3rd International AIDS Society Conference on HIV Pathogenesis and Treatment Rio de Janeiro - July 24 - 27, 2005

ROLE OF THE THYMUS IN HIV PATHOGENESIS AND IN IMMUNE RECONSTITUTION

IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract No. TuPp0106

Grossman Z.¹, Dion M.-L.², Alon H.¹, Routy J.-P.³, Sekaly R.-P.⁴, Cheynier R.^5
1 Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel, ² McGill University, Montreal, Canada, ³ McGill University Health Centre, Montreal, Canada, ⁴ Faculté de Médecine, Université de Montréal, Montreal, Canada, ⁵ Pasteur Institute, Paris, France

INTRODUCTION: Recent studies shed new light on the dynamics of recent thymic emigrants (RTEs) in mice and humans, on the effect of HIV infection on thymic function, and on the impact of HAART on these parameters. We quantitatively analyzed longitudinal changes in sjTREC- and βTREC-frequencies in PBMCs post-infection (Dion et al., Immunity 2004) and increases in sjTREC-frequencies and naïve T-cell numbers under HAART (Harris et al., Grossman [Editorial], CLIM 2005, in press). The specific objective was to better define the relation between peripheral TREC-frequency changes and variation in thymic output.

METHODS: We applied both the conventional mathematical model that assumes that RTEs soon become kinetically indistinguishable from other naïve cells, and a revised model in which the turnover of RTEs is faster than that of established naïve cells and their incorporation into the general naïve population is variable and regulated.

RESULTS: A 3.5-fold increase in βTREC-frequency with opposite 2-fold decrease in sjTREC-frequency within weeks post-infection (Dion et al.), and 10-fold increase in sjTRECs with subnormal naïve T-cell numbers in HAART-treated patients (Harris et al.), are findings consistent only with the revised model. The TREC content of the naïve population is determined primarily by the size of a transitional RTE compartment and by the degree to which RTEs are allowed to be incorporated in the stationary population rather than by the degree of peripheral cell-division induced dilution. We estimate that normal thymic output in adults is at least 107 cells/day. Following infection it is reduced 10-30 fold, but can be largely normalized by HAART, with increased incorporation of RTEs into the general population.

CONCLUSIONS: Suppression of thymic production by HIV may contribute to disease progression, contrary to what has recently been suggested by others. Under HAART, the thymus probably contributes to immune reconstitution both numerically and by providing clones with a diverse repertoire.

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Basic | TuPp0106 | Zvi Grossman
T-cell homeostasis

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