ABSTRACT
In chronic HIV infection, most untreated patients lose naive CD4+ and CD8+ T cells, whereas a minority preserve them despite persistent high viremia. Although 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/betaTREC 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, whereas 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, whereas 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.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Infections/immunology , Lymphopoiesis , Adult , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/pathology , Case-Control Studies , Cell Proliferation , HIV Infections/drug therapy , HIV Infections/pathology , Homeostasis , Humans , Lymphopoiesis/drug effects , Middle Aged , Viremia/drug therapy , Viremia/immunology , Viremia/pathologyABSTRACT
Protection of human subjects from investigators' conflicts of interest is critical to the integrity of clinical investigation. Personal financial conflicts of interest are addressed by university policies, professional society guidelines, public standards, and government regulation, but "intrinsic conflict of interest"--conflicts of interest inherent in all clinical research--have received relatively less attention. Such conflicts arise in all clinical research endeavors as a result of the tension among professionals' responsibilities to their research and to their patients and both academic and financial incentives. These conflicts should be disclosed to research subjects and managed as assiduously as are financial conflicts of interest.
