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Multicenter Study
. 2006 Jun;22(6):501-7.
doi: 10.1089/aid.2006.22.501.

Longitudinal assessment of de novo T cell production in relation to HIV-associated T cell homeostasis failure

Pratip K Chattopadhyay  1 , Daniel C Douek, Stephen J Gange, Karen R Chadwick, Marc Hellerstein, Joseph B Margolick
Affiliations
Multicenter Study

Longitudinal assessment of de novo T cell production in relation to HIV-associated T cell homeostasis failure

Pratip K Chattopadhyay et al. AIDS Res Hum Retroviruses. 2006 Jun.

Abstract

Loss of circulating CD4+ T cells in HIV-1 disease is balanced by CD8+ lymphocytosis to maintain normal CD3+ T cell counts [blind T cell homeostasis (TCH)]. However, for unknown reasons TCH generally fails 1.5-2.5 years before clinically defined AIDS. We investigated whether TCH failure was associated with changes in thymic production of T cells. Using specimens stored prospectively in the Multicenter AIDS Cohort Study (MACS), we measured expression of signal-joint T cell receptor excision circles (sjTRECs), a marker for thymic T cell production, and the fraction of proliferating naive and memory T cells during a 6-8 year period bracketing TCH failure. Segmented regression modeling assessed (1) rates of change in TREC levels before and after TCH failure, and (2) whether these were affected by cellular proliferation, which may dilute sjTREC levels. TCH failure was associated with a large decline in sjTREC (median 1109-fold, p = 0.028); the rate of this decline was only slightly affected when increased proliferation of naive T cells or other peripheral lymphocytes was taken into account. Preferential loss of naive CD4+ T cells was also noted before TCH failure, as has been seen in other studies. These results suggest that deficits in de novo T cell production, either through the decline of thymic function or the destruction of naive T cells, are likely to play an important role in TCH failure and progression of HIV-1 disease.

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Figures

FIG. 1
FIG. 1
Changes in relative sjTREC levels in relation to TCH failure. To normalize for inter-individual variation, TREC levels for each participant were expressed relative to the mean of the participant's measurement before failure of TCH. Segmented regression analysis showed that TRECs did not change significantly before TCH failure, but declined substantially (at a rate of 46% per year) after TCH failure (thick black trend line).
FIG. 2
FIG. 2
Changes in the percentage of proliferating (Ki-67+) cells over the study period. The proportion of Ki-67+ cells increased over time for all cell types examined (black trend lines); however, the rates of increase were similar before and after TCH failure. Therefore, these rates of proliferation were unlikely to account for the sharp decline in TREC levels after TCH failure, as confirmed by segmented regression analysis (see text).
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