title: Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa.
abstract: BACKGROUND
  Viruses can evade immune surveillance, but the underlying mechanisms are insufficiently understood. Here, we sought to understand the mechanisms by which natural killer (NK) cells recognize HIV-1-infected cells and how this virus can evade NK-cell-mediated immune pressure.
  
  
  RESULTS
  Two sequence mutations in p24 Gag associated with the presence of specific KIR/HLA combined genotypes were identified in HIV-1 clade C viruses from a large cohort of infected, untreated individuals in South Africa (n = 392), suggesting viral escape from KIR+ NK cells through sequence variations within HLA class I-presented epitopes. One sequence polymorphism at position 303 of p24 Gag (TGag303V), selected for in infected individuals with both KIR2DL3 and HLA-C*03:04, enabled significantly better binding of the inhibitory KIR2DL3 receptor to HLA-C*03:04-expressing cells presenting this variant epitope compared to the wild-type epitope (wild-type mean 18.01 ± 10.45 standard deviation [SD] and variant mean 44.67 ± 14.42 SD, p = 0.002). Furthermore, activation of primary KIR2DL3+ NK cells from healthy donors in response to HLA-C*03:04+ target cells presenting the variant epitope was significantly reduced in comparison to cells presenting the wild-type sequence (wild-type mean 0.78 ± 0.07 standard error of the mean [SEM] and variant mean 0.63 ± 0.07 SEM, p = 0.012). Structural modeling and surface plasmon resonance of KIR/peptide/HLA interactions in the context of the different viral sequence variants studied supported these results. Future studies will be needed to assess processing and antigen presentation of the investigated HIV-1 epitope in natural infection, and the consequences for viral control.
  
  
  CONCLUSIONS
  These data provide novel insights into how viruses can evade NK cell immunity through the selection of mutations in HLA-presented epitopes that enhance binding to inhibitory NK cell receptors. Better understanding of the mechanisms by which HIV-1 evades NK-cell-mediated immune pressure and the functional validation of a structural modeling approach will facilitate the development of novel targeted immune interventions to harness the antiviral activities of NK cells.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.|Heinrich-Pette-Institut, Leibniz Institute for Experimental Virology, Hamburg, Germany.|First Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Angelique
authors.initials: A
authors.lastname: Hölzemer
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.|HIV Pathogenesis Programme, Doris Duke Medical Research Institute, KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Christina F
authors.initials: CF
authors.lastname: Thobakgale
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York, United States of America.
authors.forename: Camilo A
authors.initials: CA
authors.lastname: Jimenez Cruz
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Wilfredo F
authors.initials: WF
authors.lastname: Garcia-Beltran
authors.affiliation: Microsoft Research, Los Angeles, California, United States of America.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.affiliation: Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Nienke H
authors.initials: NH
authors.lastname: van Teijlingen
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Jaclyn K
authors.initials: JK
authors.lastname: Mann
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Manjeetha
authors.initials: M
authors.lastname: Jaggernath
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York, United States of America.
authors.forename: Seung-gu
authors.initials: SG
authors.lastname: Kang
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.|Heinrich-Pette-Institut, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Körner
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Amy W
authors.initials: AW
authors.lastname: Chung
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America.|Division of Microbiology, New England Primate Research Center, Southborough, Massachusetts, United States of America.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Schafer
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America.|Division of Microbiology, New England Primate Research Center, Southborough, Massachusetts, United States of America.|Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
authors.forename: David T
authors.initials: DT
authors.lastname: Evans
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Galit
authors.initials: G
authors.lastname: Alter
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.|Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Goulder
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.|Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.affiliation: First Department of Internal Medicine, Division of Infectious Diseases, University of Cologne, Cologne, Germany.|Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
authors.forename: Pia
authors.initials: P
authors.lastname: Hartmann
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pertel
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York, United States of America.
authors.forename: Ruhong
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.|HIV Pathogenesis Programme, Doris Duke Medical Research Institute, KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.|Max Planck Institute for Infection Biology, Berlin, Germany.|KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.|Heinrich-Pette-Institut, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
mesh_terms: D015331:Cohort Studies; D000939:Epitopes; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D016655:HIV Core Protein p24 / Q000235:genetics*; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D015236:HLA-C Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D057131:Immune Evasion; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D012367:RNA, Viral / Q000235:genetics; D054344:Receptors, KIR2DL3 / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D013019:South Africa; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D000939:Epitopes; D016655:HIV Core Protein p24; D015236:HLA-C Antigens; D012367:RNA, Viral; D054344:Receptors, KIR2DL3; D054301:gag Gene Products, Human Immunodeficiency Virus