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Open Access Role of Wild-type and Recombinant Human T-cell Leukemia Viruses in Lymphoproliferative Disease in Humanized NSG Mice

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Chronic infection with human T-cell leukemia virus type 1 (HTLV1) can lead to adult T-cell leukemia (ATL). In contrast, infection with HTLV2 does not lead to leukemia, potentially because of distinct virus–host interactions and an active immune response that controls virus replication and, therefore, leukemia development. We created a humanized mouse model by injecting human umbilical-cord stem cells into the livers of immunodeficient neonatal NSG mice, resulting in the development of human lymphocytes that cannot mount an adaptive immune response. We used these mice to compare the ability of molecular clones of HTLV1, HTLV2, and select recombinant viruses to induce leukemia–lymphoma in vivo. Infection with HTLV1 strongly stimulated the proliferation of CD4 + T cells, whereas HTLV2 preferentially stimulated the proliferation of CD8+ T cells; both HTLV1 and HTLV2 induced lymphoproliferative disease. Uninfected and HTLV-infected humanized mice both showed granulomatous inflammation as a background lesion. Similarly, recombinant viruses that expressed the HTLV1 envelope protein (Env) on an HTLV2 background (HTLV2–Env1) or Env2 on an HTLV1 background (HTLV1–Env2) induced lymphoproliferative disease. HTLV2–Env1 stimulated the proliferation of CD4+ T cells, whereas HTLV1–Env2 stimulated both CD4+ and CD8+ T-cell subsets. Our results show that T-cell transformation in vivo is guided by the Env protein of the virus. Furthermore, our humanized mouse model is useful for exploring the preferred T-cell tropisms of HTLV1 and HTLV2.

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Document Type: Research Article

Affiliations: 1: Department of Veterinary Biosciences, Center for Retrovirus Research, College of Veterinary Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 2: Department of Veterinary Biosciences, Comparative Pathology and Mouse Phenotyping Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 3: Neuroimmunology Branch, National Institute of Neurologic Disorders and Stroke, Bethesda, Maryland 4: Division of Oncology, Washington University School of Medicine, St Louis, Missouri 5: Department of Veterinary Biosciences, Center for Retrovirus Research, College of Veterinary Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH;, Email: [email protected]

Publication date: February 1, 2018

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  • Comparative Medicine (CM), an international journal of comparative and experimental medicine, is the leading English-language publication in the field and is ranked by the Science Citation Index in the upper third of all scientific journals. The mission of CM is to disseminate high-quality, peer-reviewed information that expands biomedical knowledge and promotes human and animal health through the study of laboratory animal disease, animal models of disease, and basic biologic mechanisms related to disease in people and animals.

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