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.

Fig 1.

Scheme of the model with two cell populations, resting and activated, used to fit d-glucose experimental data.

Fig 2.

Best fit of the model to the CD4⁺ DNA labeling data of each subject studied, both uninfected (C1–C4) and infected (P1–P7). The data are indicated by the following symbols: •, first infusion study; ▪, second infusion study; and ▴, third infusion study. The lines are the best-fit model solutions.

Fig 3.

Parameter estimates from the fitting of d-glucose data to the model in Fig. 1. (A and B) Death rate of activated cells. (C and D) Transition rate from the resting to the activated population. (E and F) Fraction of activated cells. The four columns in each graph represent the four groups studied: ♦, uninfected; •, infected; ▪, short-term HAART; and ▴, long-term HAART.

Fig 4.

Correlations between fraction of cells dividing per day and baseline parameters.

Fig 5.

Representation of the main findings regarding the differential dynamics of CD4⁺ (A) and CD8⁺ (B) T cells. Bold arrows mean that the parameter is increased in relation to normal individuals, and the larger size of the activated population box in CD8⁺ represents the increase in this population in relation to healthy individuals.