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Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 2.0

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

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 28308

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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 (7 papers)

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Research

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17 pages, 2731 KiB

Open AccessArticle

Convalescent Immunity to Guinea Pig Cytomegalovirus Induces Limited Cross Strain Protection against Re-Infection but High-Level Protection against Congenital Disease

by K. Yeon Choi, Nadia S. El-Hamdi and Alistair McGregor

Int. J. Mol. Sci. 2020, 21(17), 5997; https://doi.org/10.3390/ijms21175997 - 20 Aug 2020

Cited by 7 | Viewed by 2607

Abstract

The guinea pig is the only small animal model for congenital cytomegalovirus (cCMV) but requires guinea pig cytomegalovirus (GPCMV). Current GPCMV research utilizes prototype strain 22122, which limits the translational impact of GPCMV as numerous human CMV strains exist and cCMV is possible in the setting of re-infection. A novel strain of GPCMV (TAMYC) exhibited differences to 22122 in various glycoproteins with GP74 (gO homolog) the most variable (25% difference). Antibody ELISAs for TAMYC-convalescent animals evoked similar immune response to viral glycoprotein complexes (gB, gH/gL, gM/gN, pentamer) and cell-mediated response to pp65 homolog (GP83). Convalescent sera from TAMYC-infected animals neutralized GPCMV infection on fibroblasts but was less effective on epithelial cells. TAMYC-convalescent animals were not protected from dissemination of heterogenous virus challenge (22122). However, in a cCMV protection study, TAMYC-convalescent animals challenged mid-pregnancy (22122) exhibited high-level protection against cCMV compared to seronegative animals with pup transmission reduced from 80% (control) to 12%. Overall, pre-existing immunity in guinea pigs provides limited ability to prevent GPCMV re-infection by a different viral strain but provides a high level of protection against cCMV in heterogenous strain challenge. This level of cross protection against cCMV should be a prerequisite of any CMV vaccine. Full article

(This article belongs to the Special Issue Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 2.0)

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6 pages, 198 KiB

Open AccessCommunication

Diagnostic Value of Cytomegalovirus IgM Antibodies at Birth in PCR-Confirmed Congenital Cytomegalovirus Infection

by Shohei Ohyama, Kazumichi Fujioka, Sachiyo Fukushima, Shinya Abe, Mariko Ashina, Toshihiko Ikuta, Kosuke Nishida, Hisayuki Matsumoto, Yuji Nakamachi, Kenji Tanimura, Hideto Yamada and Kazumoto Iijima

Int. J. Mol. Sci. 2019, 20(13), 3239; https://doi.org/10.3390/ijms20133239 - 01 Jul 2019

Cited by 17 | Viewed by 3498

Abstract

Although cytomegalovirus (CMV) DNA detection in urine is the standard method for diagnosing congenital cytomegalovirus infection (CCMVI), polymerase chain reaction (PCR) is not comprehensively available. Currently, the efficacy of CMV-specific IgM (CMV-IgM) and CMV-specific IgG (CMV-IgG) detection remains unclear. To determine the sensitivity and specificity of CMV-specific antibodies at birth, we investigated CMV-IgM and CMV-IgG titers in CCMVI cases and non-CCMVI controls, with confirmed diagnoses by urine quantitative real-time PCR within 3 weeks after birth. We included 174 infants with suspected CCMVI in whom serological testing was performed within the first 2 weeks after birth during 2012–2018. We classified the participants into a CCMVI group (n = 32) and non-CCMVI group (n = 142) based on their urine PCR results. The CMV-IgM-positive rate was 27/32 (84.4%) in the CCMVI group, compared with 1/142 (0.7%) in the non-CCMVI group (p < 0.0001). The positive CMV-IgG rates were 32/32 (100%) in the CCMVI group and 141/142 (99.3%) in the non-CCMVI group. The positive predictive value for CMV-IgM was high at 96.4% (27/28). This value may be sufficient for clinical use, especially in settings with limited resources where PCR is unavailable. However, CCMVI screening by CMV-IgM alone appears insufficient because of the considerable number of false-negative cases. Full article

(This article belongs to the Special Issue Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 2.0)

Review

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19 pages, 1480 KiB

Open AccessReview

Impact of Natural Occurring ERAP1 Single Nucleotide Polymorphisms within miRNA-Binding Sites on HCMV Infection

by Ombretta Melaiu, Silvia D’Amico, Patrizia Tempora, Valeria Lucarini and Doriana Fruci

Int. J. Mol. Sci. 2020, 21(16), 5861; https://doi.org/10.3390/ijms21165861 - 15 Aug 2020

Cited by 8 | Viewed by 2570

Abstract

Human cytomegalovirus (HCMV) is a β-herpesvirus that causes serious problems in people with a compromised immune system, whereas it coexists asymptomatically within the host with a healthy immune system. Like other viruses, HCMV has adopted multiples strategies to manipulate the host’s immune responses. Among them, expression of viral microRNAs (miRNAs) is one of the most intriguing. HCMV miR-UL112-5p and miR-US4-1 have been found to contribute to immune evasion by targeting the endoplasmic reticulum aminopeptidase 1 (ERAP1), a highly polymorphic key component of antigen processing. The current incomplete picture on the interplay between viral miRNAs and host immunity implies the need to better characterize the host genetic determinants. Naturally occurring single nucleotide polymorphisms (SNPs) within the miRNA binding sites of target genes may affect miRNA–target interactions. In this review, we focus on the relevance of 3′ untranslated region (3′UTR) ERAP1 SNPs within miRNA binding sites in modulating miRNA–mRNA interactions and the possible consequent individual susceptibility to HCMV infection. Moreover, we performed an in silico analysis using different bioinformatic algorithms to predict ERAP1 variants with a putative powerful biological function. This evidence provides a basis to deepen the knowledge on how 3′UTR ERAP1 variants may alter the mechanism of action of HCMV miRNAs, in order to develop targeted antiviral therapies. Full article

(This article belongs to the Special Issue Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 2.0)

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11 pages, 2504 KiB

Open AccessReview

Current Diagnostic and Therapeutic Approaches to Cytomegalovirus Infections in Ulcerative Colitis Patients Based on Clinical and Basic Research Data

by Yoshihiro Yokoyama, Tsukasa Yamakawa, Takehiro Hirano, Tomoe Kazama, Daisuke Hirayama, Kohei Wagatsuma and Hiroshi Nakase

Int. J. Mol. Sci. 2020, 21(7), 2438; https://doi.org/10.3390/ijms21072438 - 31 Mar 2020

Cited by 13 | Viewed by 4935

Abstract

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus (the human herpesvirus 5) and an opportunistic pathogen that primarily infects HIV-positive and other immuno-compromised patients. Retrospective studies in the field of inflammatory bowel disease (IBD) have suggested a relationship between a concomitant colonic HCMV infection and poor outcomes in patients with an ulcerative colitis (UC) due to the presence of HCMV in surgical specimens of patients with a toxic megacolon or a steroid-resistant UC. Therefore, gastroenterologists have focused on the contribution of HCMV infections in the exacerbation of UC. Numerous studies have addressed the benefits of treating colonic HCMV reactivation in UC using an antiviral treatment. However, its clinical relevance remains uncertain as only a few prospective studies have assessed the direct relationship between clinical outcomes and the viral load of HCMV in colonic tissues. HCMV reactivation can be triggered by inflammation according to fundamental research studies. Thus, optimal control of intestinal inflammation is essential for preventing an HCMV reactivation in the intestinal mucosa. Indeed, several reports have indicated the effectiveness of an anti-tumor necrosis factor-alpha (TNFα) treatment in patients with an active UC and concomitant HCMV infections. In this review, we describe the mechanism of HCMV reactivation in UC cases and discuss the current issues regarding diagnosis and treatment of HCMV infections in UC patients. Full article

(This article belongs to the Special Issue Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 2.0)

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13 pages, 293 KiB

Open AccessReview

Potential Therapeutic Approaches Against Brain Diseases Associated with Cytomegalovirus Infections

by Shao-Cheng Wang, Shiu-Jau Chen and Yuan-Chuan Chen

Int. J. Mol. Sci. 2020, 21(4), 1376; https://doi.org/10.3390/ijms21041376 - 18 Feb 2020

Cited by 2 | Viewed by 3761

Abstract

Cytomegalovirus (CMV) is one of the major human health threats worldwide, especially for immunologically comprised patients. CMV may cause opportunistic infections, congenital infections, and brain diseases (e.g., mental retardation and glioblastoma). The etiology of brain diseases associated with human CMV (HCMV) infections is usually complex and it is particularly difficult to treat because HCMV has a life-long infection in its hosts, high mutation rate, and latent infections. Moreover, it is almost impossible to eradicate latent viruses in humans. Although there has been progress in drug discovery recently, current drugs used for treating active CMV infections are still limited in efficacy due to side effects, toxicity, and viral resistance. Fortunately, letermovir which targets the HCMV terminase complex rather than DNA polymerase with fewer adverse reactions has been approved to treat CMV infections in humans. The researchers are focusing on developing approaches against both productive and latent infections of CMV. The gene or RNA targeting approaches including the external guide sequences (EGSs)-RNase, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and transcription activator-like effector nucleases (TALENs) are being investigated to remove acute and/or latent CMV infections. For the treatment of glioblastoma, vaccine therapy through targeting specific CMV antigens has improved patients’ survival outcomes significantly and immunotherapy has also emerged as an alternative modality. The advanced research for developing anti-CMV agents and approaches is promising to obtain significant outcomes and expecting to have a great impact on the therapy of brain diseases associated with CMV infections. Full article

(This article belongs to the Special Issue Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 2.0)

16 pages, 259 KiB

Open AccessReview

Promising Cytomegalovirus-Based Vaccine Vector Induces Robust CD8⁺ T-Cell Response

by Jian Liu, Dabbu Kumar Jaijyan, Qiyi Tang and Hua Zhu

Int. J. Mol. Sci. 2019, 20(18), 4457; https://doi.org/10.3390/ijms20184457 - 10 Sep 2019

Cited by 26 | Viewed by 4446

Abstract

Vaccination has had great success in combating diseases, especially infectious diseases. However, traditional vaccination strategies are ineffective for several life-threatening diseases, including acquired immunodeficiency syndrome (AIDS), tuberculosis, malaria, and cancer. Viral vaccine vectors represent a promising strategy because they can efficiently deliver foreign genes and enhance antigen presentation in vivo. However, several limitations, including pre-existing immunity and packaging capacity, block the application of viral vectors. Cytomegalovirus (CMV) has been demonstrated as a new type of viral vector with additional advantages. CMV could systematically elicit and maintain high frequencies of effector memory T cells through the “memory inflation” mechanism. Studies have shown that CMV can be genetically modified to induce distinct patterns of CD8⁺ T-cell responses, while some unconventional CD8⁺ T-cell responses are rarely induced through conventional vaccine strategies. CMV has been used as a vaccine vector to deliver many disease-specific antigens, and the efficacy of these vaccines was tested in different animal models. Promising results demonstrated that the robust and unconventional T-cell responses elicited by the CMV-based vaccine vector are essential to control these diseases. These accumulated data and evidence strongly suggest that a CMV-based vaccine vector represents a promising approach to develop novel prophylactic and therapeutic vaccines against some epidemic pathogens and tumors. Full article

(This article belongs to the Special Issue Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 2.0)

26 pages, 1055 KiB

Open AccessReview

Battle between Host Immune Cellular Responses and HCMV Immune Evasion

by Trishna Manandhar, Gia-Gia T. Hò, Wiebke C. Pump, Rainer Blasczyk and Christina Bade-Doeding

Int. J. Mol. Sci. 2019, 20(15), 3626; https://doi.org/10.3390/ijms20153626 - 24 Jul 2019

Cited by 30 | Viewed by 6108

Abstract

Human cytomegalovirus (HCMV) is ubiquitously prevalent. HCMV infection is typically asymptomatic and controlled by the immune system in healthy individuals, yet HCMV can be severely pathogenic for the fetus during pregnancy and in immunocompromised persons, such as transplant recipients or HIV infected patients. HCMV has co-evolved with the hosts, developed strategies to hide from immune effector cells and to successfully survive in the human organism. One strategy for evading or delaying the immune response is maintenance of the viral genome to establish the phase of latency. Furthermore, HCMV immune evasion involves the downregulation of human leukocyte antigens (HLA)-Ia molecules to hide infected cells from T-cell recognition. HCMV expresses several proteins that are described for downregulation of the HLA class I pathway via various mechanisms. Here, we review the wide range of immune evasion mechanisms of HCMV. Understanding the mechanisms of HCMV immune evasion will contribute to the development of new customized therapeutic strategies against the virus. Full article

(This article belongs to the Special Issue Host-Cytomegalovirus Interactions: Pro- and Antiviral Key Factors Affecting CMV Infection Outcome or Therapeutic Approaches 2.0)

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