Subordinate Effect of -21M HLA-B Dimorphism on NK Cell Repertoire Diversity and Function in HIV-1 Infected Individuals of African Origin.
Elia Moreno Cubero,Ane Ogbe,Isabela Pedroza-Pacheco,Myron S. Cohen,Barton F. Haynes,Persephone Borrow,Dimitra Peppa,Dimitra Peppa +7 more
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TLDR
During HIV/HCMV co-infection exposure of NK cells to an environment that displays altered HLA-E ligands drives adaptive NKG2C+ NK cell expansions influencing effector responses, suggesting increased efforts to understand how NK cells are functionally calibrated to self-HLA during chronic viral infections will pave the way to developing targeted therapeutic interventions.Abstract:
Natural Killer (NK) cells play an important role in antiviral defense and their potent effector function identifies them as key candidates for immunotherapeutic interventions in chronic viral infections. Their remarkable functional agility is achieved by virtue of a wide array of germline-encoded inhibitory and activating receptors ensuring a self-tolerant and tunable repertoire. NK cell diversity is generated by a combination of factors including genetic determinants and infections/environmental factors, which together shape the NK cell pool and functional potential. Recently a genetic polymorphism at position -21 of HLA-B, which influences the supply of HLA-E binding peptides and availability of HLA-E for recognition by the inhibitory NK cell receptor NKG2A, was shown to have a marked influence on NK cell functionality in healthy human cytomegalovirus (HCMV) seronegative Caucasian individuals. In this study, -21 methionine (M)-expressing alleles supplying HLA-E binding peptides were largely poor ligands for inhibitory killer immunoglobulin-like receptors (KIRs), and a bias to NKG2A-mediated education of functionally-potent NK cells was observed. Here, we investigated the effect of this polymorphism on the phenotype and functional capacity of peripheral blood NK cells in a cohort of 36 African individuals with human immunodeficiency virus type 1 (HIV-1)/HCMV co-infection. A similarly profound influence of dimorphism at position -21 of HLA-B on NK cells was not evident in these subjects. They predominantly expressed African specific HLA-B and -C alleles that contribute a distinct supply of NKG2A and KIR ligands, and these genetic differences were compounded by the marked effect of HIV-1/HCMV co-infection on NK cell differentiation. Together, these factors resulted in a lack of correlation of the HLA-B -21 polymorphism with surface abundance of HLA-E and loss of the NK cell functional advantage in subjects with -21M HLA-B alleles. Instead, our data suggest that during HIV/HCMV co-infection exposure of NK cells to an environment that displays altered HLA-E ligands drives adaptive NKG2C+ NK cell expansions influencing effector responses. Increased efforts to understand how NK cells are functionally calibrated to self-HLA during chronic viral infections will pave the way to developing targeted therapeutic interventions to overcome the current barriers to enhancing immune-based antiviral control.read more
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Journal ArticleDOI
Harnessing Natural Killer Cell Innate and Adaptive Traits in HIV Infection.
TL;DR: Recent advances in understanding of the development of NK cell adaptive/memory responses in HIV infection are discussed and new and exciting opportunities to exploit the beneficial attributes of NK cells for HIV immunotherapy are highlighted.
Journal ArticleDOI
Regulation of the human NK cell compartment by pathogens and vaccines.
TL;DR: In this article, the authors review recent evidence that pathogen-and vaccine-derived signals influence the differentiation, adaptation and subsequent effector function of human natural killer cells and conclude that the extent to which innate and acquired immune mediators influence NK cell effector functions is influenced by the maturation and differentiation state of the NK cell compartment; moreover, NK cell differentiation is driven in part by exposure to infection.
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An HLA-I signature favouring KIR-educated Natural Killer cells mediates immune control of HIV in children and contrasts with the HLA-B-restricted CD8+ T-cell-mediated immune control in adults.
Vinicius A Vieira,Vinicius A Vieira,Emily Adland,David F. G. Malone,Maureen P. Martin,Andreas Groll,M. Azim Ansari,Maria C. Garcia-Guerrero,Mari C. Puertas,Maximilian Muenchhoff,Claudia Fortuny Guash,Christian Brander,Christian Brander,Javier Martinez-Picado,Alasdair Bamford,Alasdair Bamford,Gareth Tudor-Williams,Thumbi Ndung'u,Bruce D. Walker,Bruce D. Walker,Veron Ramsuran,Veron Ramsuran,John Frater,Pieter Jooste,Dimitra Peppa,Mary Carrington,Philip J. R. Goulder,Philip J. R. Goulder +27 more
TL;DR: In this article, the authors investigated the contribution of natural killer cells (NK) to immune control in children living with HIV followed over two decades in South Africa and found that Bw4 and HLA-A expression contributions to HIV disease outcome were dwarfed by those of protective and disease-susceptible HLA B molecules.
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Human leukocyte antigen associations with protection against tuberculosis infection and disease in human immunodeficiency virus-1 infected individuals, despite household tuberculosis exposure and immune suppression.
Faheem Seedat,Ian James,Shayne Loubser,Ziyaad Waja,Simon Mallal,Christopher J. Hoffmann,Caroline T. Tiemessen,Richard E. Chaisson,Neil A. Martinson +8 more
TL;DR: Several HLA alleles are noted as correlates of TB infection, risk and natural protection in HIV-infected individuals and may enable risk stratification of those with HIV infection.
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Cytomegalovirus pneumonia of infants in Africa: a narrative literature review.
Kerusha Govender,Kerusha Govender,Nokukhanya Msomi,Nokukhanya Msomi,Pravi Moodley,Pravi Moodley,Raveen Parboosing,Raveen Parboosing +7 more
TL;DR: The development of cheap, accurate diagnostic tools and safe, effective antivirals and the maintenance of effective prevention and treatment of pediatric HIV are needed to manage cytomegalovirus pneumonia in low-resource settings.
References
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Journal ArticleDOI
HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C
Veronique M. Braud,David S.J. Allan,Christopher A. O’Callaghan,Kalle Söderström,Annalisa D'Andrea,Graham S. Ogg,Sasha Lazetic,Neil Thomas Young,John I. Bell,Joseph H. Phillips,Lewis L. Lanier,Andrew J. McMichael +11 more
TL;DR: The identification of ligands for HLA-E is reported, which shows that a subset of HLA class I alleles has been shown to inhibit killing by CD94/NKG2A+ NK-cell clones, and only the HLA alleles that possess a leader peptide capable of upregulating Hla-E surface expression confer resistance toNK-cell-mediated lysis.
Journal ArticleDOI
The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells.
George B. Cohen,George B. Cohen,Rajesh T. Gandhi,Daniel M. Davis,Ofer Mandelboim,Benjamin K. Chen,Jack L. Strominger,David Baltimore +7 more
TL;DR: Subpopulations of CTL and NK cells may be uniquely suited for combating HIV, and evidence that HIV-1 selectively downregulates HLA-A andHLA-B but does not significantly affect H LA-C or HLAE is presented.
Journal ArticleDOI
Surface Expression of HLA-E, an Inhibitor of Natural Killer Cells, Enhanced by Human Cytomegalovirus gpUL40
Peter Tomasec,Veronique M. Braud,Carole R. Rickards,Martin B. Powell,Brian P. McSharry,Stephan D. Gadola,Vincenzo Cerundolo,Leszek K. Borysiewicz,Andrew J. McMichael,Gavin William Grahame Wilkinson +9 more
TL;DR: It is shown that, independently of the transporter associated with antigen processing, gpUL40 can up-regulate expression of HLA-E, which protects targets from NK cell lysis, which is up-regulated by HCMV.
Journal ArticleDOI
Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education
Niklas K. Björkström,Peggy Riese,Frank Heuts,Sandra Andersson,Cyril Fauriat,Cyril Fauriat,Martin A. Ivarsson,Andreas T. Björklund,Malin Flodström-Tullberg,Jakob Michaëlsson,Martin E. Rottenberg,Carlos A. Guzmán,Hans-Gustaf Ljunggren,Karl-Johan Malmberg +13 more
TL;DR: It is shown that CD56(dim) NK cells continue to differentiate, and the associated functional imprint, occurs independently of NK-cell education by interactions with self-human leukocyte antigen class I ligands and is an essential part of the formation of human NK- cell repertoires.
Journal ArticleDOI
Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function.
Heinrich Schlums,Frank Cichocki,Frank Cichocki,Bianca Tesi,Jakob Theorell,Vivien Béziat,Tim D. Holmes,Hongya Han,Samuel C. C. Chiang,Bree Foley,Kristin Mattsson,Stella Larsson,Marie Schaffer,Karl-Johan Malmberg,Karl-Johan Malmberg,Karl-Johan Malmberg,Hans-Gustaf Ljunggren,Jeffrey S. Miller,Yenan T. Bryceson,Yenan T. Bryceson +19 more
TL;DR: The emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins after human cytomegalovirus (HCMV) infection is described, uncovering a spectrum of epigenetically unique adaptive NK cell subsets that diversify in response to viral infection and have distinct functional capabilities compared to canonical NK cells.
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