Early studies of the effects of combination antiretroviral therapy (ART) on CD4 T cell reconstitution showed that recovery of naive CD4 T cells is slow and occurs over a period of years, contrasting with the rapid increase in levels of memory CD4 T cells that typically happens within weeks (a result of the redistribution of memory CD4 T cells trapped in lymphoid tissues). A new study now reports that robust naive CD4 T cell production by the thymus (referred to as thymopoiesis) is associated with both slower disease progression and better recovery of CD4 T cells after ART initiation. The study authors use the ratio of two types of DNA that are present in recently produced naive CD4 T cells as measure of thymopoiesis because this method appears to be more accurate than techniques that have been employed previously.
Study abstract:
Blood First Edition Paper, prepublished online December 12, 2006; DOI 10.1182/blood-2006-09-047308.
Marie-Lise Dion, Rebeka Bordi, Joumana Zeidan, Robert Asaad, Mohammed-Rachid Boulassel, Jean-Pierre Routy, Michael M. Lederman, Rafick-Pierre Sekaly, and Remi Cheynier
In chronic HIV infection, most untreated patients lose naive CD4+ and CD8+ T-cells while a minority preserves them despite persistent high viremia. While antiretroviral therapy (ART)-mediated viral suppression generally results in a rise of naive and total CD4+ T cells, certain patients experience very little or no T-cell reconstitution. High peripheral T cell activation has been linked to poor clinical outcomes, interfering with previous evaluations of thymic function in disease progression and therapy-mediated T-cell recovery. To circumvent this, we used the sj/{beta}TREC ratio, a robust index of thymopoiesis that is independent of peripheral T cell proliferation, to evaluate the thymic contribution to the preservation and restoration of naive CD4+ T cells. We show that the loss of naive and total CD4+ T cells is the result of or is exacerbated by a sustained thymic defect, while efficient thymopoiesis supports naive and total CD4+ T-cell maintenance in slow progressor patients. In ART-treated patients, CD4+ T-cell recovery was associated with the normalization of thymopoiesis, while the thymic defect persisted in aviremic patients who failed to recover CD4+ T-cell counts. Overall, we demonstrate that efficient thymopoiesis is key in the natural maintenance and in therapy-mediated recovery of naive and total CD4+ T cells.
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