HTLV-1 Infection and Neuropathogenesis in the Context of Rag1-/-γc-/- (RAG1-Hu) and BLT Mice
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To date, the lack of a suitable small animal model has hindered our understanding of Human T-cell lymphotropic virus (HTLV)-1 chronic infection and associated neuropathogenesis defined as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The host immune response plays a critical role in the outcome of HTLV-1 infection, which could be better tested in the context of humanized (hu) mice. Thus, we employ here the Balb/c-Rag1−/−γc−/− or Rag1 as well as Bone marrow-Liver-Thymic (BLT) mouse models for engraftment of human CD34+ hematopoietic stem cells. Flow cytometry and histological analyses confirmed reconstitution of Rag1 and BLT mice with human immune cells. Following HTLV-1 infection, proviral load (PVL) was detected in the blood of Rag-1 and BLT hu-mice as early as 2 weeks post-infection (wpi) with sustained elevation in the subsequent weeks followed by Tax expression. Additionally, infection was compared between adult and neonatal Rag1 mice with both PVL and Tax expression considerably higher in the adult Rag1 mice as compared to the neonates. Establishment of peripheral infection led to lymphocytic infiltration with concomitant Tax expression and resulting myelin disruption within the central nervous system of infected mice. In addition, up-regulation in the expression of several immune checkpoint mediators such as programmed cell death-1 (PD-1), T-cell Ig and ITIM domain (TIGIT), and T cell Ig and mucin domain-3 protein (Tim-3) were observed on CD8+ T cells in various organs including the CNS of infected hu-mice. Collectively, these studies represent the first attempt to establish HTLV-1 neuropathogenesis in the context of Rag-1 and BLT hu-mice as potential novel tools for understanding HTLV-1 neuropathogenesis and testing of novel therapies such as immune checkpoint blockade in the amelioration of chronic HTLV-1 infection.
KeywordsHTLV-1 Chronic viral infection Humanized mice RAG1 BLT
These studies were supported by the National Institutes of Health (NIH) via NINDS R01NS097147-01A1 and NCI R01CA054559-20 Revised awarded to PJ. We wish to acknowledge the help of Dr. Paige Charlins and Dr. Ramesh Akkina (Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collin, USA) in hu-mice experimentation. We would also like to thank Dr. Owen Chan and Dr. Brenda Hernandez from the University of Hawaii Cancer Center Pathology Shared Resource (funded in part by NIH/NCI P30 CA071789-17 to LN) for their contributions in immunohistochemistry data.
Compliance with Ethical Standards
Conflict of Interest
The authors declare no competing financial interests.
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