Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) Tax-specific T-cell exhaustion in HTLV-1-infected individuals.

Adult T-cell leukemia/lymphoma (ATL) is caused by Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1), and a higher HTLV-1 provirus load in PBMC is a risk factor for ATL development. Here, we document a significant inverse correlation between the function of HTLV-1 Tax-specific CTL (Tax-CTL), as assessed by ex vivo cytokine production in response to cognate peptide, and the HTLV-1 provirus load in PBMC in both HTLV-1 asymptomatic carriers (AC) (Spearman rank correlation coefficient [Rs] = -0.494, P = .037, n = 18) and ATL patients (Rs = -0.774, P = .001, n = 15). There was also a significant correlation between the HTLV-1 provirus load and the percentage of PD-1-positive Tax-CTL in both HTLV-1 AC (Rs = 0.574, P = .013) and ATL patients (Rs = 0.676, P = .006). Furthermore, the percentage of PD-1-positive Tax-CTL was inversely correlated with their function in HTLV-1 AC (Rs = -0.542, P = .020), and ATL patients (Rs = -0.639, P = .010). These findings indicate that the function of Tax-CTL decreased as their programmed cell death protein 1 (PD-1) levels increased, parallel to the increased HTLV-1 provirus load in PBMC. We propose that functional Tax-CTL are crucial for determining the HTLV-1 provirus load in PBMC, not only in HTLV-1 AC, but also in ATL, and that PD-1 expression levels are reliable markers of Tax-CTL function. Thus, modulating the immunological equilibrium between Tax-CTL and HTLV-1-infected cells to achieve dominance of functional effectors could represent an ideal strategy for controlling HTLV-1-associated disease.