AUTHOR=Cheng Liang , Ma Jianping , Li Guangming , Su Lishan 

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

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00817

DOI=10.3389/fimmu.2018.00817

ISSN=1664-3224

ABSTRACT=<p>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<sup>−/−</sup>/γ<sub>c</sub><sup>−/−</sup> (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.</p>