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Differential Association of Programmed Death-1 and CD57 with Ex Vivo Survival of CD8⁺ T Cells in HIV Infection¹

Constantinos Petrovas^2,*, Benjamin Chaon^*, David R. Ambrozak^*, David A. Price^,, J. Joseph Melenhorst, Brenna J. Hill, Christof Geldmacher^*, Joseph P. Casazza^*, Pratip K. Chattopadhyay^¶, Mario Roederer^¶, Daniel C. Douek, Yvonne M. Mueller^||, Jeffrey M. Jacobson^||, Viraj Kulkarni^#, Barbara K. Felber^#, George N. Pavlakis^**, Peter D. Katsikis^|| and Richard A. Koup^2,*

*Immunology Laboratory, Human Immunology Section and ^¶ImmunoTechnology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814; Department of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Cardiff, Wales, U.K.; Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20814; ^||Department of Microbiology and Immunology, and Department of Medicine, Drexel University College of Medicine, Philadelphia, PA 19102; ^#Human Retrovirus Pathogenesis Section and **Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21701

Recent studies have revealed the critical role of programmed death-1 (PD-1) in exhaustion of HIV- and SIV-specific CD8⁺ T cells. In this study, we show that high expression of PD-1 correlates with increased ex vivo spontaneous and CD95/Fas-induced apoptosis, particularly in the "effector-memory" CD8⁺ T cell population from HIV⁺ donors. High expression of PD-1 was linked to a proapoptotic phenotype characterized by low expression of Bcl-2 and IL7-R, high expression of CD95/Fas and high mitochondrial mass. Expression of PD-1 and CD57 was differentially associated with the maturation status of CD8⁺ T cells in HIV infection. CD57 was linked to higher apoptosis resistance, with cells expressing a PD-1^LCD57^H phenotype exhibiting lower levels of cell death. The majority of HIV-specific CD8⁺ T cells were found to express a PD-1^HCD57^L or PD-1^HCD57^H phenotype. No correlation was found between PD-1 expression and ex vivo polyfunctionality of either HIV- or CMV-specific CD8⁺ T cells. Contrary to CD57, high expression of PD-1 was characterized by translocation of PD-1 into the area of CD95/Fas-capping, an early necessary step of CD95/Fas-induced apoptosis. Thus, our data further support the role of PD-1 as a preapoptotic factor for CD8⁺ T cells in HIV infection.

Address correspondence and reprint requests to Drs. Constantinos Petrovas and Richard A. Koup, Vaccine Research Center, NIAID, National Institutes of Health, 40 Convent Drive, Bethesda, MD 20892. E-mail addresses: petrovasc{at}mail.nih.gov and rk{at}mail.nih.gov

¹ The studies were supported in part by R01 AI46719 (to P.D.K.); D.A.P. is a Medical Research Council (U.K.) Senior Clinical Fellow.