Background:  The mechanisms leading to preferential naïve T-cell depletion in HIV-1 infection are uncertain. Debate continues as to whether increased T-cell turnover or inhibition of de novo production of T cells at the level of thymic output plays a predominant role. In this study, we have examined thymic function and lymphocyte kinetics in 2 groups of HIV-1 infected patients during highly active antiretroviral therapy (HAART).

Methods:  T-cell receptor recombination (TREC) group: 20 patients were evaluated with immunophenotyping, intracellular Ki67 staining, TREC quantitation in bead-separated CD4 and CD8 cells, and thymic computer tomography (CT) scans prior to and at 6 and 18 months after initiating HAART. BrdU group: the turnover of CD4 and CD8 naïve T cells was examined in 6 HIV-1-infected patients by in vivo pulse labeling with BrdU prior and 4 to 6 months after the initiation of HAART.

Results:  Thymic scores and volumes did not change significantly over time. A faster increase in the number of TREC/ml than in the naïve T-cell counts, in both CD4 (median fold changes:  2.2 and 1.7, respectively, p < 0.01) and CD8 T-cell pools (1.4 and 1.2, p < 0.01) was observed at 6 months, followed by a slower increase. A mathematical model describing the dynamics of TREC  + cells and naïve T cells predicts a greater decrease in proliferation than disappearance rate during the first 6 months of therapy; this effect is reversed during the following year of treatment. The disappearance rate is here generalized as death rate and rate of priming into memory cells. Increased thymic output alone cannot account for this observation. In the BrdU analysis group, a semi-empirical equation describing the kinetics of BrdU-labeled naïve T cells shows a decrease in disappearance rate of naïve T cells after initiation of HAART less pronounced than the decrease in proliferation rate, consistent with the prediction of the former model for the dynamics of TRECs during HAART.

Conclusions:  This model suggests that the HIV-induced increase in naïve T-cell proliferation is an ineffective compensatory mechanism in response to a loss of naïve T cells that have been activated into memory cells. Alternatively, the first effect of activation might consist of inducing naïve T cells to proliferate faster without losing their phenotype, bringing these cells closer to the priming activation threshold. The short-term effect of HAART on T-cell turnover is mainly dominated by the normalization of this proliferation, followed by a delayed normalization of the death rate.

Keywords: turnover; naive