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Special Issue "Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2019)

Special Issue Editor

Guest Editor
Dr. Vera Rebmann

Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
Website | E-Mail
Interests: NK cell and tumor biology; allotransplantation; immune modulation of T and NK cells; extracellular vesicle; CMV; classical and non-classical HLA molecules; HLA-G; HLA-E; immune checkpoints

Special Issue Information

Dear Colleagues,

Human cytomegalovirus (CMV) is a ubiquitous DNA herpesvirus with a high prevalence. While primary infection usually causes mild symptoms in the healthy population, it can cause severe congenital malformation during pregnancy. Furthermore, life-threatening illnesses can occur upon CMV reactivation particularly in immunocompromised individuals (e.g., AIDS patients and transplant recipients). Recently, CMV has additionally been implicated as a potential co-factor in the pathogenesis of arteriosclerosis, immune senescence and in oncogenesis. Despite the availability of several antiviral agents, CMV remains one of the foremost hazards in the immunocompromised host and a major source of morbidity and sometimes mortality. Thus, the currently available therapeutic options are far from sufficient. Consequently, a great deal of current research is directed towards understanding the molecular biology of viral latency and immune evasion, including host innate and adaptive control of virus reactivation.

The Special Issue is now open to receive manuscripts on all aspects of CMV with particular emphasis on the immunocompromised host.

In this Special Issue, we welcome the submission of mini and full review, original research, short communications, as well as perspectives that cover, but are not limited to, the following topics:

  1. Mechanisms of protective immunity in acute infection
  2. Immunological evasion mechanisms of viral latency
  3. Contributions of specific immune effector cells and mediators of infection control
  4. Immunopathology of acute or latent infection
  5. Predisposing genetic host mechanism associated with CMV infection
  6. Vaccine approaches and new (immune) therapeutical strategies
  7. Mechanisms of innate immune system in the generation of specific immunity
  8. Biomarkers and immune surveillance strategies in CMV infection

Dr. Vera Rebmann
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • CMV 
  • immune evasion mechanisms 
  • immune surveillance mechanisms 
  • acute and latent CMV infection 
  • vaccine approaches 
  • biomarkers 
  • genetic predisposition 
  • innate mediators of infection control 
  • immunocompromised host 
  • animal models

Published Papers (16 papers)

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Research

Jump to: Review

Open AccessArticle
Between Innate and Adaptive Immune Responses: NKG2A, NKG2C, and CD8+ T Cell Recognition of HLA-E Restricted Self-Peptides Acquired in the Absence of HLA-Ia
Int. J. Mol. Sci. 2019, 20(6), 1454; https://doi.org/10.3390/ijms20061454
Received: 18 January 2019 / Revised: 15 March 2019 / Accepted: 19 March 2019 / Published: 22 March 2019
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Abstract
On healthy cells the non-classical HLA class Ib molecule HLA-E displays the cognate ligand for the NK cell receptor NKG2A/CD94 when bound to HLA class I signal peptide sequences. In a pathogenic situation when HLA class I is absent, HLA-E is bound to [...] Read more.
On healthy cells the non-classical HLA class Ib molecule HLA-E displays the cognate ligand for the NK cell receptor NKG2A/CD94 when bound to HLA class I signal peptide sequences. In a pathogenic situation when HLA class I is absent, HLA-E is bound to a diverse set of peptides and enables the stimulatory NKG2C/CD94 receptor to bind. The activation of CD8+ T cells by certain p:HLA-E complexes illustrates the dual role of this low polymorphic HLA molecule in innate and adaptive immunity. Recent studies revealed a shift in the HLA-E peptide repertoire in cells with defects in the peptide loading complex machinery. We recently showed that HLA-E presents a highly diverse set of peptides in the absence of HLA class Ia and revealed a non-protective feature against NK cell cytotoxicity mediated by these peptides. In the present study we have evaluated the molecular basis for the impaired NK cell inhibition by these peptides and determined the cell surface stability of individual p:HLA-E complexes and their binding efficiency to soluble NKG2A/CD94 or NKG2C/CD94 receptors. Additionally, we analyzed the recognition of these p:HLA-E epitopes by CD8+ T cells. We show that non-canonical peptides provide stable cell surface expression of HLA-E, and these p:HLA-E complexes still bind to NKG2/CD94 receptors in a peptide-restricted fashion. Furthermore, individual p:HLA-E complexes elicit activation of CD8+ T cells with an effector memory phenotype. These novel HLA-E epitopes provide new implications for therapies targeting cells with abnormal HLA class I expression. Full article
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Open AccessArticle
Robust Identification of Suitable T-Cell Subsets for Personalized CMV-Specific T-Cell Immunotherapy Using CD45RA and CD62L Microbeads
Int. J. Mol. Sci. 2019, 20(6), 1415; https://doi.org/10.3390/ijms20061415
Received: 28 February 2019 / Revised: 15 March 2019 / Accepted: 18 March 2019 / Published: 20 March 2019
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Abstract
Viral infections and reactivations remain a serious obstacle to successful hematopoietic stem cell transplantation (HSCT). When antiviral drug treatment fails, adoptive virus-specific T-cell transfer provides an effective alternative. Assuming that naive T cells (TN) are mainly responsible for GvHD, methods were [...] Read more.
Viral infections and reactivations remain a serious obstacle to successful hematopoietic stem cell transplantation (HSCT). When antiviral drug treatment fails, adoptive virus-specific T-cell transfer provides an effective alternative. Assuming that naive T cells (TN) are mainly responsible for GvHD, methods were developed to generate naive T-cell-depleted products while preserving immune memory against viral infections. We compared two major strategies to deplete potentially alloreactive T cells: CD45RA and CD62L depletion and analyzed phenotype and functionality of the resulting CD45RA/CD62L naive T-cell-depleted as well as CD45RA+/CD62L+ naive T-cell-enriched fractions in the CMV pp65 and IE1 antigen model. CD45RA depletion resulted in loss of terminally differentiated effector memory T cells re-expressing CD45RA (TEMRA), and CD62L depletion in loss of central memory T cells (TCM). Based on these differences in target cell-dependent and target cell-independent assays, antigen-specific T-cell responses in CD62L-depleted fraction were consistently 3–5 fold higher than those in CD45RA-depleted fraction. Interestingly, we also observed high donor variability in the CD45RA-depleted fraction, resulting in a substantial loss of immune memory. Accordingly, we identified donors with expected response (DER) and unexpected response (DUR). Taken together, our results showed that a naive T-cell depletion method should be chosen individually, based on the immunophenotypic composition of the T-cell populations present. Full article
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Open AccessCommunication
Efficacy of Valganciclovir Treatment Depends on the Severity of Hearing Dysfunction in Symptomatic Infants with Congenital Cytomegalovirus Infection
Int. J. Mol. Sci. 2019, 20(6), 1388; https://doi.org/10.3390/ijms20061388
Received: 30 January 2019 / Revised: 12 March 2019 / Accepted: 15 March 2019 / Published: 19 March 2019
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Abstract
Although earlier studies have shown that antiviral treatment regimens using valganciclovir (VGCV) improved hearing function in some infants with congenital cytomegalovirus (CMV) infection; its efficacy on the severity of hearing dysfunction is unclear. We conducted a prospective study among 26 infants with congenital [...] Read more.
Although earlier studies have shown that antiviral treatment regimens using valganciclovir (VGCV) improved hearing function in some infants with congenital cytomegalovirus (CMV) infection; its efficacy on the severity of hearing dysfunction is unclear. We conducted a prospective study among 26 infants with congenital CMV infections from 2009 to 2018. Oral VGCV (32 mg/kg/day) was administered for 6 weeks (November 2009 to June 2015; n = 20) or 6 months (July 2015 to March 2018, n = 6). Hearing function was evaluated by measuring the auditory brainstem response before VGCV treatment and at 6 months. Hearing dysfunction, defined as a V-wave threshold >40 dB, was categorized into: most severe, ≥91 dB; severe, 61–90 dB; and moderate, 41–60 dB. Hearing improvement was defined as a decrease of ≥20 dB from the pretreatment V-wave threshold. Of 52 ears in 26 infants with congenital CMV infection, 29 (56%) had hearing dysfunction, and of 29 ears, 16 (55%) improved after VGCV treatment. Although, 16 (84%) of 19 ears with moderate or severe hearing dysfunction improved after treatment (p < 0.001), 10 ears with the most severe form did not. In conclusion, VGCV treatment is effective in improving moderate and severe hearing dysfunction in infants with congenital CMV infection. Full article
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Open AccessCommunication
Association between CMV and Invasive Fungal Infections After Autologous Stem Cell Transplant in Lymphoproliferative Malignancies: Opportunistic Partnership or Cause-Effect Relationship?
Int. J. Mol. Sci. 2019, 20(6), 1373; https://doi.org/10.3390/ijms20061373
Received: 11 January 2019 / Revised: 11 March 2019 / Accepted: 14 March 2019 / Published: 19 March 2019
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Abstract
Unlike allogeneic transplant, autologous stem cell transplantation (ASCT) represents a procedure with a low-risk of cytomegalovirus (CMV) symptomatic reactivation-infection/end-organ disease (CMV complications) and invasive fungal disease (IFD). However, novel drugs for the treatment of lymphoproliferative malignancies could cause an increase of such opportunistic [...] Read more.
Unlike allogeneic transplant, autologous stem cell transplantation (ASCT) represents a procedure with a low-risk of cytomegalovirus (CMV) symptomatic reactivation-infection/end-organ disease (CMV complications) and invasive fungal disease (IFD). However, novel drugs for the treatment of lymphoproliferative malignancies could cause an increase of such opportunistic infections, even after ASCT. To the best of our knowledge, there are no published data demonstrating an association between CMV and IFD in the autologous setting, while this association has been widely reported in allogeneic transplantation. We have reviewed our series of 347 ASCT in myeloma and lymphoma patients performed over a period of 14 years with the aim of investigating the descriptive and analytical epidemiology of bacterial, CMV and IFD complications, focusing on the association between CMV and IFD. Patients with myeloma have significantly fewer bacterial infections and IFD than patients with lymphoma, but a similar rate of CMV complications. Descriptive epidemiological data are consistent with the literature, indicating an overall incidence of 36%, 3.5% and 15.5% for bacterial infections, IFD and CMV complications, with a case mortality rate of 4%, 16.7% and 3.7%, respectively. A strong correlation between CMV and IFD exists, with 8 cases of IFD out of a total of 12 presenting a CMV complication. At multivariate analysis, a diagnosis of lymphoma, ≥3 previous treatment lines and age ≥60 years were found to be independent risk factors for IFD. Duration of neutropenia (ANC < 500/mm3) ≥7 days represents an independent risk factor for CMV complications, where neutropenia most likely represents a crude surrogate biomarker indicating a deeper and longer state of overall immunosuppression. From our data we conclude that (1) myeloma patients are at lower risk of bacterial infections and IFD as compared with lymphoma patients but are at equal risk of CMV complications, most likely as a consequence of a selective impact of bortezomib on Herpes Viruses infection control; (2) a significant association exists between CMV and IFD, although a possible cause-effect relationship remains to be determined; (3) IFD is a rare complication after ASCT but burdened by a mortality rate of about 17%, with peak rates in older lymphoma patients who underwent more intensive therapeutic regimens. Full article
Open AccessArticle
Copy-Paste Mutagenesis: A Method for Large-Scale Alteration of Viral Genomes
Int. J. Mol. Sci. 2019, 20(4), 913; https://doi.org/10.3390/ijms20040913
Received: 28 January 2019 / Revised: 14 February 2019 / Accepted: 15 February 2019 / Published: 20 February 2019
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Abstract
The cloning of the large DNA genomes of herpesviruses, poxviruses, and baculoviruses as bacterial artificial chromosomes (BAC) in Escherichia coli has opened a new era in viral genetics. Several methods of lambda Red-mediated genome engineering (recombineering) in E. coli have been described, which [...] Read more.
The cloning of the large DNA genomes of herpesviruses, poxviruses, and baculoviruses as bacterial artificial chromosomes (BAC) in Escherichia coli has opened a new era in viral genetics. Several methods of lambda Red-mediated genome engineering (recombineering) in E. coli have been described, which are now commonly used to generate recombinant viral genomes. These methods are very efficient at introducing deletions, small insertions, and point mutations. Here we present Copy-Paste mutagenesis, an efficient and versatile strategy for scarless large-scale alteration of viral genomes. It combines gap repair and en passant mutagenesis procedures and relies on positive selection in all crucial steps. We demonstrate that this method can be used to generate chimeric strains of human cytomegalovirus (HCMV), the largest human DNA virus. Large (~15 kbp) genome fragments of HCMV strain TB40/E were tagged with an excisable marker and cloned (copied) in a low-copy plasmid vector by gap repair recombination. The cloned fragment was then excised and inserted (pasted) into the HCMV AD169 genome with subsequent scarless removal of the marker by en passant mutagenesis. We have done four consecutive rounds of this procedure, thereby generating an AD169-TB40/E chimera containing 60 kbp of the donor strain TB40/E. This procedure is highly useful for identifying gene variants responsible for phenotypic differences between viral strains. It can also be used for repair of incomplete viral genomes, and for modification of any BAC-cloned sequence. The method should also be applicable for large-scale alterations of bacterial genomes. Full article
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Open AccessArticle
hCMV-Mediated Immune Escape Mechanisms Favor Pathogen Growth and Disturb the Immune Privilege of the Eye
Int. J. Mol. Sci. 2019, 20(4), 858; https://doi.org/10.3390/ijms20040858
Received: 15 January 2019 / Revised: 5 February 2019 / Accepted: 12 February 2019 / Published: 16 February 2019
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Abstract
Human retinal pigment epithelial (hRPE) cells are important for the establishment and maintenance of the immune privilege of the eye. They function as target cells for human cytomegalovirus (hCMV), but are able to restrict viral replication. hCMV causes opportunistic posterior uveitis such as [...] Read more.
Human retinal pigment epithelial (hRPE) cells are important for the establishment and maintenance of the immune privilege of the eye. They function as target cells for human cytomegalovirus (hCMV), but are able to restrict viral replication. hCMV causes opportunistic posterior uveitis such as retinitis and chorioretinitis. Both mainly occur in severely immunocompromised patients and rarely manifest in immunocompetent individuals. In this study, hRPE cells were infected with hCMV in vitro and activated with proinflammatory cytokines. The enzymatic activities of indoleamine 2,3-dioxygenase-1 (IDO1) and inducible nitric oxide synthase (iNOS) were determined. The antimicrobial capacity of both molecules was analyzed in co-infection experiments using Staphylococcus aureus (S. aureus) and Toxoplasma gondii (T. gondii), causing uveitis in patients. We show that an hCMV infection of hRPE cells blocks IDO1 and iNOS mediated antimicrobial defense mechanisms necessary for the control of S. aureus and T. gondii. hCMV also inhibits immune suppressive effector mechanisms in hRPE. The interferon gamma-induced IDO1 dependent immune regulation was severely blocked, as detected by the loss of T cell inhibition. We conclude that an active hCMV infection in the eye might favor the replication of pathogens causing co-infections in immunosuppressed individuals. An hCMV caused blockade of IDO1 might weaken the eye’s immune privilege and favor the development of post-infectious autoimmune uveitis. Full article
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Open AccessArticle
Killer Immunoglobulin-Like Receptor 2DS2 (KIR2DS2), KIR2DL2-HLA-C1, and KIR2DL3 as Genetic Markers for Stratifying the Risk of Cytomegalovirus Infection in Kidney Transplant Recipients
Int. J. Mol. Sci. 2019, 20(3), 546; https://doi.org/10.3390/ijms20030546
Received: 18 December 2018 / Revised: 10 January 2019 / Accepted: 24 January 2019 / Published: 28 January 2019
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Abstract
Infection with cytomegalovirus (CMV) remains a major problem in kidney transplant recipients, resulting in serious infectious complications and occasionally mortality. Accumulating evidence indicates that natural killer cell immunoglobulin-like receptors (KIRs) and their ligands affect the susceptibility to various diseases, including viral infections (e.g., [...] Read more.
Infection with cytomegalovirus (CMV) remains a major problem in kidney transplant recipients, resulting in serious infectious complications and occasionally mortality. Accumulating evidence indicates that natural killer cell immunoglobulin-like receptors (KIRs) and their ligands affect the susceptibility to various diseases, including viral infections (e.g., CMV infection). We investigated whether KIR genes and their ligands affect the occurrence of CMV infection in a group of 138 kidney transplant recipients who were observed for 720 days posttransplantation. We typed the recipients for the presence of KIR genes (human leukocyte antigen C1 [HLA-C1], HLA-C2, HLA-A, HLA-B, and HLA-DR1) by polymerase chain reaction with sequence-specific primers. The multivariate analysis revealed that the lack of KIR2DS2 (p = 0.035), the presence of KIR2DL3 (p = 0.075), and the presence of KIR2DL2–HLA-C1 (p = 0.044) were risk factors for posttransplant CMV infection. We also found that a lower estimated glomerular filtration rate (p = 0.036), an earlier time of antiviral prophylaxis initiation (p = 0.025), lymphocytopenia (p = 0.012), and pretransplant serostatus (donor-positive/recipient-negative; p = 0.042) were independent risk factors for posttransplant CMV infection. In conclusion, our findings confirm that the KIR/HLA genotype plays a significant role in anti-CMV immunity and suggest the contribution of both environmental and genetic factors to the incidence of CMV infection after kidney transplantation. Full article
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Open AccessCommunication
CMV-Specific Immune Response—New Patients, New Insight: Central Role of Specific IgG during Infancy and Long-Lasting Immune Deficiency after Allogenic Stem Cell Transplantation
Int. J. Mol. Sci. 2019, 20(2), 271; https://doi.org/10.3390/ijms20020271
Received: 19 December 2018 / Revised: 2 January 2019 / Accepted: 3 January 2019 / Published: 11 January 2019
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Abstract
Although the existing paradigm states that cytomegalovirus (CMV) reactivation is under the control of the cellular immune response, the role of humoral and innate counterparts are underestimated. The study analyzed the host–virus interaction i.e., CMV-immune response evolution during infection in three different clinical [...] Read more.
Although the existing paradigm states that cytomegalovirus (CMV) reactivation is under the control of the cellular immune response, the role of humoral and innate counterparts are underestimated. The study analyzed the host–virus interaction i.e., CMV-immune response evolution during infection in three different clinical situations: (1) immunodeficient CMV-positive human leukocyte antigen (HLA)-matched bone marrow recipients after immunoablative conditioning as well as immunocompetent, (2) adult, and (3) infant with primary immune response. In the first situation, a fast and significant decrease of specific immunity was observed but reconstitution of marrow-derived B and natural killer (NK) cells was observed prior to thymic origin of T cells. The lowest CMV-IgG (93.2 RU/mL) was found just before CMV viremia. It is noteworthy that the sole and exclusive factor of CMV-specific immune response is a residual recipient antibody class IgG. The CMV-quantiferon increase was detected later, but in the first phase, phytohemagglutinin (PHA)-induced IFN-γ release was significantly lower than that of CMV-induced (“indeterminate” results). It corresponds with the increase of NK cells at the top of lymphocyte reconstitution and undetected CMV-specific CD8 cells using a pentamer technique. In immunocompetent adult (CMV-negative donor), the cellular and humoral immune response increased in a parallel manner, but symptoms of CMV mononucleosis persisted until the increase of specific IgG. During infancy, the decrease of the maternal CMV-IgG level to 89.08 RU/mL followed by clinical sequel, i.e., CMV replication, were described. My observations shed light on a unique host-CMV interaction and CMV-IgG role: they indicate that its significant decrease predicts CMV replication. Before primary cellular immune response development, the high level of residual CMV-IgG (about >100 R/mL) from mother or recipient prevents virus reactivation. The innate immune response and NK-dependent IFN-secretion should be further investigated. Full article
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Open AccessArticle
The Cytomegalovirus-Specific IL-21 ELISpot Correlates with Allograft Function of Kidney Transplant Recipients
Int. J. Mol. Sci. 2018, 19(12), 3945; https://doi.org/10.3390/ijms19123945
Received: 30 October 2018 / Revised: 5 December 2018 / Accepted: 5 December 2018 / Published: 8 December 2018
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Abstract
In kidney transplant recipients, the cytomegalovirus (CMV) is frequently causing infection/reactivation and can trigger allograft rejection. To assess the risk of reactivation, the cellular immune response against CMV is increasingly assessed by cellular in vitro methods, such as the interferon (IFN)-γ ELISpot. In [...] Read more.
In kidney transplant recipients, the cytomegalovirus (CMV) is frequently causing infection/reactivation and can trigger allograft rejection. To assess the risk of reactivation, the cellular immune response against CMV is increasingly assessed by cellular in vitro methods, such as the interferon (IFN)-γ ELISpot. In the current study we compared the IFN-γ ELISpot with our newly established CMV-specific ELISpot assays determining IL-17A, IL-21, IL-22, granzyme B, and perforin and correlated the results with flow cytometric data and clinical parameters. In 77 kidney transplant recipients, the highest frequency was observed for CMV pp65-specific cells secreting IFN-γ, followed by cells secreting IL-21 (62.9 and 23.2 Δ spot forming cells/105 cells). We observed a positive correlation between the percentage of CMV-specific CD3+ CD4+ CD154+ cells and results of the CMV-specific IL-21 ELISpot (p = 0.002). Results of the CMV pp65-specific IL-21 ELISpot correlated negatively with kidney function (estimated glomerular filtration rate, p = 0.006) and were significantly higher in women (p = 0.005). IL-21, a cytokine involved in aging that is secreted by activated CD4+ T cells, may also impact on allograft function. Thus, the CMV-specific IL-21 ELISpot could become a new tool to assess if CMV seropositivity represents a hazard for the graft. Full article
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Open AccessArticle
A Valine Mismatch at Position 129 of MICA Is an Independent Predictor of Cytomegalovirus Infection and Acute Kidney Rejection in Simultaneous Pancreas–Kidney Transplantation Recipients
Int. J. Mol. Sci. 2018, 19(9), 2618; https://doi.org/10.3390/ijms19092618
Received: 19 August 2018 / Revised: 30 August 2018 / Accepted: 31 August 2018 / Published: 4 September 2018
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Abstract
The polymorphic major histocompatibility complex class I chain-related molecule A (MICA) and its soluble form (sMICA) interact with activating receptor natural-killer group 2 member D (NKG2D) on natural-killer (NK) and T cells, thereby modifying immune responses to transplantation and infectious agents (e.g., cytomegalovirus). [...] Read more.
The polymorphic major histocompatibility complex class I chain-related molecule A (MICA) and its soluble form (sMICA) interact with activating receptor natural-killer group 2 member D (NKG2D) on natural-killer (NK) and T cells, thereby modifying immune responses to transplantation and infectious agents (e.g., cytomegalovirus). Two single-nucleotide polymorphisms (SNPs), rs2596538GA in the MICA promoter and rs1051792AG in the coding region (MICA-129Val/Met), influence MICA expression or binding to NKG2D, with MICA-129Met molecules showing higher receptor affinity. To investigate the impact of these SNPs on the occurrence of cytomegalovirus infection or acute rejection (AR) in individuals who underwent simultaneous pancreas–kidney transplantation (SPKT), 50 recipient-donor pairs were genotyped, and sMICA levels were measured during the first year post-transplantation. Recipients with a Val-mismatch (recipient Met/Met and donor Val/Met or Val/Val) showed shorter cytomegalovirus infection-free and shorter kidney AR-free survival. Additionally, Val mismatch was an independent predictor of cytomegalovirus infection and kidney AR in the first year post-transplantation. Interestingly, sMICA levels were lower in rs2596538AA and MICA129Met/Met-homozygous recipients. These results provide further evidence that genetic variants of MICA influence sMICA levels, and that Val mismatch at position 129 increases cytomegalovirus infection and kidney AR risk during the first year post-SPKT. Full article
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Review

Jump to: Research

Open AccessReview
Clinically Relevant Immune Responses against Cytomegalovirus: Implications for Precision Medicine
Int. J. Mol. Sci. 2019, 20(8), 1986; https://doi.org/10.3390/ijms20081986
Received: 2 March 2019 / Revised: 16 April 2019 / Accepted: 16 April 2019 / Published: 23 April 2019
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Abstract
Immune responses to human cytomegalovirus (CMV) can be used to assess immune fitness in an individual. Further to its clinical significance in posttransplantation settings, emerging clinical and translational studies provide examples of immune correlates of protection pertaining to anti-CMV immune responses in the [...] Read more.
Immune responses to human cytomegalovirus (CMV) can be used to assess immune fitness in an individual. Further to its clinical significance in posttransplantation settings, emerging clinical and translational studies provide examples of immune correlates of protection pertaining to anti-CMV immune responses in the context of cancer or infectious diseases, e.g., tuberculosis. In this viewpoint, we provide a brief overview about CMV-directed immune reactivity and immune fitness in a clinical context and incorporate some of our own findings obtained from peripheral blood or tumour-infiltrating lymphocytes (TIL) from patients with advanced cancer. Observations in patients with solid cancers whose lesions contain both CMV and tumour antigen-specific T-cell subsets are highlighted, due to a possible CMV-associated “bystander” effect in amplifying local inflammation and subsequent tumour rejection. The role of tumour-associated antibodies recognising diverse CMV-derived epitopes is also discussed in light of anti-cancer immune responses. We discuss here the use of anti-CMV immune responses as a theranostic tool—combining immunodiagnostics with a personalised therapeutic potential—to improve treatment outcomes in oncological indications. Full article
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Open AccessReview
Cellular Cullin RING Ubiquitin Ligases: Druggable Host Dependency Factors of Cytomegaloviruses
Int. J. Mol. Sci. 2019, 20(7), 1636; https://doi.org/10.3390/ijms20071636
Received: 15 March 2019 / Revised: 27 March 2019 / Accepted: 28 March 2019 / Published: 2 April 2019
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Abstract
Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that frequently causes morbidity and mortality in individuals with insufficient immunity, such as transplant recipients, AIDS patients, and congenitally infected newborns. Several antiviral drugs are approved to treat HCMV infections. However, resistant HCMV mutants can arise [...] Read more.
Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that frequently causes morbidity and mortality in individuals with insufficient immunity, such as transplant recipients, AIDS patients, and congenitally infected newborns. Several antiviral drugs are approved to treat HCMV infections. However, resistant HCMV mutants can arise in patients receiving long-term therapy. Additionally, side effects and the risk to cause birth defects limit the use of currently approved antivirals against HCMV. Therefore, the identification of new drug targets is of clinical relevance. Recent work identified DNA-damage binding protein 1 (DDB1) and the family of the cellular cullin (Cul) RING ubiquitin (Ub) ligases (CRLs) as host-derived factors that are relevant for the replication of human and mouse cytomegaloviruses. The first-in-class CRL inhibitory compound Pevonedistat (also called MLN4924) is currently under investigation as an anti-tumor drug in several clinical trials. Cytomegaloviruses exploit CRLs to regulate the abundance of viral proteins, and to induce the proteasomal degradation of host restriction factors involved in innate and intrinsic immunity. Accordingly, pharmacological blockade of CRL activity diminishes viral replication in cell culture. In this review, we summarize the current knowledge concerning the relevance of DDB1 and CRLs during cytomegalovirus replication and discuss chances and drawbacks of CRL inhibitory drugs as potential antiviral treatment against HCMV. Full article
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Open AccessReview
Human Vascular Pericytes and Cytomegalovirus Pathobiology
Int. J. Mol. Sci. 2019, 20(6), 1456; https://doi.org/10.3390/ijms20061456
Received: 3 February 2019 / Revised: 1 March 2019 / Accepted: 20 March 2019 / Published: 22 March 2019
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Abstract
Pericytes are multipotent cells of the vascular system with cytoplasmic extensions proximal to endothelial cells that occur along the abluminal surface of the endothelium. The interactions between endothelial cells and pericytes are essential for proper microvascular formation, development, stabilization, and maintenance. Pericytes are [...] Read more.
Pericytes are multipotent cells of the vascular system with cytoplasmic extensions proximal to endothelial cells that occur along the abluminal surface of the endothelium. The interactions between endothelial cells and pericytes are essential for proper microvascular formation, development, stabilization, and maintenance. Pericytes are essential for the regulation of paracellular flow between cells, transendothelial fluid transport, angiogenesis, and vascular immunosurveillance. They also influence the chemical composition of the surrounding microenvironment to protect endothelial cells from potential harm. Dysregulation or loss of pericyte function can result in microvascular instability and pathological consequences. Human pericytes have been shown to be targets for human cytomegalovirus (HCMV) infection and lytic replication that likely contribute to vascular inflammation. This review focuses on human vascular pericytes and their permissiveness for HCMV infection. It also discusses their implication in pathogenesis in the blood–brain barrier (BBB), the inner blood–retinal barrier (IBRB), the placenta–blood barrier, and the renal glomerulus as well as their potential role in subclinical vascular disease. Full article
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Open AccessReview
Role of Immunogenetics in the Outcome of HCMV Infection: Implications for Ageing
Int. J. Mol. Sci. 2019, 20(3), 685; https://doi.org/10.3390/ijms20030685
Received: 17 January 2019 / Revised: 31 January 2019 / Accepted: 1 February 2019 / Published: 5 February 2019
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Abstract
The outcome of host-virus interactions is determined by a number of factors, some related to the virus, others to the host, such as environmental factors and genetic factors. Therefore, different individuals vary in their relative susceptibility to infections. Human cytomegalovirus (HCMV) is an [...] Read more.
The outcome of host-virus interactions is determined by a number of factors, some related to the virus, others to the host, such as environmental factors and genetic factors. Therefore, different individuals vary in their relative susceptibility to infections. Human cytomegalovirus (HCMV) is an important pathogen from a clinical point of view, as it causes significant morbidity and mortality in immunosuppressed or immunosenescent individuals, such as the transplanted patients and the elderly, respectively. It is, therefore, important to understand the mechanisms of virus infection control. In this review, we discuss recent advances in the immunobiology of HCMV-host interactions, with particular emphasis on the immunogenetic aspects (human leukocyte antigens, HLA; killer cell immunoglobulin-like receptors, KIRs; immunoglobulin genetic markers, GM allotypes) to elucidate the mechanisms underlying the complex host-virus interaction that determine various outcomes of HCMV infection. The results, which show the role of humoral and cellular immunity in the control of infection by HCMV, would be valuable in directing efforts to reduce HCMV spurred health complications in the transplanted patients and in the elderly, including immunosenescence. In addition, concerning GM allotypes, it is intriguing that, in a Southern Italian population, alleles associated with the risk of developing HCMV symptomatic infection are negatively associated with longevity. Full article
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Open AccessReview
A Native Human Monoclonal Antibody Targeting HCMV gB (AD-2 Site I)
Int. J. Mol. Sci. 2018, 19(12), 3982; https://doi.org/10.3390/ijms19123982
Received: 11 November 2018 / Revised: 4 December 2018 / Accepted: 8 December 2018 / Published: 11 December 2018
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Abstract
Hyperimmune globulin (HIG) has shown efficacy against human cytomegalovirus (HCMV) for both transplant and congenital transmission indications. Replicating that activity with a monoclonal antibody (mAb) offers the potential for improved consistency in manufacturing, lower infusion volume, and improved pharmacokinetics, as well as reduced [...] Read more.
Hyperimmune globulin (HIG) has shown efficacy against human cytomegalovirus (HCMV) for both transplant and congenital transmission indications. Replicating that activity with a monoclonal antibody (mAb) offers the potential for improved consistency in manufacturing, lower infusion volume, and improved pharmacokinetics, as well as reduced risk of off-target reactivity leading to toxicity. HCMV pathology is linked to its broad cell tropism. The glycoprotein B (gB) envelope protein is important for infections in all cell types. Within gB, the antigenic determinant (AD)-2 Site I is qualitatively more highly-conserved than any other region of the virus. TRL345, a high affinity (Kd = 50 pM) native human mAb to this site, has shown efficacy in neutralizing the infection of fibroblasts, endothelial and epithelial cells, as well as specialized placental cells including trophoblast progenitor cells. It has also been shown to block the infection of placental fragments grown ex vivo, and to reduce syncytial spread in fibroblasts in vitro. Manufacturing and toxicology preparation for filing an IND (investigational new drug) application with the US Food and Drug Administration (FDA) are expected to be completed in mid-2019. Full article
Open AccessReview
Potential Biomarkers for Predicting Congenital Cytomegalovirus Infection
Int. J. Mol. Sci. 2018, 19(12), 3760; https://doi.org/10.3390/ijms19123760
Received: 17 October 2018 / Revised: 22 November 2018 / Accepted: 23 November 2018 / Published: 27 November 2018
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Abstract
Early diagnosis and treatment of infants with symptomatic congenital cytomegalovirus (CMV) infection may improve neurological outcomes. For this reason, prenatal detection of newborns at high risk for congenital CMV infection is important. A polymerase chain reaction (PCR) assay for CMV DNA in the [...] Read more.
Early diagnosis and treatment of infants with symptomatic congenital cytomegalovirus (CMV) infection may improve neurological outcomes. For this reason, prenatal detection of newborns at high risk for congenital CMV infection is important. A polymerase chain reaction (PCR) assay for CMV DNA in the amniotic fluid is the gold standard for the diagnosis of intrauterine CMV infection; however, amniocentesis is an invasive procedure. Recently, we have found that the presence of CMV DNA in the maternal uterine cervical secretion is predictive of the occurrence of congenital CMV infection in CMV immunoglobulin M (IgM)-positive pregnant women. In contrast, we have suggested that maternal serological screening for primary CMV infection using CMV-specific immunoglobulin G (IgG), the IgG avidity index, or CMV-specific IgM overlooks a number of newborns with congenital CMV infection. We will review current knowledge of the potential biomarkers for predicting congenital CMV infection. Full article
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Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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