Degeneracy and repertoire of the human HIV-1 Gag p17(77-85) CTL response.

Abstract

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 beta2m 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.

• Authors: June Kan-Mitchell, Melissa Bajcz, Keri L Schaubert, David A Price, Jason M Brenchley, Tedi E Asher, Daniel C Douek, Hwee L Ng, Otto O Yang, Charles R Rinaldo Jr, Jose Miguel Benito, Brygida Bisikirska, Ramakrishna Hegde, Franco M Marincola, César Boggiano, Dianne Wilson, Judith Abrams, Sylvie E Blondelle, Darcy B Wilson
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 176 Issue 11 Pg. 6690-701 (Jun 01 2006) ISSN: 0022-1767 [Print] United States
• PMID: 16709828 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Epitopes, T-Lymphocyte
• Gene Products, gag
• HIV Antigens
• Peptide Fragments
• Peptide Library
• Viral Proteins
• gag Gene Products, Human Immunodeficiency Virus
• p17 protein, Human Immunodeficiency Virus Type 1

Topics

• Amino Acid Sequence
• Animals
• Cell Death (immunology)
• Cell Proliferation
• Cells, Cultured
• Cross-Priming
• Cytotoxicity Tests, Immunologic
• Epitopes, T-Lymphocyte (immunology, metabolism)
• Gene Products, gag (immunology, metabolism)
• Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
• HIV Antigens (immunology, metabolism)
• HIV-1 (immunology)
• Humans
• Lymphocyte Activation (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Sequence Data
• Peptide Fragments (agonists, immunology, metabolism)
• Peptide Library
• Predictive Value of Tests
• T-Lymphocytes, Cytotoxic (immunology, metabolism, virology)
• Viral Proteins (immunology, metabolism)
• gag Gene Products, Human Immunodeficiency Virus