RESUMEN
Human cytomegalovirus (HCMV) is under constant selective pressure from the immune system in vivo. Study of HCMV genes that have been lost in the absence of, or genetically altered by, such selection can focus research toward findings of in vivo significance. We have been particularly interested in the most pronounced change in the highly passaged laboratory strains AD169 and Towne-the deletion of 13-15 kb of sequence (designated the UL/b' region) that encodes up to 22 canonical genes, UL133-UL150. At least 5 genes have been identified in UL/b' that inhibit NK cell function. UL135 suppresses formation of the immunological synapse (IS) by remodeling the actin cytoskeleton, thereby illustrating target cell cooperation in IS formation. UL141 inhibits expression of two activating ligands (CD155, CD112) for the activating receptor CD226 (DNAM-1), and two receptors (TRAIL-R1, R2) for the apoptosis-inducing TRAIL. UL142, ectopically expressed in isolation, and UL148A, target specific MICA allotypes that are ligands for NKG2D. UL148 impairs expression of CD58 (LFA-3), the co-stimulatory cell adhesion molecule for CD2 found on T and NK cells. Outside UL/b', studies on natural variants have shown UL18 mutants change affinity for their inhibitory ligand LIR-1, while mutations in UL40's HLA-E binding peptide differentially drive NKG2C+ NK expansions. Research into HCMV genomic stability and its effect on NK function has provided important insights into virus:host interactions, but future studies will require consideration of genetic variability and the effect of genes expressed in the context of infection to fully understand their in vivo impact.
Asunto(s)
Infecciones por Citomegalovirus/metabolismo , Citomegalovirus/genética , Citomegalovirus/metabolismo , Células Asesinas Naturales/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Cromosomas Artificiales Bacterianos/genética , Infecciones por Citomegalovirus/prevención & control , Variación Genética , Inestabilidad Genómica , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Evasión Inmune , Activación de Linfocitos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Proteínas Virales/genética , Proteínas Virales/metabolismoRESUMEN
CD58 is an adhesion molecule that is known to play a critical role in costimulation of effector cells and is intrinsic to immune synapse structure. Herein, we describe a virally encoded gene that inhibits CD58 surface expression. Human cytomegalovirus (HCMV) UL148 was necessary and sufficient to promote intracellular retention of CD58 during HCMV infection. Blocking studies with antagonistic anti-CD58 mAb and an HCMV UL148 deletion mutant (HCMV∆UL148) with restored CD58 expression demonstrated that the CD2/CD58 axis was essential for the recognition of HCMV-infected targets by CD8+ HCMV-specific cytotoxic T lymphocytes (CTLs). Further, challenge of peripheral blood mononuclear cells ex vivo with HCMV∆UL148 increased both CTL and natural killer (NK) cell degranulation against HCMV-infected cells, including NK-driven antibody-dependent cellular cytotoxicity, showing that UL148 is a modulator of the function of multiple effector cell subsets. Our data stress the effect of HCMV immune evasion functions on shaping the immune response, highlighting the capacity for their potential use in modulating immunity during the development of anti-HCMV vaccines and HCMV-based vaccine vectors.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Evasión Inmune , Inmunidad Celular , Células Asesinas Naturales/inmunología , Proteínas Virales de Fusión/inmunología , Linfocitos T CD8-positivos/patología , Línea Celular Transformada , Citomegalovirus/genética , Infecciones por Citomegalovirus/genética , Infecciones por Citomegalovirus/patología , Humanos , Células Asesinas Naturales/patología , Proteínas Virales de Fusión/genéticaRESUMEN
The effect of abrogating the interferon (IFN) response on human cytomegalovirus (HCMV) replication was investigated using primary human cells engineered to block either the production of or the response to type I IFNs. In IFN-deficient cells, HCMV produced larger plaques and spread and replicated more rapidly than in parental cells. These cells demonstrate the vital role of IFNs in controlling HCMV replication and provide useful tools to investigate the IFN response to HCMV.
Asunto(s)
Citomegalovirus/inmunología , Citomegalovirus/fisiología , Interferón Tipo I/inmunología , Replicación Viral , Células Cultivadas , Humanos , Interferón Tipo I/deficiencia , Ensayo de Placa ViralRESUMEN
Regulation of the lectin galectin 9 (Gal-9) was investigated for the first time during human cytomegalovirus (HCMV) infection. Gal-9 transcription was significantly upregulated in transplant recipients with reactivated HCMV in vivo. In vitro, Gal-9 was potently upregulated by HCMV independently of viral gene expression, with interferon beta (IFN-ß) identified as the mediator of this effect. This study defines an immunoregulatory protein potently increased by HCMV infection and a novel mechanism to control Gal-9 through IFN-ß induction.