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1.
Eur J Med Res ; 26(1): 107, 2021 Sep 16.
Article in English | MEDLINE | ID: covidwho-1412355

ABSTRACT

BACKGROUND: COVID-19, the pandemic disease caused by infection with SARS-CoV-2, may take highly variable clinical courses, ranging from symptom-free and pauci-symptomatic to fatal disease. The goal of the current study was to assess the association of COVID-19 clinical courses controlled by patients' adaptive immune responses without progression to severe disease with patients' Human Leukocyte Antigen (HLA) genetics, AB0 blood group antigens, and the presence or absence of near-loss-of-function delta 32 deletion mutant of the C-C chemokine receptor type 5 (CCR5). PATIENT AND METHODS: An exploratory observational study including 157 adult COVID-19 convalescent patients was performed with a median follow-up of 250 days. The impact of different HLA genotypes, AB0 blood group antigens, and the CCR5 mutant CD195 were investigated for their role in the clinical course of COVID-19. In addition, this study addressed levels of severity and morbidity of COVID-19. The association of the immunogenetic background parameters were further related to patients' humoral antiviral immune response patterns by longitudinal observation. RESULTS: Univariate HLA analyses identified putatively protective HLA alleles (HLA class II DRB1*01:01 and HLA class I B*35:01, with a trend for DRB1*03:01). They were associated with reduced durations of disease instead decreased (rather than increased) total anti-S IgG levels. They had a higher virus neutralizing capacity compared to non-carriers. Conversely, analyses also identified HLA alleles (HLA class II DQB1*03:02 und HLA class I B*15:01) not associated with such benefit in the patient cohort of this study. Hierarchical testing by Cox regression analyses confirmed the significance of the protective effect of the HLA alleles identified (when assessed in composite) in terms of disease duration, whereas AB0 blood group antigen heterozygosity was found to be significantly associated with disease severity (rather than duration) in our cohort. A suggestive association of a heterozygous CCR5 delta 32 mutation status with prolonged disease duration was implied by univariate analyses but could not be confirmed by hierarchical multivariate testing. CONCLUSION: The current study shows that the presence of HLA class II DRB1*01:01 and HLA class I B*35:01 is of even stronger association with reduced disease duration in mild and moderate COVID-19 than age or any other potential risk factor assessed. Prospective studies in larger patient populations also including novel SARS-CoV-2 variants will be required to assess the impact of HLA genetics on the capacity of mounting protective vaccination responses in the future.


Subject(s)
ABO Blood-Group System/genetics , COVID-19/etiology , HLA Antigens/genetics , Receptors, CCR5/genetics , Adult , Aged , COVID-19/epidemiology , COVID-19/genetics , Female , Genetic Predisposition to Disease , Genotype , HLA-DRB1 Chains/genetics , Histocompatibility Antigens Class I/genetics , Humans , Immunoglobulin G/blood , Male , Middle Aged , Morbidity , Mutation , Severity of Illness Index
2.
Virus Res ; 286: 198040, 2020 09.
Article in English | MEDLINE | ID: covidwho-1328562

ABSTRACT

The interactions between chemokine receptors and their ligands may affect susceptibility to infectious diseases as well as their clinical manifestations. These interactions mediate both the traffic of inflammatory cells and virus-associated immune responses. In the context of viral infections, the human C-C chemokine receptor type 5 (CCR5) receives great attention from the scientific community due to its role as an HIV-1 co-receptor. The genetic variant CCR5Δ32 (32 base-pair deletion in CCR5 gene) impairs CCR5 expression on the cell surface and is associated with protection against HIV infection in homozygous individuals. Also, the genetic variant CCR5Δ32 modifies the CCR5-mediated inflammatory responses in various conditions, such as inflammatory and infectious diseases. CCR5 antagonists mimic, at least in part, the natural effects of the CCR5Δ32 in humans, which explains the growing interest in the potential benefits of using CCR5 modulators for the treatment of different diseases. Nevertheless, beyond HIV infection, understanding the effects of the CCR5Δ32 variant in multiple viral infections is essential to shed light on the potential effects of the CCR5 modulators from a broader perspective. In this context, this review discusses the involvement of CCR5 and the effects of the CCR5Δ32 in human infections caused by the following pathogens: West Nile virus, Influenza virus, Human papillomavirus, Hepatitis B virus, Hepatitis C virus, Poliovirus, Dengue virus, Human cytomegalovirus, Crimean-Congo hemorrhagic fever virus, Enterovirus, Japanese encephalitis virus, and Hantavirus. Subsequently, this review addresses the impacts of CCR5 gene editing and CCR5 modulation on health and viral diseases. Also, this article connects recent findings regarding extracellular vesicles (e.g., exosomes), viruses, and CCR5. Neglected and emerging topics in "CCR5 research" are briefly described, with focus on Rocio virus, Zika virus, Epstein-Barr virus, and Rhinovirus. Finally, the potential influence of CCR5 on the immune responses to coronaviruses is discussed.


Subject(s)
Flavivirus/pathogenicity , HIV Infections/immunology , Receptors, CCR5/genetics , Receptors, CCR5/immunology , Virus Diseases/immunology , Animals , Flavivirus/classification , Genetic Variation , Genotype , HIV-1 , Humans , Mice
3.
Int Immunopharmacol ; 98: 107825, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1318871

ABSTRACT

The chemokine receptor CCR5 has been implicated in COVID-19. CCR5 and its ligands are overexpressed in patients. The pharmacological targeting of CCR5 would improve the COVID-19 severity. We sought to investigate the role of the CCR5-Δ32 variant (rs333) in COVID-19. The CCR5-Δ32 was genotyped in 801 patients (353 in the intensive care unit, ICU) and 660 healthy controls, and the deletion was significantly less frequent in hospitalysed COVID-19 than in healthy controls (p = 0.01, OR = 0.66, 95%CI = 0.49-0.88). Of note, we did not find homozygotes among the patients, compared to 1% of the controls. The CCR5 transcript was measured in leukocytes from 85 patients and 40 controls. We found a significantly higher expression of the CCR5 transcript among the patients, with significant difference when comparing the non-deletion carriers (controls = 35; patients = 81; p = 0.01). ICU-patients showed non-significantly higher expression than no-ICU cases. Our study points to CCR5 as a genetic marker for COVID-19. The pharmacological targeting of CCR5 should be a promising treatment for COVID-19.


Subject(s)
COVID-19/genetics , Genetic Variation , Receptors, CCR5/genetics , SARS-CoV-2/pathogenicity , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/virology , Case-Control Studies , Female , Genetic Predisposition to Disease , Host-Pathogen Interactions , Humans , Intensive Care Units , Male , Middle Aged , Patient Admission , Phenotype , Risk Assessment , Risk Factors , Severity of Illness Index
4.
Sci Adv ; 7(25)2021 06.
Article in English | MEDLINE | ID: covidwho-1276874

ABSTRACT

The human CC chemokine receptor 5 (CCR5) is a G protein-coupled receptor (GPCR) that plays a major role in inflammation and is involved in cancer, HIV, and COVID-19. Despite its importance as a drug target, the molecular activation mechanism of CCR5, i.e., how chemokine agonists transduce the activation signal through the receptor, is yet unknown. Here, we report the cryo-EM structure of wild-type CCR5 in an active conformation bound to the chemokine super-agonist [6P4]CCL5 and the heterotrimeric Gi protein. The structure provides the rationale for the sequence-activity relation of agonist and antagonist chemokines. The N terminus of agonist chemokines pushes onto specific structural motifs at the bottom of the orthosteric pocket that activate the canonical GPCR microswitch network. This activation mechanism differs substantially from other CC chemokine receptors that bind chemokines with shorter N termini in a shallow binding mode involving unique sequence signatures and a specialized activation mechanism.


Subject(s)
Receptors, CCR5/chemistry , Receptors, CCR5/metabolism , Chemokine CCL5/chemistry , Chemokine CCL5/metabolism , Cryoelectron Microscopy , Humans , Models, Molecular , Molecular Dynamics Simulation , Protein Conformation , Receptors, CCR5/agonists , Receptors, CCR5/genetics , Signal Transduction , Structure-Activity Relationship
5.
Int J Mol Sci ; 22(10)2021 May 20.
Article in English | MEDLINE | ID: covidwho-1244036

ABSTRACT

Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (P ≤ 1 × 10-5) at the 3p21.31 locus in public GWAS datasets (6406 COVID-19 hospitalized patients and 902,088 controls) with gene expression data from 208 lung tissues, Hi-C, and Chip-seq data. Through whole exome sequencing (WES), we explored rare coding variants in 147 severe COVID-19 patients. We identified three SNPs (rs9845542, rs12639314, and rs35951367) associated with severe COVID-19 whose risk alleles correlated with low CCR5 expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with CCR5 gene in lung tissues and was confirmed to be associated with severe COVID-19 in two independent datasets. We also identified a rare coding variant (rs34418657) associated with the risk of developing severe COVID-19. Our results suggest a biological role of CCR5 in the progression of COVID-19 as common and rare genetic variants can increase the risk of developing severe COVID-19 by affecting the functions of CCR5.


Subject(s)
COVID-19/genetics , COVID-19/metabolism , Genetic Predisposition to Disease , Receptors, CCR5/genetics , Receptors, CCR5/metabolism , Alleles , Bronchi/metabolism , Bronchi/pathology , Bronchi/virology , COVID-19/physiopathology , Chromosomes, Human/genetics , Cohort Studies , Computational Biology , Databases, Genetic , Genome-Wide Association Study , Genotype , Humans , Lung/metabolism , Lung/pathology , Lung/virology , Polymorphism, Single Nucleotide , Whole Exome Sequencing
6.
Int J Infect Dis ; 105: 653-655, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1120241

ABSTRACT

OBJECTIVES: To determine the impact of the 32 bp deletion (CCR5Δ32) in the coding region of the C-C chemokine receptor 5 (CCR5) on the risk of contracting SARS-CoV-2 and severe COVID-19. METHODS: Cross-sectional study among stem cell donors registered with DKMS in Germany. Genetic information was linked to self-reported COVID-19 outcome data. Multivariable regression models were fitted to determine the risk of contracting SARS-CoV-2, severe respiratory tract infection (RTI) and respiratory hospitalization. RESULTS: CCR5 information was available for 110 544 donors who were tested at least once for SARS-CoV-2; 5536 reported SARS-CoV-2 infection. For 4758 donors, the COVID-19 disease course was fully evaluable; 498 reported no symptoms, 1227 described symptoms of severe respiratory tract infection, of whom 164 required respiratory hospitalization. The distribution of CCR5Δ32 genotypes (homozygous wild-type vs CCR5Δ32 present) did not differ significantly between individuals with or without SARS-CoV-2 infection (odds ratio (OR) 0.96, 95% CI 0.89-1.03, P = 0.21) nor between individuals with or without symptomatic infection (OR 1.13, 95% CI 0.88-1.45, P = 0.32), severe RTI (OR 1.03, 95% CI 0.88-1.22, P = 0.68) or respiratory hospitalization (OR 1.16, 95% CI 0.79-1.69, P = 0.45). CONCLUSIONS: Our data implicate that CCR5Δ32 mutations do not determine the risk of SARS-CoV-2 infections nor the disease course. TRIAL REGISTRATION: We registered the study with the German Center for Infection Research (https://dzif.clinicalsite.org/de/cat/2099/trial/4361).


Subject(s)
COVID-19/genetics , Receptors, CCR5/genetics , Sequence Deletion , Adolescent , Adult , COVID-19/physiopathology , Cross-Sectional Studies , Disease Progression , Female , Genotype , Germany , Hospitalization , Humans , Male , Middle Aged , Odds Ratio , Risk Factors , SARS-CoV-2 , Self Report , Young Adult
7.
Braz J Microbiol ; 51(4): 1711-1717, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-688814

ABSTRACT

Recent UNAIDS reports (December 2019) indicate that 37.9 million people have been affected by HIV infection around the globe in 2018, of which 1.7 million are cited as new infections. Human immunodeficiency virus-1 (HIV-1) requires both the CD4 receptor, as the primary receptor, and a chemokine co-receptor to gain entry into the cell. In addition to the WT allele for C-C motif chemokine receptor 5 (CCR5-wt), there is another allele with a 32 bp deletion in the protein coding region (CCR5-Δ32). Individuals who are homozygous for the mutant allele are resistant towards M-tropic HIV infections. In the current study, we aimed to determine the CCR5-Δ32 allele frequency in the Turkish Cypriot population with 326 subjects, 141 men (43.1%) and 185 (56.9%) women. The region of the CCR5 gene containing the Δ32 deletion was amplified using flanking primers. The CCR5 gene Δ32 allele frequency was calculated at 3% and only observed in heterozygous individuals. We hope that our current publication could be a point of dialog between the physicians, the government officials and the public set up a more modern and well-structured HIV screening program in an effort to control and hopefully eliminate HIV from the Turkish Cypriot population.


Subject(s)
Receptors, CCR5/genetics , /genetics , Alleles , Cyprus/ethnology , Female , Gene Frequency , Genetic Predisposition to Disease/ethnology , Genetic Predisposition to Disease/genetics , Genotype , HIV Infections/ethnology , HIV Infections/genetics , HIV-1 , Humans , Male , Mutation , Turkey/epidemiology
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