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Journal of Neuro-ophthalmology : the... Jun 2024
Topics: Humans; Optic Neuritis; Cytomegalovirus Infections; Cytomegalovirus; Immunocompetence; Male; Female; Magnetic Resonance Imaging; Eye Infections, Viral
PubMed: 38741247
DOI: 10.1097/WNO.0000000000001834 -
Frontiers in Immunology 2024Polymorphisms in the KIR and HLA genes contribute to the diversity of the NK cell repertoire. Extrinsic factors also play a role in modifying this repertoire. The best...
INTRODUCTION
Polymorphisms in the KIR and HLA genes contribute to the diversity of the NK cell repertoire. Extrinsic factors also play a role in modifying this repertoire. The best example is cytomegalovirus, which promotes the expansion of memory-like NK cells. However, the mechanisms governing this phenotypic structure are poorly understood. Furthermore, the influence of age and sex has been understudied.
METHODS
In this study, we examined these parameters in a cohort of 200 healthy volunteer blood donors, focusing on the major inhibitory KIR receptors and CD94/NKG2A, as well as the differentiation marker CD57 and the memory-like population marker NKG2C. Flow cytometry and two joint analyses, unsupervised and semi-supervised, helped define the impact of various intrinsic and extrinsic markers on the phenotypic structure of the NK cell repertoire.
RESULTS
In the KIR NK cell compartment, the KIR3DL1 gene is crucial, as unexpressed alleles lead to a repertoire dominated by KIR2D interacting only with HLA-C ligands, whereas an expressed KIR3DL1 gene allows for a greater diversity of NK cell subpopulations interacting with all HLA class I ligands. KIR2DL2 subsequently favors the KIR2D NK cell repertoire specific to C1/C2 ligands, whereas its absence promotes the expression of KIR2DL1 specific to the C2 ligand. The C2C2Bw4+ environment, marked by strong -21T motifs, favors the expansion of the NK cell population expressing only CD57, whereas the absence of HLA-A3/A11 ligands favors the population expressing only NKG2A, a population highly represented within the repertoire. The AA KIR genotype favors NK cell populations without KIR and NKG2A receptors, whereas the KIR B+ genotypes favor populations expressing KIR and NKG2A. Interestingly, we showed that women have a repertoire enriched in CD57- NK cell populations, while men have more CD57+ NK cell subpopulations.
DISCUSSION
Overall, our data demonstrate that the phenotypic structure of the NK cell repertoire follows well-defined genetic rules and that immunological history, sex, and age contribute to shaping this NK cell diversity. These elements can contribute to the better selection of hematopoietic stem cell donors and the definition of allogeneic NK cells for cell engineering in NK cell-based immunotherapy approaches.cters are displayed correctly.
Topics: Humans; Killer Cells, Natural; Female; Male; Adult; Cytomegalovirus Infections; Cytomegalovirus; Genotype; Receptors, KIR; Middle Aged; Sex Factors; Age Factors; CD57 Antigens; Histocompatibility Testing; Young Adult; NK Cell Lectin-Like Receptor Subfamily C; HLA Antigens; Aged; Receptors, KIR3DL1
PubMed: 38736873
DOI: 10.3389/fimmu.2024.1389358 -
Science Advances May 2024The nonpolymorphic major histocompatibility complex E (MHC-E) molecule is up-regulated on many cancer cells, thus contributing to immune evasion by engaging inhibitory...
The nonpolymorphic major histocompatibility complex E (MHC-E) molecule is up-regulated on many cancer cells, thus contributing to immune evasion by engaging inhibitory NKG2A/CD94 receptors on NK cells and tumor-infiltrating T cells. To investigate whether MHC-E expression by cancer cells can be targeted for MHC-E-restricted T cell control, we immunized rhesus macaques (RM) with rhesus cytomegalovirus (RhCMV) vectors genetically programmed to elicit MHC-E-restricted CD8 T cells and to express established tumor-associated antigens (TAAs) including prostatic acidic phosphatase (PAP), Wilms tumor-1 protein, or Mesothelin. T cell responses to all three tumor antigens were comparable to viral antigen-specific responses with respect to frequency, duration, phenotype, epitope density, and MHC restriction. Thus, CMV-vectored cancer vaccines can bypass central tolerance by eliciting T cells to noncanonical epitopes. We further demonstrate that PAP-specific, MHC-E-restricted CD8 T cells from RhCMV/PAP-immunized RM respond to PAP-expressing HLA-E prostate cancer cells, suggesting that the HLA-E/NKG2A immune checkpoint can be exploited for CD8 T cell-based immunotherapies.
Topics: Animals; CD8-Positive T-Lymphocytes; Histocompatibility Antigens Class I; Macaca mulatta; Antigens, Neoplasm; HLA-E Antigens; Humans; Cancer Vaccines; Antigen Presentation; Cell Line, Tumor; Male; Cytomegalovirus; Mesothelin; Acid Phosphatase
PubMed: 38728394
DOI: 10.1126/sciadv.adm7515 -
Cells Apr 2024Assessing immune responses to cytomegalovirus (CMV) after liver transplant in patients on immunosuppressive therapy remains challenging. In this study, employing ELISPOT...
Assessing immune responses to cytomegalovirus (CMV) after liver transplant in patients on immunosuppressive therapy remains challenging. In this study, employing ELISPOT assays, 52 liver-transplant recipients were evaluated for antiviral T-cell activity in peripheral blood mononuclear cells (PBMCs), measuring interferon-γ (IFN-γ) secretion upon stimulation with CMV-specific peptides (CMV peptide pool, CMV IE-1, and pp65 antigens). Parameters such as stimulation index, mean spot size, and mean spot count were measured. The study found that heightened immunosuppression, especially with prednisolone in triple therapy, significantly dampened CMV-specific immune responses. This was demonstrated by decreased IFN-γ production by CMV-specific T-cells (CMV peptide pool: = 0.036; OR = 0.065 [95% CI: 0.005-0.840], pp65 antigen: = 0.026; OR = 0.048 [95% CI: 0.003-0.699]). Increased immunosuppression correlated with reduced IFN-γ secretion per cell, reflected in smaller mean spot sizes for the CMV peptide pool ( = 0.019). Notably, shorter post-transplant intervals correlated with diminished antiviral T-cell IFN-γ release at two years (CMV peptide pool: = 0.019; IE antigen: = 0.010) and five years (CMV peptide pool: = 0.0001; IE antigen: = 0.002; pp65 antigen: = 0.047), as did advancing age (pp65 antigen: = 0.016, OR = 0.932, 95% CI: 0.881-0.987). Patients with undetectable CMV antigens had a notably higher risk of CMV reactivation within six months from blood collection, closely linked with triple immunosuppression and prednisolone use. These findings highlight the intricate interplay between immunosuppression, immune response dynamics, and CMV reactivation risk, emphasizing the necessity for tailored immunosuppressive strategies to mitigate CMV reactivation in liver-transplant recipients. It can be concluded that, particularly in the early months post-transplantation, the use of prednisolone as a third immunosuppressant should be critically reconsidered. Additionally, the use of prophylactic antiviral therapy effective against CMV in this context holds significant importance.
Topics: Humans; Liver Transplantation; Cytomegalovirus; Male; Female; Enzyme-Linked Immunospot Assay; Middle Aged; Immunocompromised Host; Cytomegalovirus Infections; T-Lymphocytes; Interferon-gamma; Aged; Adult; Immunosuppressive Agents; Immunosuppression Therapy
PubMed: 38727277
DOI: 10.3390/cells13090741 -
Scientific Reports May 2024Herpesviruses are large double-stranded DNA viruses that cause infections in animals and humans with a characteristic of latent infectious within specific tissues. Bats...
Herpesviruses are large double-stranded DNA viruses that cause infections in animals and humans with a characteristic of latent infectious within specific tissues. Bats are natural hosts of variety human-infecting viruses and recently have been described as hosts for herpesviruses in several countries around the world. In this study we collected 140 insectivorous bats in the neighboring urban areas of Wuhan City, Hubei Province in the central China between 2020 and 2021. Nested PCR targeting the dpol gene sequence indicated that a total of 22 individuals (15.7% of the sample) tested positive for herpesvirus with 4 strains belonging to the genus Betaherpesvirus and the remaining 18 strains classified as Gammahersvirus. Furthermore, the herpesvirus prevalence in Rhinolophus pusillus was higher at 26.3%, compared to 8.4% in Myotis davidii. The RP701 strain from R. pusillus was the predominant gammaherpesvirus strain detected in bats, accounting for 94.4% (17/18) of all strains. The variations in γ-herpesviruses genomic sequences was evident in phylogenetic tree, where RP701 strain was clustered together with ruminant γ-herpesviruses, while MD704 strain formed a distinct clade with a hedgehog γ-herpesvirus. Four betaherpesviruses exclusively identified from M. davidii, with nucleotide identities ranging from 79.7 to 82.6% compared to known betaherpesviruses. Our study provided evidence that M. davidii can sever as natural host for β-herpesviruses, which extended the host species range. In conclusion, we found that bats from central China harbored novel β-herpesviruses and γ-herpesviruses which were phylogenetically related to ruminant γ-herpesvirus and hedgehog γ-herpesvirus. Our study indicates that bats are natural hosts of β- and γ-herpesviruses and further studies are needed to determine whether there is cross-species transmission of herpesviruses between bats and other animals, or humans.
Topics: Animals; Chiroptera; China; Gammaherpesvirinae; Phylogeny; Betaherpesvirinae; Herpesviridae Infections; Genome, Viral; DNA, Viral
PubMed: 38724545
DOI: 10.1038/s41598-024-61290-1 -
Ugeskrift For Laeger Apr 2024Cytomegalovirus infection (CMV) can be fatal for organ transplant recipients as shown in this case report. Maribavir is a recently approved drug, which can be used for...
Cytomegalovirus infection (CMV) can be fatal for organ transplant recipients as shown in this case report. Maribavir is a recently approved drug, which can be used for therapy-refractory CMV infection or when other treatment options cannot be used. The patient in this case report was a CMV-infected liver transplant recipient, who developed a severe erythema and high CMV DNA during valganciclovir therapy. Toxic epidermal necrolysis was suspected. The patient was treated with maribavir, and both CMV DNA and the skin normalised. This case illustrates that maribavir is a useful alternative to other antiviral drugs for CMV infection.
Topics: Humans; Cytomegalovirus Infections; Liver Transplantation; Antiviral Agents; Ribonucleosides; Benzimidazoles; Male; Middle Aged; Cytomegalovirus; Dichlororibofuranosylbenzimidazole
PubMed: 38708697
DOI: 10.61409/V11230726 -
Scientific Reports May 2024The tegument protein pp150 of Human Cytomegalovirus (HCMV) is known to be essential for the final stages of virus maturation and mediates its functions by interacting...
The tegument protein pp150 of Human Cytomegalovirus (HCMV) is known to be essential for the final stages of virus maturation and mediates its functions by interacting with capsid proteins. Our laboratory has previously identified the critical regions in pp150 important for pp150-capsid interactions and designed peptides similar in sequence to these regions, with a goal to competitively inhibit capsid maturation. Treatment with a specific peptide (PepCR2 or P10) targeted to pp150 conserved region 2 led to a significant reduction in murine CMV (MCMV) growth in cell culture, paving the way for in vivo testing in a mouse model of CMV infection. However, the general pharmacokinetic parameters of peptides, including rapid degradation and limited tissue and cell membrane permeability, pose a challenge to their successful use in vivo. Therefore, we designed a biopolymer-stabilized elastin-like polypeptide (ELP) fusion construct (ELP-P10) to enhance the bioavailability of P10. Antiviral efficacy and cytotoxic effects of ELP-P10 were studied in cell culture, and pharmacokinetics, biodistribution, and antiviral efficacy were studied in a mouse model of CMV infection. ELP-P10 maintained significant antiviral activity in cell culture, and this conjugation significantly enhanced P10 bioavailability in mouse tissues. The fluorescently labeled ELP-P10 accumulated to higher levels in mouse liver and kidneys as compared to the unconjugated P10. Moreover, viral titers from vital organs of MCMV-infected mice indicated a significant reduction of virus load upon ELP-P10 treatment. Therefore, ELP-P10 has the potential to be developed into an effective antiviral against CMV infection.
Topics: Animals; Elastin; Cytomegalovirus Infections; Mice; Antiviral Agents; Peptides; Muromegalovirus; Humans; Capsid Proteins; Cytomegalovirus; Capsid; Recombinant Fusion Proteins; Disease Models, Animal; Elastin-Like Polypeptides; Phosphoproteins; Viral Matrix Proteins
PubMed: 38704431
DOI: 10.1038/s41598-024-60691-6 -
The New Microbiologica May 2024Monitoring Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection after transplantation is recommended to enable preemptive therapy. However, the most suitable... (Comparative Study)
Comparative Study
Monitoring Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection after transplantation is recommended to enable preemptive therapy. However, the most suitable sample type remains unclear. Patients who underwent hematopoietic stem cell or liver transplantation were included in this study. Viral loads in sequential whole-blood and plasma samples were retrospectively analyzed. EBV DNA was detected more frequently in whole blood (55%) than in plasma (18%). The detection rate of CMV DNA was similar between the two sample types. The correlation of viral loads between the two sample types were 0.515 and 0.688 for EBV and CMV, respectively. Among paired samples in which EBV DNA was detected in whole blood, the plasma EBV detection rate was significantly higher in patients who underwent hematopoietic stem cell transplantation than in those who underwent liver transplantation. The viral DNA load in whole blood and plasma showed similar trends. The EBV detection rate was higher in whole blood, and a high correlation was observed between CMV DNA loads and whole blood and plasma. These results indicate that whole blood is more sensitive for monitoring both EBV and CMV, whereas plasma is a potential alternative sample for monitoring CMV.
Topics: Humans; Cytomegalovirus; Cytomegalovirus Infections; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Male; Female; Middle Aged; Adult; Viral Load; Retrospective Studies; DNA, Viral; Young Adult; Hematopoietic Stem Cell Transplantation; Aged; Plasma; Liver Transplantation; Adolescent
PubMed: 38700884
DOI: No ID Found -
Biological & Pharmaceutical Bulletin 2024The human herpesviruses (HHVs) are classified into the following three subfamilies: Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae. These HHVs have... (Review)
Review
The human herpesviruses (HHVs) are classified into the following three subfamilies: Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae. These HHVs have distinct pathological features, while containing a highly conserved viral replication pathway. Among HHVs, the basic viral particle structure and the sequential processes of viral replication are nearly identical. In particular, the capsid formation mechanism has been proposed to be highly similar among herpesviruses, because the viral capsid-organizing proteins are highly conserved at the structural and functional levels. Herpesviruses form capsids containing the viral genome in the nucleus of infected cells during the lytic phase, and release infectious virus (i.e., virions) to the cell exterior. In the capsid formation process, a single-unit-length viral genome is encapsidated into a preformed capsid. The single-unit-length viral genome is produced by cleavage from a viral genome precursor in which multiple unit-length viral genomes are tandemly linked. This encapsidation and cleavage is carried out by the terminase complex, which is composed of viral proteins. Since the terminase complex-mediated encapsidation and cleavage is a virus-specific mechanism that does not exist in humans, it may be an excellent inhibitory target for anti-viral drugs with high virus specificity. This review provides an overview of the functions of the terminase complexes of HHVs.
Topics: Humans; Herpesviridae; Endodeoxyribonucleases; Viral Proteins; Animals; Genome, Viral; Capsid; Virus Replication
PubMed: 38692868
DOI: 10.1248/bpb.b23-00717 -
Archives of Iranian Medicine May 2024Human cytomegalovirus (HCMV) is classified within the order and is prevalent in 50%‒80% of the general population. Most carriers experience this infection without... (Review)
Review
Human cytomegalovirus (HCMV) is classified within the order and is prevalent in 50%‒80% of the general population. Most carriers experience this infection without noticeable clinical symptoms. HCMV causes a lifelong latent infection that can be reactivated due to immune disorders and inflammation. The reactivation of HCMV becomes particularly significant when it coincides with inflammatory bowel disease (IBD). While cytomegalovirus (CMV) colitis in IBD patients was identified years ago, the role of CMV in triggering flare-ups, acute severe colitis, treatment resistance, and other outcomes in IBD patients experiencing CMV reactivation remains a subject of ongoing debate. In this review, we aim to address an updated insight into aspects related to the CMV colitis in IBD patients including epidemiology, risk factors, clinical features, diagnostic tests, histology, place of immunosuppressants and indications for antiviral treatment. We suggest for personalized and thorough assessment based on the disease phase and colitis severity when prescribing drugs to these patients. Furthermore, we emphasize the importance of regular patient follow-up to monitor drug side effects, ensuring treatment success, and minimizing the risk of colectomy.
Topics: Humans; Cytomegalovirus Infections; Inflammatory Bowel Diseases; Antiviral Agents; Risk Factors; Cytomegalovirus; Immunosuppressive Agents; Adult; Colitis
PubMed: 38690795
DOI: 10.34172/aim.2024.40