409   Thymic Reconstitution in Primary HIV Infection (PHI) following HAART Is Polyclonal.

J. F. Poulin*¹, R. Cheynier¹, M. Sylvestre¹, R. P. Sekaly*¹, C. Tsoukas², P. M. Girard³, J. Modai⁴, S. Kinloch⁵, B. Gazzard⁶, L. Perrin⁷, L. Goh⁸, S. Pratt⁸, and J. Lambert⁸.
¹Lab. d'Immunologie, Univ. de Montréal,²Montreal Gen. Hosp., Quebec, Canada;³Hosp. Rothschild and⁴Hop. Saint-Louis, Paris, France;⁵Royal Free Hosp. and⁶Chelsea and Westminster Hosp., London, UK;⁷Hop. Cantonal, Geneve, Switzerland; and⁸Glaxo Wellcome.

Background:Infection with HIV leads to a dramatic and rapid decrease in CD4⁺T-cells. Evidence in experimental models suggests that an early burst of thymic activity balances this CD4 loss and that such thymic reconstitution should be polyclonal.

Methods:In the QUEST study of PHI patients treated with quadruple HAART (Combivir/Abacavir/ Amprenavir), the diversity of thymic output was monitored by quantitative PCR amplification of the deletion circles (TREC) generated during the first step of T cell receptor (TCR)α;gene rearrangements. Two assays were used: one to evaluate diversity of TCR Vbrearrangement (7 different probes of the Db-Jbrearrangement) measured by excision circles, and one to evaluate total thymic output using the TREC assay (TCR a chain rearrangement). Quantitative assays sensitive to a single copy of DNA/10⁶cells were used in samples from 6 QUEST patients, enrolled with a mean 1 Western blot band, collected at entry and weeks 1, 3, 8, 16, and 24. Additional samples are undergoing analysis. Comparisons of the qualitative and quantitative features of thymic reconstitution in this population are compared with those observed in untreated PHI patients or patients with chronic HIV infection (CHI).

Results:Rapid, synchronous and transient newly rearranged T cells were observed in all treated patients. Excision circles spanning the 7 Db-Jbrearrangements were evident as early as 8 weeks on HAART. The breadth and magnitude of frequency of excision circles ranged from 5—50 fold (67% of pts.), compared to that found in chronically CHI patients (usually 3- fold).

Conclusion:Potent HAART in PHI leads to de novo and broad T-cell repertoire production, suggesting better immune reconstitution in PHI than in CHI; this is likely explained by more intact thymic function in PHI patients.