Degeneracy and Repertoire of the Human HIV-1 Gag p1777-85 CTL Response

• Published in: The Journal of immunology (1950) 2006-06, Vol.176 (11), p.6690-6701
• Main Authors: Kan-Mitchell, June, Bajcz, Melissa, Schaubert, Keri L, Price, David A, Brenchley, Jason M, Asher, Tedi E, Douek, Daniel C, Ng, Hwee L, Yang, Otto O, Rinaldo, Charles R., Jr, Benito, Jose Miguel, Bisikirska, Brygida, Hegde, Ramakrishna, Marincola, Franco M, Boggiano, Cesar, Wilson, Dianne, Abrams, Judith, Blondelle, Sylvie E, Wilson, Darcy B
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.176.11.6690

CD8+ CTL responses are important for the control of HIV-1 infection. The immunodominant HLA-A2-restricted Gag epitope, SLYNTVATL (SL9), is considered to be a poor immunogen because reactivity to it is rare in acute infection despite its paradoxical dominance in patients with chronic infection. We have previously reported SL9 to be a help-independent epitope in that it primes highly activated CTLs ex vivo from CD8+ T cells of seronegative healthy donors. These CTLs produce sufficient cytokines for extended autocrine proliferation but are sensitive to activation-induced cell death, which may cause them to be eliminated by a proinflammatory cytokine storm. Here we identified an agonist variant of the SL9 peptide, p41 (SLYNTVAAL), by screening a large synthetic combinatorial nonapeptide library with ex vivo-primed SL9-specific T cells. p41 invariably immunized SL9-cross-reactive CTLs from other donors ex vivo and H-2Db β2m double knockout mice expressing a chimeric HLA-A*0201/H2-Db MHC class I molecule. Parallel human T cell cultures showed p41-specific CTLs to be less fastidious than SL9-CTLs in the level of costimulation required from APCs and the need for exogenous IL-2 to proliferate (help dependent). TCR sequencing revealed that the same clonotype can develop into either help-independent or help-dependent CTLs depending on the peptide used to activate the precursor CD8+ T cells. Although Ag-experienced SL9-T cells from two patients were also sensitive to IL-2-mediated cell death upon restimulation in vitro, the loss of SL9 T cells was minimized with p41. This study suggests that agonist sequences can replace aberrantly immunogenic native epitopes for the rational design of vaccines targeting HIV-1.