HIV Controller CD4+ T Cells Respond to Minimal Amounts of Gag Antigen Due to High TCR Avidity

PLoS Pathogens

Faroudy Boufassa¹  Jacques Thèze²  Ioannis Theodorou³  Lisa A. Chakrabarti⁴  Jean-François Delfraissy⁵  William W. Kwok⁶  for the ANRS EP36 HIV Controllers Study Group⁷  Olivier Lambotte⁷  Benoît Vingert⁸  Santiago Perez-Patrigeon⁸  Patricia Jeannin⁸  Fabrice Lemaître⁹ 

[1] Assistance Publique - Hôpitaux de Paris (AP-HP), Department of Internal Medicine and Infectious Diseases, Bicêtre Hospital, Le Kremlin-Bicêtre, France;Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America;G5 Dynamiques des Réponses Immunes, Institut Pasteur, Paris, France;INSERM U543, Pitié-Salpêtrière Hospital, Paris, France;INSERM U668, Equipe Avenir, Institut Pasteur, Paris, France;INSERM U822, Bicêtre Hospital, Le Kremlin-Bicêtre, France;Institut National de la Santé et de la Recherche Médicale (INSERM) U802, Le Kremlin-Bicêtre, France;Unité d'Immunogénétique Cellulaire, Institut Pasteur, Paris, France;Université Paris-Sud, Le Kremlin-Bicêtre, France

关键词: T cells;    HIV;    Highly-active antiretroviral therapy;    Enzyme-linked immunoassays;    Memory T cells;    Cytotoxic T cells;    Immune response;    Viral load;   

DOI  :  10.1371/journal.ppat.1000780

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral treatment. Emerging evidence indicates that HIV control is mediated through very active cellular immune responses, though how such responses can persist over time without immune exhaustion is not yet understood. To investigate the nature of memory CD4+ T cells responsible for long-term anti-HIV responses, we characterized the growth kinetics, Vβ repertoire, and avidity for antigen of patient-derived primary CD4+ T cell lines. Specific cell lines were obtained at a high rate for both HIV controllers (16/17) and efficiently treated patients (19/20) in response to the immunodominant Gag293 peptide. However, lines from controllers showed faster growth kinetics than those of treated patients. After normalizing for growth rates, IFN-γ responses directed against the immunodominant Gag293 peptide showed higher functional avidity in HIV controllers, indicating differentiation into highly efficient effector cells. In contrast, responses to Gag161, Gag263, or CMV peptides did not differ between groups. Gag293-specific CD4+ T cells were characterized by a diverse Vβ repertoire, suggesting that multiple clones contributed to the high avidity CD4+ T cell population in controllers. The high functional avidity of the Gag293-specific response could be explained by a high avidity interaction between the TCR and the peptide-MHC complex, as demonstrated by MHC class II tetramer binding. Thus, HIV controllers harbor a pool of memory CD4+ T cells with the intrinsic ability to recognize minimal amounts of Gag antigen, which may explain how they maintain an active antiviral response in the face of very low viremia.

【 授权许可】

CC BY