Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy

Abstract

The mechanism of CD4(+) T cell depletion in human immunodeficiency virus (HIV)-1 infection remains controversial. Using deuterated glucose to label the DNA of proliferating cells in vivo, we studied T cell dynamics in four normal subjects and seven HIV-1-infected patients naive to antiretroviral drugs. The results were analyzed using a newly developed mathematical model to determine fractional rates of lymphocyte proliferation and death. In CD4(+) T cells, mean proliferation and death rates were elevated by 6.3- and 2.9-fold, respectively, in infected patients compared with normal controls. In CD8(+) T cells, the mean proliferation rate was 7.7-fold higher in HIV-1 infection, but the mean death rate was not significantly increased. Five of the infected patients underwent subsequent deuterated glucose labeling studies after initiating antiretroviral therapy. The lymphocyte proliferation and death rates in both CD4(+) and CD8(+) cell populations were substantially reduced by 5-11 weeks and nearly normal by one year. Taken together, these new findings strongly indicate that CD4(+) lymphocyte depletion seen in AIDS is primarily a consequence of increased cellular destruction, not decreased cellular production.

Figure 1.

A newly developed mathematical model to track labeled and unlabeled strands of DNA before, during and after D-glucose administration. A full explanation is given in Materials and Methods.

Figure 2.

Sequential changes in the fraction of labeled DNA in blood monocytes. The data points are represented by symbols, and the lines show the best fit of the data to a mathematical model. The calculated half-lives (t_1/2) for monocytes in blood are indicated.

Figure 3.

Sequential changes in the fraction of labeled DNA in blood T lymphocytes. The data of healthy controls (C1–C4) versus HIV-1–infected patients (P1–P7) are shown in each graph. The period of D-glucose administration is indicated by a box (top left corner). The data points are represented by symbols, and the lines show the best fit of the data to a mathematical model.

Figure 4.

Comparison of T cell kinetics before and during antiretroviral therapy. (A) Changes in viral load as well as CD4⁺ and CD8⁺ lymphocyte counts during treatment. The data from each patient are represented by a unique symbol. The periods of repeat D-glucose labeling studies are indicated by rectangular boxes marked by each patient's identification number followed by the episode of labeling. (B) Fraction of labeled DNA in CD4⁺ and CD8⁺ lymphocytes from P1–P5 during the first (pretreatment) (○), second (gray square), and third (▴) episodes of labeling. The duration of D-glucose administration is indicated by a box in each graph. Again, the data points are represented by symbols, and the lines show the best fit of the data to the mathematical model. Note that the fraction of labeled DNA on day 0 in the second or third episode is not zero because of residual label from the previous labeling episode. (C) Changes in the estimated values of p (proliferation rate) and d (death rate) with antiretroviral therapy.

Figure 5.

Correlation among parameters. (A) Correlation of the fraction of CD4⁺ and CD8⁺ lymphocytes expressing Ki67 antigen or TUNEL with p, the lymphocyte proliferation rate. Significant correlations were observed between values of p and fractions of Ki67⁺ CD4⁺ T cells (r = 0.91, P value <0.00001) or CD8⁺ T cells (r = 0.90, P value <0.00001), as well as between values of p and fractions of TUNEL⁺ CD4⁺ T cells (r = 0.79, P value = 0.00006) or CD8⁺ T cells (r = 0.87, P value <0.00001). Note that these regression lines are parallel in CD8⁺ lymphocytes (P value = 0.86), but not in CD4⁺ lymphocytes (P value = 0.0017). (B) Significant correlation between baseline CD4⁺ T cell count or plasma viral load and values of p, fraction of Ki67⁺ cells, or fraction of TUNEL⁺ cells in both CD4⁺ and CD8⁺ cell populations (P values <0.05). Results of patients with undetectable plasma viral load are plotted as of 50 copies/ml (detection limit).