Huey Devra D, Bolon Brad, La Perle Krista M D, Kannian Priya, Jacobson Steven, Ratner Lee, Green Patrick L, Niewiesk Stefan
Department of Veterinary Biosciences, Center for Retrovirus Research, College of Veterinary Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH.
Department of Veterinary Biosciences, Comparative Pathology and Mouse Phenotyping Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, OH.
Comp Med. 2018 Feb 1;68(1):4-14.
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.
人类嗜T淋巴细胞病毒1型（HTLV1）的慢性感染可导致成人T细胞白血病（ATL）。相比之下，HTLV2感染不会导致白血病，这可能是由于不同的病毒-宿主相互作用以及一种活跃的免疫反应，该免疫反应可控制病毒复制，进而抑制白血病的发展。我们通过将人脐带干细胞注射到免疫缺陷的新生NSG小鼠肝脏中，创建了一种人源化小鼠模型，从而产生了无法产生适应性免疫反应的人类淋巴细胞。我们使用这些小鼠比较了HTLV1、HTLV2的分子克隆以及选定的重组病毒在体内诱导白血病-淋巴瘤的能力。HTLV1感染强烈刺激CD4+ T细胞增殖，而HTLV2优先刺激CD8+ T细胞增殖；HTLV1和HTLV2均诱导淋巴细胞增殖性疾病。未感染和感染HTLV的人源化小鼠均表现出肉芽肿性炎症作为背景病变。同样，在HTLV2背景上表达HTLV1包膜蛋白（Env）的重组病毒（HTLV2-Env1）或在HTLV1背景上表达Env2的重组病毒（HTLV1-Env2）也诱导淋巴细胞增殖性疾病。HTLV2-Env1刺激CD4+ T细胞增殖，而HTLV1-Env2刺激CD4+和CD8+ T细胞亚群。我们的结果表明，体内T细胞转化受病毒Env蛋白的引导。此外，我们的人源化小鼠模型有助于探索HTLV1和HTLV2对T细胞的偏好嗜性。
