A Molecular Basis for the Control of Preimmune Escape Variants by HIV-Specific CD8+ T Cells

• Published in: Immunity (Cambridge, Mass.) Vol. 38; no. 3; pp. 425 - 436
• Main Authors: Ladell, Kristin, Hashimoto, Masao, Iglesias, Maria Candela, Wilmann, Pascal G., McLaren, James E., Gras, Stéphanie, Chikata, Takayuki, Kuse, Nozomi, Fastenackels, Solène, Gostick, Emma, Bridgeman, John S., Venturi, Vanessa, Arkoub, Zaïna Aït, Agut, Henri, van Bockel, David J., Almeida, Jorge R., Douek, Daniel C., Meyer, Laurence, Venet, Alain, Takiguchi, Masafumi, Rossjohn, Jamie, Price, David A., Appay, Victor
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.03.2013; Elsevier Limited
• Subjects: Acquired immune deficiency syndrome; AIDS; Amino Acid Sequence; Antigen Presentation - immunology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - virology; Clone Cells - immunology; Clone Cells - metabolism; Clone Cells - virology; Councils; Crystallography, X-Ray; Drug therapy; Epitopes, T-Lymphocyte - chemistry; Epitopes, T-Lymphocyte - immunology; Epitopes, T-Lymphocyte - metabolism; Flow cytometry; HIV; HIV Core Protein p24 - genetics; HIV Core Protein p24 - immunology; HIV Core Protein p24 - metabolism; HIV Infections - immunology; HIV Infections - virology; HIV-1 - genetics; HIV-1 - immunology; HIV-1 - metabolism; HLA-B27 Antigen - chemistry; HLA-B27 Antigen - immunology; HLA-B27 Antigen - metabolism; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Immune system; Immunodominant Epitopes - chemistry; Immunodominant Epitopes - immunology; Immunodominant Epitopes - metabolism; Infections; Models, Molecular; Molecular Sequence Data; Mutation; Patients; Peptides; Protein Binding - immunology; Protein Structure, Tertiary; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; T cell receptors; Vaccines
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2012.11.021

The capacity of the immune system to adapt to rapidly evolving viruses is a primary feature of effective immunity, yet its molecular basis is unclear. Here, we investigated protective HIV-1-specific CD8+ T cell responses directed against the immunodominant p24 Gag-derived epitope KK10 (KRWIILGLNK263-272) presented by human leukocyte antigen (HLA)-B∗2705. We found that cross-reactive CD8+ T cell clonotypes were mobilized to counter the rapid emergence of HIV-1 variants that can directly affect T cell receptor (TCR) recognition. These newly recruited clonotypes expressed TCRs that engaged wild-type and mutant KK10 antigens with similar affinities and almost identical docking modes, thereby accounting for their antiviral efficacy in HLA-B∗2705+ individuals. A protective CD8+ T cell repertoire therefore encompasses the capacity to control TCR-accessible mutations, ultimately driving the development of more complex viral escape variants that disrupt antigen presentation. ► New T cell clonotypes are recruited to counter TCR-accessible HIV mutations ► These T cells express TCRs that crossrecognize wild-type and mutant epitopes ► Crossreactive CD8+ T cells underpin anti-HIV efficacy in HLA-B∗27+ patients ► T cell efficacy ultimately drives escape mutations that impact antigen presentation