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Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 13289

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Special Issue Editor

Dr. Vera Rebmann

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Guest Editor

Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
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 Issues, Collections and Topics in MDPI journals

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:

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

Dr. Vera Rebmann
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 (6 papers)

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Research

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22 pages, 16206 KiB

Open AccessArticle

Cyclin-Dependent Kinases (CDKs) and the Human Cytomegalovirus-Encoded CDK Ortholog pUL97 Represent Highly Attractive Targets for Synergistic Drug Combinations

by Markus Wild, Friedrich Hahn, Nadine Brückner, Martin Schütz, Christina Wangen, Sabrina Wagner, Mona Sommerer, Stefan Strobl and Manfred Marschall

Int. J. Mol. Sci. 2022, 23(5), 2493; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052493 - 24 Feb 2022

Cited by 11 | Viewed by 1839

Abstract

Human cytomegalovirus (HCMV) is a pathogenic human herpesvirus associated with serious, potentially life-threatening symptoms in the immunocompromised or immunonaïve host. The limitations encountered by antiviral therapy options currently available include a narrow panel of accessible targets, the induction of viral drug resistance as well as severe drug dosage-mediated side-effects. Improved drug-targeting strategies to resolve these issues are the focus of our investigations. In particular, pharmaceutical kinase inhibitors (PKIs), either directed to host kinases or directed to the viral protein kinase pUL97, have been considered to overcome these restrictions. Recently, we reported the identification of a synergistic combination of two PKIs directed to host cyclin-dependent kinase 7 (CDK7) and viral CDK ortholog pUL97. Here, we substantiate these findings with the following results: (i) true drug synergy was exhibited by various chemical classes of PKI pairs directed to pUL97 and CDK7; (ii) no putative amplification of cytotoxicity by these drug combinations was observed; (iii) a reduction in drug dosage levels for synergistic combinations was defined on a quantitative basis and compared to monotreatments; (iv) the quantities of target proteins CDK7 and pUL97 expressed in HCMV-infected cells were assessed by confocal imaging, indicating a strong down-modulation of CDK7 levels as a result of synergistic drug treatment; (v) the functional importance of these target kinases, both binding to cyclin H, was illustrated by assessing HCMV replication under the viral genomic deletion of ORF-UL97 or cellular cyclin knock-out; (vi) new combinations of HCMV-specific drug synergy were demonstrated for solely host-directed treatments using PKIs against CDK2, CDK7, CDK8 and/or CDK9 and (vii) a triple PKI combination provided further support for the synergy approach. With these combined findings, this study highlights the potential of therapeutic drug combinations of approved, developmental and preclinical PKIs for expanding future options for anti-HCMV therapy. Full article

(This article belongs to the Special Issue Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 3.0)

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12 pages, 3284 KiB

Open AccessArticle

Common T-Cell-Receptor Motifs and Features in Patients with Cytomegalovirus (CMV)-Seronegative End-Stage Renal Disease Receiving a Peptide Vaccination against CMV

by Lukas Bunse, Claudia Sommerer, Chin Leng Tan, Felix Korell, Anita Schmitt, Angela Hückelhoven-Krauss, Brigitte Neuber, Thomas Mertens, Michael Platten, Edward W. Green, Martin Zeier and Michael Schmitt

Int. J. Mol. Sci. 2022, 23(3), 1029; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031029 - 18 Jan 2022

Cited by 1 | Viewed by 2162

Abstract

After solid-organ transplantation, reactivation of the cytomegalovirus (CMV) is often observed in seronegative patients and associated with a high risk of disease and mortality. CMV-specific T cells can prevent CMV reactivation. In a phase 1 trial, CMV-seronegative patients with end-stage renal disease listed for kidney transplantation were subjected to CMV phosphoprotein 65 (CMVpp65) peptide vaccination and further investigated for T-cell responses. To this end, CMV-specific CD8⁺ T cells were characterized by bulk T-cell-receptor (TCR) repertoire sequencing and combined single-cell RNA and TCR sequencing. In patients mounting an immune response to the vaccine, a common SYE(N)E TCR motif known to bind CMVpp65 was detected. CMV-peptide-vaccination-responder patients had TCR features distinct from those of non-responders. In a non-responder patient, a monoclonal inflammatory T-cell response was detected upon CMV reactivation. The identification of vaccine-induced CMV-reactive TCRs motifs might facilitate the development of cellular therapies for patients wait-listed for kidney transplantation. Full article

(This article belongs to the Special Issue Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 3.0)

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12 pages, 1454 KiB

Open AccessArticle

Analysis and Fine Specificity of the HCMV-Specific Cell-Free and Cell-Associated Antibody-Dependent Cellular Phagocytosis (ADCP) Responses in Lung Transplant Recipients

by Simone Eberhard, Hannes Vietzen, Irene Görzer, Peter Jaksch and Elisabeth Puchhammer-Stöckl

Int. J. Mol. Sci. 2021, 22(15), 8206; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158206 - 30 Jul 2021

Cited by 3 | Viewed by 1772

Abstract

Human Cytomegalovirus (HCMV) may cause severe infections in transplant recipients. HCMV-replication can be limited by HCMV-specific antibody responses. The impact of the antibody-dependent cellular phagocytosis (ADCP) on inhibition of HCMV-replication in natural infections has not been clarified. Therefore, we investigated the HCMV-specific ADCP response in a study cohort of lung-transplant recipients (LTRs) with different donor (D) and recipient (R) HCMV-serostatus. Follow-up plasma samples from 39 non/low-viremic and 36 highly viremic (>1000 HCMV copies/mL plasma) LTRs were collected for one (R+ LTRs) or two (D+/R− LTRs) years post-transplantation. The HCMV-specific ADCP responses were assessed by focal expansion assays (FEA) and flow-cytometry. In all LTRs, ADCP responses were detected against HCMV-infected cells and cell-free virions. When measured in fibroblasts as well as with cell-free virus, the HCMV-specific ADPC response was higher in LTRs than in HCMV-seropositive healthy controls. In D+/R− LTRs, a significant ADCP response developed over time after the receipt of an HCMV positive lung, and a level of <19 IE⁺ cells/focus in the FEA on fibroblasts was associated with further protection from high-level viremia. Taken together, a strong HCMV-specific ADCP response is elicited in transplant recipients, which may contribute to protection from high-level viremia in primary HCMV infection. Full article

(This article belongs to the Special Issue Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 3.0)

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17 pages, 7056 KiB

Open AccessArticle

The Role of Caspase-12 in Retinal Bystander Cell Death and Innate Immune Responses against MCMV Retinitis

by Xinyan Zhang, Jinxian Xu, Brendan Marshall, Zheng Dong, Sylvia B. Smith and Ming Zhang

Int. J. Mol. Sci. 2021, 22(15), 8135; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158135 - 29 Jul 2021

Cited by 2 | Viewed by 1538

Abstract

(1) Background: caspase-12 is activated during cytomegalovirus retinitis, although its role is presently unclear. (2) Methods: caspase-12^−/− (KO) or caspase-12^+/+ (WT) mice were immunosup eyes were analyzed by plaque assay, TUNEL assay, immunohistochemical staining, western blotting, and real-time PCR. (3) Results: increased retinitis and a more extensive virus spread were detected in the retina of infected eyes of KO mice compared to WT mice at day 14 p.i. Compared to MCMV injected WT eyes, mRNA levels of interferons α, β and γ were significantly reduced in the neural retina of MCMV-infected KO eyes at day 14 p.i. Although similar numbers of MCMV infected cells, similar virus titers and similar numbers of TUNEL-staining cells were detected in injected eyes of both KO and WT mice at days 7 and 10 p.i., significantly lower amounts of cleaved caspase-3 and p53 protein were detected in infected eyes of KO mice at both time points. (4) Conclusions: caspase-12 contributes to caspase-3-dependent and independent retinal bystander cell death during MCMV retinitis and may also play an important role in innate immunity against virus infection of the retina. Full article

(This article belongs to the Special Issue Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 3.0)

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Review

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12 pages, 978 KiB

Open AccessReview

The Current Challenges in Developing Biological and Clinical Predictors of Congenital Cytomegalovirus Infection

by Kenji Tanimura, Akiko Uchida, Hitomi Imafuku, Shinya Tairaku, Kazumichi Fujioka, Ichiro Morioka and Hideto Yamada

Int. J. Mol. Sci. 2021, 22(24), 13487; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413487 - 15 Dec 2021

Cited by 3 | Viewed by 2476

Abstract

Congenital cytomegalovirus (CMV) infection may cause severe long-term sequelae. Recent studies have demonstrated that early antiviral therapy for infants with symptomatic congenital CMV (cCMV) infection may improve neurological outcomes; thus, accurate identification of newborns at high risk of cCMV infection may contribute to improved outcomes in affected children. However, maternal serological screening for cCMV infection by diagnosing primary infection during pregnancy, which is a popular screening strategy, is inefficient, because the number of cCMV infections with nonprimary causes, including reactivation of or reinfection with CMV, is larger than that of cCMV infections with primary causes. Low levels of neutralizing antibodies against pentameric complex and potent CMV-specific T cell-mediated immune responses are associated with an increased risk of cCMV infection. Conversely, our prospective cohort studies revealed that the presence of maternal fever/flu-like symptoms, threatened miscarriage/premature delivery, or actual premature delivery are risk factors for cCMV infection among both women with normal pregnancies and those with high-risk ones, regardless of whether the infection is primary or nonprimary. This review focused on host immune responses to human CMV and current knowledge of potential biological and clinical factors that are predictive of cCMV infection. Full article

(This article belongs to the Special Issue Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 3.0)

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16 pages, 388 KiB

Open AccessReview

Immune Prophylaxis and Therapy for Human Cytomegalovirus Infection

by Evi B. Struble, Haruhiko Murata, Takashi Komatsu and Dorothy Scott

Int. J. Mol. Sci. 2021, 22(16), 8728; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168728 - 13 Aug 2021

Cited by 6 | Viewed by 2592

Abstract

Human Cytomegalovirus (HCMV) infection is widespread and can result in severe sequelae in susceptible populations. Primary HCMV infection of naïve individuals results in life-long latency characterized by frequent and sporadic reactivations. HCMV infection elicits a robust antibody response, including neutralizing antibodies that can block the infection of susceptible cells in vitro and in vivo. Thus, antibody products and vaccines hold great promise for the prevention and treatment of HCMV, but to date, most attempts to demonstrate their safety and efficacy in clinical trials have been unsuccessful. In this review we summarize publicly available data on these products and highlight new developments and approaches that could assist in successful translation of HCMV immunotherapies. Full article

(This article belongs to the Special Issue Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 3.0)

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