title: NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation.
abstract: HSV-1 latently infects most humans, causing a variable clinical picture that depends, in part, on host genetic factors. Both IgG and its cellular FcRs, CD16A and CD32A-C (encoded by FCGR3A and FCGR2A-C, respectively, on chromosome 1), display polymorphisms that could affect their defensive function. Of potential relevance are a FCGR3A dimorphism resulting in CD16A-valine/phenylalanine-158 allotypes with different IgG affinity, variations conditioning NK cell expression of CD32B or CD32C, and IgG1 H chain (IGHG1) and kappa-chain (IGKC) polymorphisms determining allotypes designated G1m and Km. In this study, we assessed the contribution of Ig genetic variations and their interaction with FcR polymorphism to HSV-1 susceptibility, as well as their impact on NK cell-mediated Ab-dependent cellular cytotoxicity (ADCC). Our results show an epistatic interaction between IGHG1 and FCGR3A such that the higher affinity CD16A-158V/V genotype associates with an asymptomatic course of HSV-1 infection only in homozygotes for G1m3. Furthermore, CD16A-158V and G1m3 allotypes enhanced ADCC against opsonized HSV-1-infected fibroblasts. Conversely, Km allotypes and CD32B or CD32C expression on NK cells did not significantly influence HSV-1 susceptibility or ADCC. NK cells degranulating against immune serum-opsonized HSV-1-infected fibroblasts had heterogeneous phenotypes. Yet, enhanced ADCC was observed among NK cells showing a differentiated, memory-like phenotype (NKG2C(bright)NKG2A(-)CD57(+)FcRγ(-)), which expand in response to human CMV. These results extend our knowledge on the importance of immunogenetic polymorphisms and NK cell-Ab interplay in the host response against HSV-1 and point to the relevance of interactions between immune responses elicited during chronic coinfection by multiple herpesviruses.
authors.affiliation: Inmunogenética e Histocompatibilidad, Instituto de Investigación Sanitaria Puerta de Hierro, 28222 Majadahonda, Madrid, Spain;
authors.forename: Manuela
authors.initials: M
authors.lastname: Moraru
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Laurel E
authors.initials: LE
authors.lastname: Black
authors.affiliation: Institut Hospital del Mar d'Investigaciones Médiques, 08002 Barcelona, Spain;
authors.forename: Aura
authors.identifier: http://orcid.org/0000-0003-2894-0486
authors.initials: A
authors.lastname: Muntasell
authors.affiliation: Servicio de Microbiología, Instituto de Investigación Sanitaria Puerta de Hierro, 28222 Majadahonda, Madrid, Spain; and.
authors.forename: Francisca
authors.initials: F
authors.lastname: Portero
authors.affiliation: Institut Hospital del Mar d'Investigaciones Médiques, 08002 Barcelona, Spain;
authors.forename: Miguel
authors.initials: M
authors.lastname: López-Botet
authors.affiliation: Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain.
authors.forename: Hugh T
authors.initials: HT
authors.lastname: Reyburn
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Janardan P
authors.initials: JP
authors.lastname: Pandey
authors.affiliation: Inmunogenética e Histocompatibilidad, Instituto de Investigación Sanitaria Puerta de Hierro, 28222 Majadahonda, Madrid, Spain; carlos.vilches@yahoo.com.
authors.forename: Carlos
authors.initials: C
authors.lastname: Vilches
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics / Q000276:immunology; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D004198:Disease Susceptibility; D004843:Epistasis, Genetic; D015870:Gene Expression; D014644:Genetic Variation; D005838:Genotype; D006561:Herpes Simplex / Q000235:genetics / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000276:immunology; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology*; D010641:Phenotype; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation / Q000276:immunology
chemical_list: C496124:FCGR3A protein, human; C080571:Fc gamma receptor IIB; C080572:Fc gamma receptor IIC; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007145:Immunoglobulin kappa-Chains; D017452:Receptors, IgG