Factors influencing T-cell turnover in HIV-1-seropositive patients

Abstract

HIV-1 disease is associated with pathological effects on T-cell production, destruction, and distribution. Using the deuterated (2H) glucose method for endogenous labeling, we have analyzed host factors that influence T-cell turnover in HIV-1-uninfected and -infected humans. In untreated HIV-1 disease, the average half life of circulating T cells was diminished without compensatory increases in cell production. Within 12 weeks of the initiation of highly active antiretroviral therapy (HAART), the absolute production rates of circulating T cells increased, and normal half-lives and production rates were restored by 12-36 months. Interpatient heterogeneity in the absolute degree of turnover correlated with the relative proportion of naive- and memory/effector-phenotype T cells in each of the CD4+ and CD8+ populations. The half-lives of naive-phenotype T cells ranged from 116-365 days (fractional replacement rates of 0.19-0.60% per day), whereas memory/effector-phenotype T cells persisted with half-lives from 22-79 days (fractional replacement rates of 0.87-3.14% per day). Naive-phenotype T cells were more abundant, and the half-life of total T cells was prolonged in individuals with abundant thymic tissue, as assessed by computed tomography. Such interpatient variation in T-cell kinetics may be reflective of differences in functional immune reconstitution after treatment for HIV-1 disease.

Figure 1

k and absolute production rates of CD4+ and CD8+ T cells in HIV-1–seronegative and HIV-1–seropositive subjects who were either untreated or treated with HAART. Values of k (per day) and of absolute production rates (cells/μL per day) for peripheral blood CD4+ and CD8+ T cells are shown for different groups of subjects, including HIV-1–seronegative subjects (HIV–) and HIV-1–seropositive subjects who were either untreated (HIV+) or treated with HAART for 12 weeks (ST) or for 12–36 months (LT). Some of the data points shown in this figure are from subjects previously described in ref. (see Table 1 for details).

Figure 2

Relationship between k, percent naive CD4+ T cells, and thymic index. (a) Correlations between k of total CD4+ T cells, percent naive CD4+ T cells, and thymic index are derived from the data presented in Table 1. (b) Pairwise correlations in the short-term HAART group between k of CD4+ T cells and thymic index (top) and between k and percent naive-phenotype CD4+ T cells (bottom).

Figure 3

Biphasic kinetics of memory/effector-phenotype CD4+ and CD8+ T cells. Incorporation/decay kinetics for memory/effector- and naive-phenotype T cells. Results from a healthy, HIV-1–seronegative control subject are shown (as enrichment of dA isolated from the DNA of sorted subpopulations) with [²H]glucose labeling over a 4-day period (arrow) and blood sampling on days 4, 10, 18, 30, and 40. Subpopulations isolated: M/E, memory/effector; N, naive; T, total. Left: CD4+ T cells. Right: CD8+ T cells.

Figure 4

Prospective analysis of k as a function of time after initiation of HAART. Values for k (per day) for peripheral blood CD4+ (dotted lines) and CD8+ T cells (solid lines) for 2 HIV-1–seropositive subjects treated for 3 or for 18 months with HAART. Table 1 provides more complete data for subject 1 (see group III, no. 1 and group IV, no. 7) and subject 2 (see group III, no. 3 and group IV, no. 8).