Session 44Poster Presentations Lymphocyte Dynamics Session Day and Time: Wednesday 1:30 - 3:30 pm Room: Hall D
334 Early Primary HIV Infection Disrupts Thymic Function as a Result of Impaired Intrathymic Proliferation M. L. Dion*1,2, R. Bordi1, J. F. Poulin1,2, M. Sylvestre1, R. Corsini1, N. Kettaf1, M. R. Boulassel2, J. P. Routy2, R. P. Sékaly1, R. Cheynier1 1Ctr de Recherche du CHUM, Montreal, Canada and 2McGill Univ Hlth Ctr, Montreal, Canada
Background:The thymus is the main site where thymocytes mature into functional T-cells and has been reported to be affected in HIV pathogenesis. In thymopoiesis, TCRB and TCRA chromosomal rearrangement gives rise to distinct excised DNA molecules, TRECs, a surrogate marker of thymic output. Proliferation-induced TREC dilution between the TCRB and TCRA rearrangement allows the evaluation of intrathymic proliferation using the sjTREC (issued from the excision of the delta locus form the alpha locus) /betaTREC ratio. Therefore, we investigated the effect of HIV in (PI) primo-infected (less than 6 months post-infection) individuals on thymic proliferation and the impact of alphaIFN levels, an innate cytokine know to be induced upon viral infection, on thymic function in HIV pathogenesis.
Methods: Longitudinal analysis of nested real-time PCR-based SJ and DJbetaTREC quantification was performed on PBMCs from treated (n = 12) and untreated (n = 11) PI HIV infected as well as from control uninfected individuals (n = 29). ELISA-based alphaIFN quantification was performed on the corresponding plasma samples.
Results: In control individuals, the sj/betaTREC ratio is age-dependant (r = -0.45) and correlates with sjTREC frequency (r = 0.78 ), the current tool for thymic output assessment. In vitro uninfected PBMCs stimulation as well as Ki67 analysis demonstrated that unlike sjTREC frequencies, the sj/betaTREC ratio does not vary following peripheral proliferation. With a mean 70 days post-infection, PHI patients have already a significant 8-fold reduction in the sj/betaTREC ratio (p = 0.002), and this is maintained for at least 1 yr post-infection. Antiretroviral treatment partially restores this defect in 6/10 cases we have studied. Plasmatic alphaIFN levels found at the time point closest to the infection date correlates with the speed of drop of ratio (r = -0.42, p = 0.03).
Conclusions: The sj/betaTREC ratio allows the evaluation of intrathymic proliferation and thymic function, irrespective of peripheral proliferation. We have found that this parameter is greatly reduced early on in infection and this is very likely to be a result of high alphaIFN levels in PHI, inhibiting the thymocyte proliferation, thus reducing thymic function.
