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EARLY EFFECTS OF HTLV-1 INFECTION ON THE ACTIVATION, EXHAUSTION, AND DIFFERENTIATION OF T-CELLS IN HUMANIZED NSG MICE
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Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em Neuroinfecções. Rio de Janeiro, RJ, Brasil / University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Amsterdam, The Netherlands.
University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Amsterdam, The Netherlands.
University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Amsterdam, The Netherlands.
University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Amsterdam, The Netherlands.
University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Laboratory of Experimental Virology. Amsterdam, The Netherlands.
University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Laboratory of Experimental Virology. Amsterdam, The Netherlands.
University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Amsterdam, The Netherlands.
University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Laboratory of Experimental Virology. Amsterdam, The Netherlands / J&S Preclinical Solutions. The Netherlands.
University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Amsterdam, The Netherlands.
University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Amsterdam, The Netherlands.
University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Amsterdam, The Netherlands.
University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Laboratory of Experimental Virology. Amsterdam, The Netherlands.
University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Laboratory of Experimental Virology. Amsterdam, The Netherlands.
University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Amsterdam, The Netherlands.
University of Amsterdam. Location AMC. Amsterdam University Medical Centers. Department of Experimental Immunology. Laboratory of Experimental Virology. Amsterdam, The Netherlands / J&S Preclinical Solutions. The Netherlands.
Abstract
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy of CD4+ T-cells associated with HTLV-1 infection. In this study, we used the model of immunodeficient NSG mice reconstituted with a functional human immune system (HIS) to investigate early events in HTLV-1 pathogenesis. Upon infection, human T-cells rapidly increased in the blood and lymphoid tissues, particularly CD4+CD25+ T-cells. Proliferation of CD4+ T-cells in the spleen and mesenteric lymph nodes (MLN) correlated with HTLV-1 proviral load and CD25 expression. In addition, splenomegaly, a common feature of ATLL in humans, was also observed. CD4+ and CD8+ T-cells predominantly displayed an effector memory phenotype (CD45RA-CCR7-) and expressed CXCR3 and CCR5 chemokine receptors, suggesting the polarization into a Th1 phenotype. Activated CD8+ T-cells expressed granzyme B and perforin; however, the interferon-γ response by these cells was limited, possibly due to elevated PD-1 expression and increased frequency of CD4+FoxP3+ regulatory T-cells in MLN. Thus, HTLV-1-infected HIS-NSG mice reproduced several characteristics of infection in humans, and it may be helpful to investigate ATLL-related events and to perform preclinical studies. Moreover, aspects of chronic infection were already present at early stages in this experimental model. Collectively, we suggest that HTLV-1 infection modulates host immune responses to favor viral persistence.
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