In vivo T lymphocyte dynamics in humans and the impact of human T-lymphotropic virus 1 infection

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) is a persistent CD4+ T-lymphotropic retrovirus. Most HTLV-1-infected individuals remain asymptomatic, but a proportion develop adult T cell leukemia or inflammatory disease. It is not fully understood how HTLV-1 persists despite a strong immune response or what determines the risk of HTLV-1-associated diseases. Until recently, it has been difficult to quantify lymphocyte kinetics in humans in vivo. Here, we used deuterated glucose labeling to quantify in vivo lymphocyte dynamics in HTLV-1-infected individuals. We then used these results to address four questions. (i) What is the impact of HTLV-1 infection on lymphocyte dynamics? (ii) How does HTLV-1 persist? (iii) What is the extent of HTLV-1 expression in vivo? (iv) What features of lymphocyte kinetics are associated with HTLV-1-associated myelopathy/tropical spastic paraparesis? We found that CD4+CD45RO+ and CD8+CD45RO+ T lymphocyte proliferation was elevated in HTLV-1-infected subjects compared with controls, with an extra 10(12) lymphocytes produced per year in an HTLV-1-infected subject. The in vivo proliferation rate of CD4+CD45RO+ cells also correlated with ex vivo viral expression. Finally, the inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis was associated with significantly increased CD4+CD45RO+ cell proliferation. We suggest that there is persistent viral gene expression in vivo, which is necessary for the maintenance of the proviral load and determines HTLV-1-associated myelopathy/tropical spastic paraparesis risk.

Fig. 1.

Deuterium enrichment in HTLV-1-infected subjects: CD45RO⁺ cells. The labeled fraction, F, and the theoretical fit of the model to the data are shown for each of the 14 subjects. The first eight graphs show labeling in ACs, and the last six graphs show labeling in HAM/TSP patients. Black diamonds, labeled fraction in CD8⁺ T cells; solid line, theoretical fit; gray squares, labeled fraction in CD4⁺ cells; dashed line, theoretical fit.

Fig. 2.

The proliferation rate of CD4⁺CD45RO⁺ T cells in vivo was correlated with Tax expression ex vivo. HTLV-1-infected individuals whose CD4⁺ cells express high levels of Tax ex vivo tended to have higher rates CD4⁺CD45RO⁺ T lymphcyte proliferation in vivo (P = 0.016 by Spearman rank correlation two-tailed test).

Fig. 3.

Tax⁺ cells proliferate more rapidly than Tax⁻ cells from the same individual. Deuterium enrichment was measured in Tax⁺ and Tax⁻ CD4⁺CD45RO⁺ cells in two individuals (L02-HAY and L07-TBI). Gray circles, enrichment in Tax⁺ CD4⁺CD45RO⁺ cells; dashed line, theoretical fit; black diamonds, enrichment in Tax⁻ CD4⁺CD45RO⁺ cells; solid line, theoretical fit. (Note the different y axis scale in the two parts of the figure.)

Fig. 4.

CD4⁺CD45RO⁺ T lymphocytes proliferate more rapidly in HAM/TSP patients than in ACs. The proliferation rates of CD4⁺CD45RO⁺ T lympocytes in ACs (black diamonds) and HAM/TSP patients (gray squares) are shown. The median proliferation rate (2.2% per day for ACs; 3.5% for HAM/TSPs) is depicted by a dashed line. HAM/TSP patients have significantly higher proliferation rates than ACs (P = 0.01 by Mann–Whitney two-tailed test).