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- Since it is suggested that a single response to B27-KK10 epitope may be responsible for the association of HLA-B*2705 patients with AIDS-free survival, B27-KK10-specific CTLs were compared to other HLA-specific CTLs in phenotype, function, clonal diversity, and antigen sensitivity in 47 treatment-naive infected slow or nonprogressing patients.
- cVL, the cell-associated viral load (number of infected cells harboring HIV DNA) correlated inversely with Gag-specific CTLs. This was most significant in HLA-B27 donors, and KK10 was identified as the peptide generating strongest CTL responses.
- B27-KK10-specific CTLs had no significant phenotypic differences from other epitope-specific CTLs upon testing a large panel of markers; however, they released higher proportions of IFN-gamma, TNF-alpha, MIP-1beta and CD107a upon antigenic stimulation.
- B27-KK10-specific and other HLA-specific CTLs had strikingly consistent domination of single clonotypes. B27-KK10-specific CTLs showed no preferential usage of CDR3 motifs, indicating that they could be recognized by diverse clonotypes with differing binding properties. Over several years, B27-KK10-specific CTLs changed their dominant clonotype as compared to other CTLs. This temporal dominant clonal turnover was attributed to a decline in replicative capacity of the dominant clonotype as seen by increases in CD57 expression, which is linked to replicative senescence.
- Studies involving functional avidity and different HLA-restricted responses proved that B27-KK10 responses had highest avidity. An inverse correlation between patient cVL and functional avidity of both dominant and highest subdominant responses suggested that functional avidity correlates with capacity to control HIV replication via infected cell elimination.
- Using the example seen in one patient, the authors stress the importance of maintaining protective stimulating activity of CTLs. When control by dominant clonotypes is lost, as in viral escape, ensuing viral replication is rapid.
- In one B27-positive patient studied, the dominantly-targeted epitope sequence changed over time from KRWIIMGLHK to KRWIIlGLnK. TCR sequences were studied in 11 patients.
Jorge R. Almeida, David A. Price, Laura Papagno, Zaïna Aït Arkoub, Delphine Sauce, Ethan Bornstein, Tedi E. Asher, Assia Samri, Aurélie Schnuriger, Ioannis Theodorou, Dominique Costagliola, Christine Rouzioux, Henri Agut, Anne-Geneviève Marcelin, Daniel Douek, Brigitte Autran, and Victor Appay. Superior Control of HIV-1 Replication by CD8+ T Cells Is Reflected by their Avidity, Polyfunctionality, and Clonal Turnover. J. Exp. Med., 204(10):2473-2485, 1 Oct 2007. PubMed ID: 17893201.
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