Increased HTLV Type 1 Tax Specific CD8 + Cells in HTLV Type 1-Asociated Myelopathy/Tropical Spastic Paraparesis: Correlation with HTLV Type 1 Proviral Load

Abstract

Less than 1% of individuals infected with the human T lymphotropic virus type 1 (HTLV-1) develop an inflammatory neurological disorder, termed HTLV-1-associated myelopathy/tropical spastic (HAM/TSP), while the vast majority of those infected remain asymptomatic HTLV-1 carriers (ACs). The fundamental viroimmunological differences between these groups are not well understood. To address this issue, we have investigated HTLV-1-specific T cell responses and measured the proviral load in these groups. Frequencies of HTLV-1-specific CD8⁺ cells were demonstrated to be significantly higher in HAM/TSP patients than in ACs by using intracellular cytokine staining and soluble divalent HLA-A2/Ig fusion protein loaded with HTLV-1 Tax 11-19 peptide. It is consistent with the observed increase in HTLV-1-specific cytotoxic T lymphocytes in HAM/TSP patients. These CD8⁺ cells produced interferon (IFN)-γ in recognition of HTLV-1 antigens bound to HLAs on the infected CD4⁺ cells. Using phenotypic markers indicative for T cell differentiation, memory and/or effector HTLV-1 Tax-specific CD8⁺ cells were found to be increased in HLA-A2 HAM/TSP patients. HTLV-1 proviral load was elevated in HAM/TSP patients when compared to ACs. In addition, the proviral load in HAM/TSP patients correlated with the frequency of HTLV-1-specific IFN-γ⁺CD8⁺ cells or Tax-HLA-A2/Ig⁺CD8⁺ cells, especially with the effector cells. In contrast, the proviral load inversely correlated with memory cells. These results suggest that HTLV-1 antigens may continuously stimulate HTLV-1-specific CD8⁺ cells and differentiate them from memory cells into effector cells in vivo. These differentiated HTLV-1-specific CD8⁺ cells may play a role in the pathogenesis of HAM/TSP.