Submitted February 19, 2009
Accepted April 15, 2009
Antigen sensitivity is a major determinant of CD8+ T-cell polyfunctionality and HIV suppressive activity
Jorge R. Almeida, Delphine Sauce, David A. Price, Laura Papagno, So Youn Shin, Arnaud Moris, Martin Larsen, Gianfranco Pancino, Daniel C. Douek, Brigitte Autran, Asier Saez-Cirion, and Victor Appay*
Cellular Immunology Laboratory, INSERM U543, Avenir Group, Hopital Pitie-Salpetriere, Universite Pierre et Marie Curie-Paris6, Paris, France
Department of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Cardiff, United Kingdom
Institut Pasteur, Unite de Regulation des Infections Retrovirales, Paris, France
Institut Pasteur, Unite Virus et Immunite, URA CNRS 1930, Paris, France
Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
* Corresponding author; email: victor.appay{at}upmc.fr.
CD8+ T-cells are major players in the immune response against HIV. However, recent failures in the development of T-cell-based vaccines against HIV-1 have emphasized the need to reassess our basic knowledge of T-cell-mediated efficacy. CD8+ T-cells from HIV-1 infected patients with slow disease progression exhibit potent polyfunctionality and HIV suppressive activity, yet the factors that unify these properties are incompletely understood. We performed a detailed study of the interplay between T-cell functional attributes using a bank of HIV-specific CD8+ T-cell clonotypes isolated in vitro; this approach enabled us to overcome inherent difficulties related to the in vivo heterogeneity of T-cell populations and address the underlying determinants that synthesize the qualities required for antiviral efficacy. Conclusions were supported by ex vivo analysis of HIV specific CD8+ T-cells from infected donors. We report that attributes of CD8+ T-cell efficacy against HIV are linked at the level of antigen sensitivity. Highly sensitive CD8+ T-cells display polyfunctional profiles and potent HIV suppressive activity. These data provides news insights into the mechanisms underlying CD8+ T-cell efficacy against HIV, and indicate that vaccine strategies should focus on the induction of HIV-specific T-cells with high levels of antigen sensitivity in order to elicit potent antiviral efficacy.
