485-M.
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Declines in CD4+ T-Cell Proliferation Rates Significantly Contribute to Increases in CD4+ T-Cell Telomere Length and TREC Levels in HIV-Infected Patients Undergoing HAART
D. Prieto1, J. Kovacs2, V. Natarajan1, D. Douek3, C. Yoder2, I. A. Sidorov4, J. W. Adelsberger1, J. A. Metcalf3, R. Stevens1, R. Koup3, M. W. Baseler1, D. S. Dimitrov4, R. T. Davey3, M. A. Polis3, and R. A. Lempicki*1
1SAIC, Frederick, MD; 2Clin. Ctr.; 3NIAID; and 4NCI, NIH, Bethesda, MD
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Background: HIV-1 infection is associated with increases in T cell proliferation and declines in telomere restriction fragment length (TRFL) and T cell receptor excision circles (TRECs), Treatment with HAART leads to increases in TRFL and TRECs. These results have been interpreted to suggest that the thymus plays a major role in immune reconstitution following HAART, although decreased proliferation can also account for these observations. We examined the relationship between changes in proliferation and the changes in TRFL and TRECs.
Methods: Proliferation rates (ex vivo BrdU incorporation), TREC contents (PCR) and/or TRFL (Southern blotting) were measured longitudinally in 14 protease-inhibitor-naïve patients following initiation of HAART and in 15 patients voluntarily terminating HAART.
Results: Changes in CD4+ T-cell proliferation rates correlated with changes in viral load and were inversely correlated with changes in CD4+ T-cell TREC levels in patients initiating HAART (n=9, r=-0.95, p<0.0001), as well as in patients terminating HAART (n=15, r=-0.60, p=0.02). TREC levels were found to increase in naïve (CD45RO-CD27+) CD4+ T cells following HAART suggesting the thymus is still functioning in these patients. TRFL were significantly increased in CD4+ (n=9, p=0.03) and CD8+ (n=9, p=0.03) T cells in patients receiving HAART for 52 weeks. Higher CD4 counts at the start of therapy were associated with greater increases in TRFL (p=0.01). Similar to the results for TREC levels, changes in CD4+ proliferation was inversely correlated with changes in TRFL following HAART (n=6, r=-0.83, p=0.04).
Conclusions: Our data suggest that TRECs, as well as TRFL, can be a measure of either the replicative history of a T-cell or thymic function. In vivo BrdU labeling of T cells has shown that HIV-1 infection induces an accumulation of a pool of T cells with high turnover rates which most likely consists of cells with shorter TRFL and lower TREC content. Thus, increases in CD4+ T-cell TREC levels and TRFL following HAART are likely the net result of increased thymic output, reduced T cell proliferation and increased clearance of the pool of rapidly turning-over cells that contain shorter TRFL and lower TREC levels.
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