Naïve T-cell dynamics in human immunodeficiency virus type 1 infection: effects of highly active antiretroviral therapy provide insights into the mechanisms of naive T-cell depletion

Abstract

Both naïve CD4+ and naïve CD8+ T cells are depleted in individuals with human immunodeficiency virus type 1 (HIV-1) infection by unknown mechanisms. Analysis of their dynamics prior to and after highly active antiretroviral therapy (HAART) could reveal possible mechanisms of depletion. Twenty patients were evaluated with immunophenotyping, intracellular Ki67 staining, T-cell receptor excision circle (TREC) quantitation in sorted CD4 and CD8 cells, and thymic computed tomography scans prior to and approximately 6 and approximately 18 months after initiation of HAART. Naïve T-cell proliferation decreased significantly during the first 6 months of therapy (P < 0.01) followed by a slower decline. Thymic indices did not change significantly over time. At baseline, naïve CD4+ T-cell numbers were lower than naive CD8+ T-cell numbers; after HAART, a greater increase in naïve CD4+ T cells than naïve CD8+ T cells was observed. A greater relative change (n-fold) in the number of TREC+ T cells/mul than in naïve T-cell counts was observed at 6 months for both CD4+ (median relative change [n-fold] of 2.2 and 1.7, respectively; P < 0.01) and CD8+ T cell pools (1.4 and 1.2; P < 0.01). A more pronounced decrease in the proliferation than the disappearance rate of naïve T cells after HAART was observed in a second group of six HIV-1-infected patients studied by in vivo pulse labeling with bromodeoxyuridine. These observations are consistent with a mathematical model where the HIV-1-induced increase in proliferation of naïve T cells is mostly explained by a faster recruitment into memory cells.

FIG. 1.

Naïve T-cell counts, TRECs per microliter of blood, and fraction of TREC⁺ T cells per 10⁶ naïve T cells for CD4 and CD8⁺ T cells at the three time points of the study. Values are the means ± standard errors of the means. *, P < 0.05; **, P < 0.01 (versus time point 0).

FIG. 2.

(A) Diagram of the model used to describe the changes in naïve T-cell counts and TREC⁺ T cells/μl during HIV infection and after initiation of HAART. The proliferation rate of naïve T cells is increased during HIV-1 infection by a factor Ω as a result of the increase in the rate of priming into memory cells. (B) HAART-induced changes in the fraction of TREC⁺ T cells per naïve T cell (left) and TREC⁺ cells/μl and naïve T-cell counts (right) predicted by a model that assumes that the HIV-1-induced increase in proliferation of naïve T cells is largely explained by the increase in rate of priming: = σ + [p + Ω(t)]T − [δ_A + δ_R + Ω(t)]T and = fσ − [δ_A + δ_R + Ω(t)]T⁺, where σ = 1 cell · μl⁻¹ · day⁻¹, f = 0.1, p = 0.01 day⁻¹, and d = δ_A + δ_R = 0.03 day⁻¹. Here, Ω(t) is modeled as a single exponential decaying function from the administration of HAART: Ω(t) = Ω₀e^−λt, with Ω₀ = 0.02 day⁻¹ and λ = 0.05 day⁻¹. The graphs show the ratio of the value of the individual parameters at time t to the value at time zero. The dynamics predicted by this model are similar to the dynamics observed for CD8⁺ naïve T cells in this study. (C) HAART-induced changes for the same variables when the death rate, δ_R, is also enhanced by a factor Ψ(t) during chronic HIV-1 infection due to activation-induced cell death. Here, Ψ(t) is modeled as a single exponential decaying function from the administration of HAART: Ψ(t) = Ψ₀e^−γt, with Ψ₀ = 0.025 day⁻¹ and γ = 0.005 day⁻¹. Other parameters are as follows: Ω₀ = 0.045 day⁻¹, λ = 0.05 day⁻¹, σ = 1 cell · μl⁻¹ · day⁻¹, f = 0.1, p = 0.01 day⁻¹, and d = δ_A + δ_R = 0.02 day⁻¹. The dynamics predicted by this model are similar to the dynamics observed for CD4⁺ naïve T cells in this study.

FIG. 3.

Comparison of experimental data with modeling of the kinetics of BrdU incorporation and decay by CD4⁺ naïve T cells for each patient. Lines represent the modeling, and symbols represent the actual data points (red, pre-HAART; blue, post-HAART).