title: Loss of the signaling adaptor TRAF1 causes CD8+ T cell dysregulation during human and murine chronic infection.
abstract: The signaling adaptor TNFR-associated factor 1 (TRAF1) is specifically lost from virus-specific CD8 T cells during the chronic phase of infection with HIV in humans or lymphocytic choriomeningitis virus (LCMV) clone 13 in mice. In contrast, TRAF1 is maintained at higher levels in virus-specific T cells of HIV controllers or after acute LCMV infection. TRAF1 expression negatively correlates with programmed death 1 expression and HIV load and knockdown of TRAF1 in CD8 T cells from viral controllers results in decreased HIV suppression ex vivo. Consistent with the desensitization of the TRAF1-binding co-stimulatory receptor 4-1BB, 4-1BBL-deficient mice have defects in viral control early, but not late, in chronic infection. TGFβ induces the posttranslational loss of TRAF1, whereas IL-7 restores TRAF1 levels. A combination treatment with IL-7 and agonist anti-4-1BB antibody at 3 wk after LCMV clone 13 infection expands T cells and reduces viral load in a TRAF1-dependent manner. Moreover, transfer of TRAF1(+) but not TRAF1(-) memory T cells at the chronic stage of infection reduces viral load. These findings identify TRAF1 as a potential biomarker of HIV-specific CD8 T cell fitness during the chronic phase of disease and a target for therapy.
authors.affiliation: Department of Immunology, 2 Clinical Sciences Division, University of Toronto, Toronto, M5S 1A8, Canada.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Ann J
authors.initials: AJ
authors.lastname: McPherson
authors.forename: R Brad
authors.initials: RB
authors.lastname: Jones
authors.forename: Kim S
authors.initials: KS
authors.lastname: Kawamura
authors.forename: Gloria H Y
authors.initials: GH
authors.lastname: Lin
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Thanuja
authors.initials: T
authors.lastname: Ambagala
authors.forename: Marc
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Thomas
authors.initials: T
authors.lastname: Calzascia
authors.forename: Nasra
authors.initials: N
authors.lastname: Aidarus
authors.forename: Alisha R
authors.initials: AR
authors.lastname: Elford
authors.forename: Feng Yun
authors.initials: FY
authors.lastname: Yue
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Colin M
authors.initials: CM
authors.lastname: Kovacs
authors.forename: Erika
authors.initials: E
authors.lastname: Benko
authors.forename: Cecile
authors.initials: C
authors.lastname: Tremblay
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Bernard
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Tania H
authors.initials: TH
authors.lastname: Watts
mesh_terms: D053330:4-1BB Ligand / Q000276:immunology / Q000378:metabolism; D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002738:Chloroquine / Q000494:pharmacology; D002908:Chronic Disease; D015536:Down-Regulation / Q000235:genetics; D015870:Gene Expression; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D015851:Interleukin-7 / Q000494:pharmacology; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047990:TNF Receptor-Associated Factor 1 / Q000172:deficiency* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019562:Viral Load / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D000906:Antibodies; D015851:Interleukin-7; D061026:Programmed Cell Death 1 Receptor; D047990:TNF Receptor-Associated Factor 1; D016212:Transforming Growth Factor beta; D002738:Chloroquine