver chimeric mice will further allow the study of human immune responses to hepatitis B virus or hepatitis C virus. However, for immunological studies it will be crucial that the transplanted human liver and immune cells are derived from the same human donor. In our study we describe the efficient engraftment of human fetal liver cells and immune cells derived from the same donor into mice. We show that liver co-engraftment resulted in an expanded human immune cell repertoire, including monocytes and natural killer cells in the liver. We further demonstrate that these mice could be infected with hepatitis B virus, which lead to an expansion of natural killer cells. In conclusion we have developed a new mouse model that could be useful to study human immune responses to human liver pathogens.

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Humanized Mice Engrafted With Human HSC Only or HSC and Thymus Support Comparable HIV-1 Replication, Immunopathology, and Responses to ART and Immune Therapy.

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