In this study, which is the first to recruit HAM/TSP patients from two endemic countries (Brazil and Peru), we reveal CD80+ B cells as a novel host biomarker for disease severity (Figure 3A), while highlighting a possible protective role for CD86+ B cells, which are preferentially upregulated by IFN-β in HAM/TSP, both uncorrelated to proviral load. This evidence concerns the gene IFNB1 and tropical spastic paraparesis.