High production rates sustain in vivo levels of PD-1high simian immunodeficiency virus-specific CD8 t cells in the face of rapid clearance

Constantinos Petrovas, Takuya Yamamoto, David A. Price, Srinivas S. Rao, Nichole R. Klat, Jason M. Brenchley, Daniel C. Douek, Emma Gostick, Bastian R. Angermann, Zvi Grossman, Derek C. Macallan, Martin Meier-Schellersheim, Richard A. Koupa

Research output: Contribution to journalArticlepeer-review

Abstract

Programmed Death 1 (PD-1) expression by human/simian immunodeficiency virus (HIV/SIV)-specific CD8 T cells has been associated with defective cytokine production and reduced in vitro proliferation capacity. However, the cellular mechanisms that sustain PD-1high virus-specific CD8 T cell responses during chronic infection are unknown. Here, we show that the PD-1high phenotype is associated with accelerated in vivo CD8 T cell turnover in SIV-infected rhesus macaques, especially within the SIVspecific CD8 T cell pool. Mathematical modeling of 5-bromo-2= deoxyuridine (BrdU) labeling dynamics demonstrated a significantly increased generation rate of PD-1high compared to PD-1low CD8 T cells in all memory compartments. Simultaneous analysis of Ki67 and BrdU kinetics revealed a complex in vivo turnover profile whereby only a small fraction of PD-1high cells, but virtually all PD-1low cells, returned to rest after activation. Similar kinetics operated in both chronic and acute SIV infection. Our data suggest that the persistence of PD-1high SIV-specific CD8 T cells in chronic infection is maintained in vivo by a mechanism involving high production coupled with a high disappearance rate.

Original languageEnglish (US)
Pages (from-to)9836-9844
Number of pages9
JournalJournal of virology
Volume87
Issue number17
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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