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

Abstract

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.