title: Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis.
abstract: Decreased HIV-specific CD8(+) T cell proliferation is a hallmark of chronic infection, but the mechanisms of decline are unclear. We analyzed gene expression profiles from antigen-stimulated HIV-specific CD8(+) T cells from patients with controlled and uncontrolled infection and identified caspase-8 as a correlate of dysfunctional CD8(+) T cell proliferation. Caspase-8 activity was upregulated in HIV-specific CD8(+) T cells from progressors and correlated positively with disease progression and programmed cell death-1 (PD-1) expression, but negatively with proliferation. In addition, progressor cells displayed a decreased ability to upregulate membrane-associated caspase-8 activity and increased necrotic cell death following antigenic stimulation, implicating the programmed cell death pathway necroptosis. In vitro necroptosis blockade rescued HIV-specific CD8(+) T cell proliferation in progressors, as did silencing of necroptosis mediator RIPK3. Thus, chronic stimulation leading to upregulated caspase-8 activity contributes to dysfunctional HIV-specific CD8(+) T cell proliferation through activation of necroptosis and increased cell death.
authors.affiliation: Ragon Institute of MGH, Cambridge, MA 02139, USA.
authors.forename: Gaurav D
authors.initials: GD
authors.lastname: Gaiha
authors.affiliation: Ragon Institute of MGH, Cambridge, MA 02139, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: McKim
authors.affiliation: Ragon Institute of MGH, Cambridge, MA 02139, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Woods
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pertel
authors.affiliation: Ragon Institute of MGH, Cambridge, MA 02139, USA.
authors.forename: Janine
authors.initials: J
authors.lastname: Rohrbach
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Barteneva
authors.affiliation: Ragon Institute of MGH, Cambridge, MA 02139, USA; Department of Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Chin
authors.affiliation: Center for Human Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Dongfang
authors.initials: D
authors.lastname: Liu
authors.affiliation: Ragon Institute of MGH, Cambridge, MA 02139, USA.
authors.forename: Damien Z
authors.initials: DZ
authors.lastname: Soghoian
authors.affiliation: Ragon Institute of MGH, Cambridge, MA 02139, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Cesa
authors.affiliation: Ragon Institute of MGH, Cambridge, MA 02139, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Wilton
authors.affiliation: Ragon Institute of MGH, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Waring
authors.affiliation: Ragon Institute of MGH, Cambridge, MA 02139, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Chicoine
authors.affiliation: Hofstra North Shore-LIJ School of Medicine, Hempstead, NY 11549, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Doering
authors.affiliation: Department of Microbiology and Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.affiliation: Ragon Institute of MGH, Cambridge, MA 02139, USA; Centre de Recherche du Centre Hospitalier de l'Universite de Montreal (CRCHUM), Montreal, QC H2X 0A9, Canada.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.affiliation: Ragon Institute of MGH, Cambridge, MA 02139, USA; Infectious Disease Division, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
authors.affiliation: Ragon Institute of MGH, Cambridge, MA 02139, USA; Department of Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Abraham L
authors.initials: AL
authors.lastname: Brass
authors.affiliation: Ragon Institute of MGH, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Infectious Disease Division, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: bwalker@partners.org.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D053181:Caspase 8 / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D018450:Disease Progression; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006678:HIV / Q000502:physiology*; D016655:HIV Core Protein p24 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D009336:Necrosis; D010446:Peptide Fragments / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D019562:Viral Load
chemical_list: D016655:HIV Core Protein p24; C105992:PDCD1 protein, human; D010446:Peptide Fragments; D061026:Programmed Cell Death 1 Receptor; D034741:RNA, Small Interfering; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053181:Caspase 8