HTLV-1 infection and neuropathogenesis in the context of Rag1−/−γc−/− (RAG1) and BLT mice

Abstract

Abstract HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a disabling chronic inflammatory disease of the central nervous system (CNS) with similarities to multiple sclerosis (MS). To date, the lack of a suitable small animal model has hindered our quest to understand the immuno- and neuropathogenesis of HTLV-1 in an in vivo system. Previous work from others have established that 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 Rag1 as well as Bone marrow-Liver-Thymic (BLT) mouse models for engraftment of human CD34+ hematopoietic stem cells and followed HTLV-1 infection. Flow cytometry and histological analyses revealed reconstitution of Rag1 and BLT mice with human immune cells, including macrophages, dendritic cells, T cells and B cells. Proviral load (PVL) was determined in the peripheral blood, spleen, and other organs of neonatal and adult Rag1 and BLT hu-mice by droplet digital PCR. Tax showed peak expression at 14 wpi in Rag1 mice with continued expression until 16 weeks. Within blood, PVL and viral protein Tax was detected as early as 2 wks post-infection (wpi) in Rag-1 and BLT hu-mice. Successful infection was followed by immune activation and Tax expression within lymphoid organs. Moreover, lymphocytic infiltration with concomitant Tax expression and resulting myelin disruption were observed in the spinal cord of the infected mice. These data represents the first attempt to establish HTLV-1 neuropathogenesis in the context of RAG1 and BLT mice suggesting possibility of developing a small animal model of HAM/TSP in humanized mice.