In vivo dynamics of T cell activation, proliferation, and death in HIV-1 infection: Why are CD4~+ but not CD8~+ T cells depleted?

摘要

Deuterated glucose labeling was used to measure the in vivo turnover of T lymphocytes. A realistic T cell kinetic model, with populations of resting and activated T cells, was fitted to D-glucose labeling data from healthy and HIV-1-infected individuals before and after antiretroviral treatment. Our analysis highlights why HIV-1 infection, which increases the fraction of both CD4~+ and CD8~+ T lymphocytes that are proliferating (Ki67~+), leads to CD4 but not CD8 depletion. We find that HIV-1 infection tends to increase the rates of death and proliferation of activated CD4~+ T cells, and to increase the rate at which resting CD4 T cells become activated, but does not increase the fraction of activated CD4~+ T cells, consistent with their preferential loss in HIV-1-infected individuals. In contrast, HIV-1 infection does not lead to an increase in proliferation or death rates of activated CD8~+ T cells, but did increase the fraction of activated CD8~+ T cells, consistent with these cells remaining in an activated state longer and undergoing more rounds of proliferation than CD4~+ T cells. Our results also explain why telomeres shorten in CD8~+ cells, but not in CD4~+ cells of HIV-1-infected patients, compared with age-matched controls.