Immunopathogenesis and Cellular Interactions in Human T-Cell Leukemia Virus Type 1 Associated Myelopathy/Tropical Spastic Paraparesis

Abstract

HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a neuropathological disorder in 1-3% of individuals infected with Human T-lymphotropic virus 1 (HTLV-1). This condition is characterized by progressive spastic lower limb weakness and paralysis, lower back pain, bladder incontinence, and mild sensory disturbances resembling spinal forms of multiple sclerosis. This disease also causes chronic disability and is therefore associated with high health burden in areas where HTLV-1 infection is endemic. Despite various efforts in understanding the virus and discovery of novel diagnostic markers, and cellular and viral interactions, HAM/TSP management is still unsatisfactory and mainly focused on symptomatic alleviation, and it hasn't been explained why only a minority of the virus carriers develop HAM/TSP. This comprehensive review focuses on host and viral factors in association with immunopathology of the disease in hope of providing new insights for drug therapies or other forms of intervention.

Keywords: HAM/TSP; HTLV-1-associated myelopathy; human T-lymphotropic virus; immunology; pathogenesis.

FIGURE 1

(A) Structure of a mature HTLV-1 virion; (B) genetic composition of HTLV-1; HBZ, p12, p13, p30 accessory proteins are not essential for immortalization of T lymphocytes in vitro, but have a significant role in viral latency and persistent infection in humans.

FIGURE 2

Intercellular Transmission of HTLV-1. (1) Cell-free virions are rarely produced in HTLV-1 infection and these particles are almost non-infectious (only 1 in 10⁵ to 10⁶). The fusion process is mediated by GLUT1, NRP-1, and HSPG. Other cell adhesion molecules including ICAM-3 and VCAM have also been associated with HTLV-1-induced cell fusion. (2) Viral transfer via Virological synapse (VS). Polarization of MTOC and expression of ICAM-1 and CCL22 is enhanced by Tax. While VS formation is primarily mediated by ICAM-1 and LFA-1, blocking CCL22 is shown to significantly reduce VS formation and viral transmission in CD4+ T-cells. (3) Concentrated viral particles in the extracellular assemblies is efficiently transferred to other cells upon contact. (4) The precise mechanisms regarding p8-mediated cellular conduits are not well understood. p8 in recipient CD8+ T-cells induces T-cell anergy which reduces effective CTL response.

FIGURE 3

Peripheral interactions of HTLV-1 and the host in HAM/TSP and the effect of the virus on the lymphoid lineage cells. When the virus is acquired via mucosal infection, the dendritic cells spread the virus to immune cells in lymph nodes and the peripheral blood. Consequently, infected T-cells can also infect dendritic cells, spreading the virus bidirectionally between T-cells and dendritic cells in the periphery. HTLV-1 can also be delivered to hematopoietic stem cells in the bone marrow. These cells give rise to all other blood cells, including both myeloid and lymphoid lineages. By virtue of vertical transmission, proviral DNA is found in cells of both lineages, regardless of productive infection. The lymphoid lineage cells are studied more extensively in the context of HTLV-1 infection and are associated with prominent changes in HTLV-1-related diseases.

FIGURE 4

Blood-brain barrier dysregulation, infiltration of immune cells, and proposed mechanisms for the pathogenesis of HAM/TSP in the central nervous system. The BBB is dysregulated due to multiple factors in HAM/TSP, leading to persistent inflammation in the CNS. The inflammation resulting from the presence of the virus and the immune response establishes a positive feedback loop that furthrer disrupts BBB and attracts other immune cells, including infected T-cells.