Early Effects of HTLV-1 Infection on the Activation, Exhaustion, and Differentiation of T-Cells in Humanized NSG Mice
Otávio de Melo Espíndola,
Esther Siteur-van Rijnstra,
Esmay Frankin,
Kees Weijer,
Yme Ubeles van der Velden,
Ben Berkhout,
Bianca Blom,
Julien Villaudy
Affiliations
Otávio de Melo Espíndola
Laboratory for Clinical Research in Neuroinfections, Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
Esther Siteur-van Rijnstra
Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Esmay Frankin
Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Kees Weijer
Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Yme Ubeles van der Velden
Laboratory of Experimental Virology, Department of Medical Microbiology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Ben Berkhout
Laboratory of Experimental Virology, Department of Medical Microbiology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Bianca Blom
Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Julien Villaudy
Laboratory of Experimental Virology, Department of Medical Microbiology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
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.
