CCR5del32 genotype in human enteroviral cardiomyopathy leads to spontaneous virus clearance and improved outcome compared to wildtype CCR5

• Published in: Journal of translational medicine Vol. 16; no. 1; p. 249
• Main Authors: Lassner, Dirk, Siegismund, Christine S, Kühl, Uwe, Rohde, Maria, Stroux, Andrea, Escher, Felicitas, Schultheiss, Heinz-Peter
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 04.09.2018; BioMed Central; BMC
• Subjects: Adult; Aged; Antigen-Presenting Cells; Antigens; Antiviral Agents - therapeutic use; Arthritis; Biological response modifiers; Biopsy; Cardiomyopathies - genetics; Cardiomyopathies - virology; Cardiomyopathy; Cardiovascular disease; Care and treatment; CCR5 protein; CCR5del32 genotype; Chemokines; Chronic infection; Clonal deletion; Coxsackievirus; Coxsackievirus infections; Cytokines - blood; Dendritic cells; Effector cells; Enterovirus; Enterovirus Infections - genetics; Enteroviruses; Female; Gene deletion; Gene polymorphism; Genetic markers; Genotype; Genotyping; Heart diseases; Heart failure; Humans; Immune clearance; Immunologic Memory; Immunological memory; Infections; Inflammation; Interferon; Interferon-beta - metabolism; Interferon-beta therapy; Kaplan-Meier Estimate; Killer cells; Killer Cells, Natural - cytology; Kinases; Ligands; Lymphocytes; Lymphocytes T; Macrophages; Male; Medical prognosis; Middle Aged; Mortality; Mutation; Natural killer cells; Patients; Phenotype; Phenotypes; Polymorphism, Genetic; Prognosis; Proteins; Receptors, CCR5 - genetics; Retrospective Studies; Ribonucleic acid; Risk factors; RNA; Survival analysis; T-Lymphocytes - immunology; Treatment Outcome; Viral infections; Viruses; West Nile virus; β-Interferon; Coxsackievirus; CCR5del32 genotype; Enterovirus; Interferon-beta therapy; Cardiomyopathy
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-018-1610-8

Enteroviral cardiomyopathy is a life-threatening disease, and detection of enterovirus (EV) RNA in the initial endomyocardial biopsy is associated with adverse prognosis and increased mortality. Some patients with EV infection may spontaneously eliminate the virus and recover, whereas those with virus persistence deteriorate and progress to heart failure. Interferon-beta (IFN-β) therapy eliminates the virus, resulting in increased survival of treated patients. CCR5 is expressed on antigen-presenting cells (both macrophages and dendritic cells) and immune effector cells (T-lymphocytes with memory/effector phenotype and natural killer cells). Its 32-bp deletion (CCR5del32) is the most frequent human coding sequence mutation. This study addresses the correlation of CCR5 polymorphism to the clinical course of EV infection and the necessity for IFN-β treatment. We examined 97 consecutive patients with chronic/inflammatory cardiomyopathy and biopsy-proven EV infection and reliable information on clinical outcomes by CCr5 genotyping. These data were evaluated in relation to virus persistence in follow-up biopsies and survival rates over a 15-year period. Genotyping revealed a strong correlation between the CCR5del32 genotype and spontaneous virus clearance with improved outcomes. All patients with CCR5del32 eliminated EV spontaneously and none of them died within the observed period. In the group of untreated CCR5 wildtype patients, 33% died (Kaplan-Meier log-rank p = 0.010). However, CCR5 wildtype individuals treated with IFN-β are more likely to survive than without therapy (Kaplan-Meier log-rank p = 0.004) in identical proportions to individuals with the CCR5del32 genotype. These data suggest that CCR5 genotyping is a novel predictive genetic marker for the clinical course of human EV cardiomyopathies. Hereby clinicians can identify those EV positive individuals who will eliminate the virus spontaneously based on CCR5 phenotype and those patients with CCR5 wildtype genotype who would be eligible for immediate antiviral IFN-β treatment to minimize irreversible cardiac damage.