A functional CD8+ cell assay reveals individual variation in CD8+ cell antiviral efficacy and explains differences in human T-lymphotropic virus type 1 proviral load

The CD8(+) lymphocyte response is a main component of host immunity, yet it is difficult to quantify its contribution to the control of persistent viruses. Consequently, it remains controversial as to whether CD8(+) cells have a biologically significant impact on viral burden and disease progression in infections such as human immunodeficiency virus-1 and human T-lymphotropic virus type 1 (HTLV-1). Experiments to ascertain the impact of CD8(+) cells on viral burden based on CD8(+) cell frequency or specificity alone give inconsistent results. Here, an alternative approach was developed that directly quantifies the impact of CD8(+) lymphocytes on HTLV-I proviral burden by measuring the rate at which HTLV-1-infected CD4(+) cells were cleared by autologous CD8(+) cells ex vivo. It was demonstrated that CD8(+) cells reduced the lifespan of infected CD4(+) cells to 1 day, considerably shorter than the 30 day lifespan of uninfected cells in vivo. Furthermore, it was shown that HTLV-1-infected individuals vary considerably in the rate at which their CD8(+) cells clear infected cells, and that this was a significant predictor of their HTLV-I proviral load. Forty to 50 % of between-individual variation in HTLV-I proviral load was explained by variation in the rate at which CD8(+) cells cleared infected cells. This novel approach demonstrates that CD8(+) cells are a major determinant of HTLV-I proviral load. This assay is applicable to quantifying the CD8(+) cell response to other viruses and malignancies and may be of particular importance in assessing vaccines.