508-M. HIV Infection Induces a Quantitative and Qualitative Impairment of Thymic Function that Is Partially Restored under HAART

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Session 70 Poster Session
Thymic Function and Immune Reconstitution
Session Time: 4:30-6:30 pm
Room 4E-F

508-M.

HIV Infection Induces a Quantitative and Qualitative Impairment of Thymic Function that Is Partially Restored under HAART
J. F. Poulin¹, R. Bordi¹, M. Sylvestre¹, J. P. Routy³, R. Woods², J. Montaner², R. P. Sekaly¹, and R. Cheynier*¹
¹Ctr. de Recherche du CHUM, Montréal, QC, Canada; ²Canadian HIV Trials Network, Vancouver, BC; and ³McGill Univ. Hlth. Ctr., Royal Victoria Hosp., Montréal, QC, Canada

Background: Evaluation of thymic function contribution to the peripheral T-cell homeostasis is a matter of great importance. Recently, a new approach to monitor thymic activity has been validated. This concept aims at detecting within peripheral blood mononuclear cells (PBMCs) by-products of T-cell receptor (TCR) alpha and beta locus gene rearrangement (sjTREC and bTREC). HIV infection induces immunological defects including a drastic reduction in thymic function that can be restored under efficient antiretroviral therapy. The detection of multiple and different bTREC within PBMC allows for the monitoring of the RTE diversity. The sjTREC/bTREC ratio directly corresponds to the level of intrathymic cell proliferation.
Methods: Patients in acute early infection, as well as chronically infected patients were analyzed for thymic function by quantification of both sjTREC and bTREC. In parallel, evaluation of peripheral T-cell proliferation (Ki-67), as well as immunological parameters such as naïve/memory ratios, and total CD4 and CD8 counts were performed on the same samples.
Results: During acute early HIV infection, frequency of recent thymic emigrants from peripheral blood was shown to rapidly decrease. In most cases, sjTREC concentration was at least 10-fold lower than age-matched seronegative controls. In parallel, sjTREC/bTREC ratios were also drastically reduced post infection, independently from treatment efficiency. In chronically infected patients, an inverse correlation was observed between viral load and sjTREC/bTREC ratios before the onset of treatment. However, efficient HAART failed to restore normal values after 1 year.
Conclusions: Reduced thymic output in HIV-infected patients is a consequence of impaired intrathymic T-cell proliferation. HIV-induced peripheral proliferation may contribute to decreased TREC content; the analysis of the sjTREC/bTREC ratios clearly demonstrates that thymopoiesis is impaired since the first month following HIV infection. Concomitant sjTREC/bTREC ratios and viral load decrease suggest that HIV-specific CTL is involved in the depletion of HIV-infected thymocytes, thereby contributing to reduce the level of thymocyte exportation. According to the reduced ratio found in PBMC from HIV-infected patients, we conclude that thymopoiesis is altered both quantitatively and qualitatively: both the amount of selected thymocytes that make it through the thymus and the extent of TCR alpha and beta chain pairing are reduced.