RESUMO
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.
Assuntos
Infecções por Citomegalovirus/metabolismo , Citomegalovirus/genética , Citomegalovirus/metabolismo , Células Matadoras Naturais/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Cromossomos Artificiais Bacterianos/genética , Infecções por Citomegalovirus/prevenção & controle , Variação Genética , Instabilidade Genômica , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Evasão da Resposta Imune , Ativação Linfocitária , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismoRESUMO
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.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Evasão da Resposta Imune , Imunidade Celular , Células Matadoras Naturais/imunologia , Proteínas Virais de Fusão/imunologia , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Transformada , Citomegalovirus/genética , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/patologia , Humanos , Células Matadoras Naturais/patologia , Proteínas Virais de Fusão/genéticaRESUMO
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.
Assuntos
Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Interferon Tipo I/imunologia , Replicação Viral , Células Cultivadas , Humanos , Interferon Tipo I/deficiência , Ensaio de Placa ViralRESUMO
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.