title: Natural Killer Cell Evasion Is Essential for Infection by Rhesus Cytomegalovirus.
abstract: The natural killer cell receptor NKG2D activates NK cells by engaging one of several ligands (NKG2DLs) belonging to either the MIC or ULBP families. Human cytomegalovirus (HCMV) UL16 and UL142 counteract this activation by retaining NKG2DLs and US18 and US20 act via lysomal degradation but the importance of NK cell evasion for infection is unknown. Since NKG2DLs are highly conserved in rhesus macaques, we characterized how NKG2DL interception by rhesus cytomegalovirus (RhCMV) impacts infection in vivo. Interestingly, RhCMV lacks homologs of UL16 and UL142 but instead employs Rh159, the homolog of UL148, to prevent NKG2DL surface expression. Rh159 resides in the endoplasmic reticulum and retains several NKG2DLs whereas UL148 does not interfere with NKG2DL expression. Deletion of Rh159 releases human and rhesus MIC proteins, but not ULBPs, from retention while increasing NK cell stimulation by infected cells. Importantly, RhCMV lacking Rh159 cannot infect CMV-naïve animals unless CD8+ cells, including NK cells, are depleted. However, infection can be rescued by replacing Rh159 with HCMV UL16 suggesting that Rh159 and UL16 perform similar functions in vivo. We therefore conclude that cytomegaloviral interference with NK cell activation is essential to establish but not to maintain chronic infection.
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Elizabeth R
authors: ER
authors: Sturgill
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Daniel
authors: D
authors: Malouli
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Scott G
authors: SG
authors: Hansen
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Benjamin J
authors: BJ
authors: Burwitz
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Seongkyung
authors: 0000-0002-3277-6140
authors: S
authors: Seo
authors: Department of Life Sciences, Carroll University, Waukesha, Wisconsin, United States of America.
authors: Christine L
authors: CL
authors: Schneider
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Jennie L
authors: JL
authors: Womack
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Marieke C
authors: MC
authors: Verweij
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Abigail B
authors: AB
authors: Ventura
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Amruta
authors: A
authors: Bhusari
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Krystal M
authors: KM
authors: Jeffries
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Alfred W
authors: AW
authors: Legasse
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Michael K
authors: MK
authors: Axthelm
authors: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors: Amy W
authors: AW
authors: Hudson
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Jonah B
authors: JB
authors: Sacha
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Louis J
authors: LJ
authors: Picker
authors: Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors: Klaus
authors: K
authors: Früh
mesh_terms: D000818:Animals; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008252:Macaca fascicularis; D008562:Membrane Glycoproteins / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology
chemical_list: C527085:KLRK1 protein, human; D008562:Membrane Glycoproteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; C512704:UL142 protein, human herpesvirus 5; C000598515:US18 protein, human cytomegalovirus; C000598516:US20 protein, human cytomegalovirus; D014764:Viral Proteins