Viruses

Editorial

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5 pages, 167 KiB

Open AccessEditorial

Perspective on the 65-Year Anniversary of the Discovery of Cytomegalovirus

by Edward S. Mocarski

Viruses 2025, 17(1), 80; https://doi.org/10.3390/v17010080 - 9 Jan 2025

Viewed by 595

Abstract

This volume presents research and reviews bringing forward new insights into cytomegalovirus (CMV) pathogenesis and biology; CMV is a herpesvirus that has long been recognized as being medically significant [...] Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

Research

Jump to: Editorial, Review

8 pages, 3541 KiB

Open AccessCommunication

Cytomegalovirus DNA Loads in Organs of Congenitally Infected Fetus

by Kuniaki Toriyabe, Asa Kitamura, Makoto Ikejiri, Ryotaro Hashizume, Maki Nakamura, Emi Teramoto, Hiroki Takeuchi, Eiji Kondo and Tomoaki Ikeda

Viruses 2024, 16(6), 891; https://doi.org/10.3390/v16060891 - 31 May 2024

Cited by 1 | Viewed by 1088

Abstract

Congenital cytomegalovirus (cCMV) infection poses significant risks to fetal development, particularly affecting the nervous system. This study reports a fetal autopsy case, examining cCMV infection and focusing on CMV DNA measurements in various fetal organs before formalin fixation, a novel approach for comprehensive [...] Read more.

Congenital cytomegalovirus (cCMV) infection poses significant risks to fetal development, particularly affecting the nervous system. This study reports a fetal autopsy case, examining cCMV infection and focusing on CMV DNA measurements in various fetal organs before formalin fixation, a novel approach for comprehensive CMV DNA evaluations in fetal organs affected by cCMV. A 20-week-old male fetus was diagnosed with cCMV following the detection of CMV DNA in ascites obtained via abdominocentesis in utero. After the termination of pregnancy, multiple organs of the fetus, including the cerebrum, thyroid gland, heart, lungs, liver, spleen, kidneys, and adrenal glands, were extracted and examined for CMV DNA loads using a real-time polymerase chain reaction. Histopathological examination involved hematoxylin–eosin and CMV-specific immunostaining. A correlation was found between CMV DNA loads and pathology, with higher CMV-infected cell numbers observed in organs positively identified with both staining methods, exhibiting CMV DNA levels of ≥1.0 × 10⁴ copies/mL, compared to those detected solely by CMV-specific immunostaining, where CMV DNA levels ranged from 1.0 × 10³ to 1.0 × 10⁴ copies/mL. These results highlight a quantifiable relationship between the organ infection extent and CMV DNA concentration, providing insights into cCMV pathogenesis and potentially informing future diagnostic and therapeutic strategies for cCMV infection. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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17 pages, 26993 KiB

Open AccessArticle

Mesenchymal Stem Cell-Derived Exosomes Attenuate Murine Cytomegalovirus-Infected Pneumonia via NF-κB/NLRP3 Signaling Pathway

by Fei Chen, Zhida Chen, Hui-Ting Wu, Xin-Xiang Chen, Peiqi Zhan, Zheng-Yi Wei, Zizhang Ouyang, Xueyan Jiang, Ao Shen, Min-Hua Luo, Qifa Liu, Yue-Peng Zhou and Aiping Qin

Viruses 2024, 16(4), 619; https://doi.org/10.3390/v16040619 - 16 Apr 2024

Cited by 3 | Viewed by 2687

Abstract

Reactivation and infection with cytomegalovirus (CMV) are frequently observed in recipients of solid organ transplants, bone marrow transplants, and individuals with HIV infection. This presents an increasing risk of allograft rejection, opportunistic infection, graft failure, and patient mortality. Among immunocompromised hosts, interstitial pneumonia [...] Read more.

Reactivation and infection with cytomegalovirus (CMV) are frequently observed in recipients of solid organ transplants, bone marrow transplants, and individuals with HIV infection. This presents an increasing risk of allograft rejection, opportunistic infection, graft failure, and patient mortality. Among immunocompromised hosts, interstitial pneumonia is the most critical clinical manifestation of CMV infection. Recent studies have demonstrated the potential therapeutic benefits of exosomes derived from mesenchymal stem cells (MSC-exos) in preclinical models of acute lung injury, including pneumonia, ARDS, and sepsis. However, the role of MSC-exos in the pathogenesis of infectious viral diseases, such as CMV pneumonia, remains unclear. In a mouse model of murine CMV-induced pneumonia, we observed that intravenous administration of mouse MSC (mMSC)-exos reduced lung damage, decreased the hyperinflammatory response, and shifted macrophage polarization from the M1 to the M2 phenotype. Treatment with mMSC-exos also significantly reduced the infiltration of inflammatory cells and pulmonary fibrosis. Furthermore, in vitro studies revealed that mMSC-exos reversed the hyperinflammatory phenotype of bone marrow-derived macrophages infected with murine CMV. Mechanistically, mMSC-exos treatment decreased activation of the NF-κB/NLRP3 signaling pathway both in vivo and in vitro. In summary, our findings indicate that mMSC-exo treatment is effective in severe CMV pneumonia by reducing lung inflammation and fibrosis through the NF-κB/NLRP3 signaling pathway, thus providing promising therapeutic potential for clinical CMV infection. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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13 pages, 705 KiB

Open AccessArticle

Comparative Analysis of Cytomegalovirus Gastrointestinal Disease in Immunocompetent and Immunocompromised Patients

by Pai-Jui Yeh, Ren-Chin Wu, Yung-Kuan Tsou, Chien-Ming Chen, Cheng-Tang Chiu, Chien-Chang Chen, Ming-Wei Lai, Yu-Bin Pan and Puo-Hsien Le

Viruses 2024, 16(3), 452; https://doi.org/10.3390/v16030452 - 14 Mar 2024

Cited by 1 | Viewed by 1392

Abstract

Background: Cytomegalovirus (CMV) gastrointestinal (GI) diseases impact both immunocompromised and immunocompetent individuals, yet comprehensive studies highlighting the differences between these groups are lacking. Methods: In this retrospective study (January 2000 to July 2022) of 401 patients with confirmed CMV GI diseases, we categorized [...] Read more.

Background: Cytomegalovirus (CMV) gastrointestinal (GI) diseases impact both immunocompromised and immunocompetent individuals, yet comprehensive studies highlighting the differences between these groups are lacking. Methods: In this retrospective study (January 2000 to July 2022) of 401 patients with confirmed CMV GI diseases, we categorized them based on immunological status and compared manifestations, treatments, outcomes, and prognostic factors. Results: The immunocompromised patients (n = 193) showed older age, severe illnesses, and higher comorbidity rates. GI bleeding, the predominant manifestation, occurred more in the immunocompetent group (92.6% vs. 63.6%, p = 0.009). Despite longer antiviral therapy, the immunocompromised patients had higher in-hospital (32.2% vs. 18.9%, p = 0.034) and overall mortality rates (91.1% vs. 43.4%, p < 0.001). The independent factors influencing in-hospital mortality in the immunocompromised patients included GI bleeding (OR 5.782, 95% CI 1.257–26.599, p = 0.024) and antiviral therapy ≥ 14 days (OR 0.232, 95% CI 0.059–0.911, p = 0.036). In the immunocompetent patients, age (OR 1.08, 95% CI 1.006–1.159, p = 0.032), GI bleeding (OR 10.036, 95% CI 1.183–85.133, p = 0.035), and time to diagnosis (OR 1.029, 95% CI 1.004–1.055, p = 0.021) were significant prognostic factors, with the age and diagnosis time cut-offs for survival being 70 years and 31.5 days, respectively. Conclusions: GI bleeding is the most common manifestation and prognostic factor in both groups. Early diagnosis and effective antiviral therapy can significantly reduce in-hospital mortality. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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15 pages, 1574 KiB

Open AccessArticle

Comprehensive Analysis of Soluble Mediator Profiles in Congenital CMV Infection Using an MCMV Model

by Dubravka Karner, Daria Kvestak, Berislav Lisnic, Maja Cokaric Brdovcak, Vanda Juranic Lisnic, Paola Kucan Brlic, Milena Hasan and Tihana Lenac Rovis

Viruses 2024, 16(2), 208; https://doi.org/10.3390/v16020208 - 30 Jan 2024

Cited by 1 | Viewed by 1810

Abstract

Congenital human cytomegalovirus (HCMV) infection may cause life-threatening disease and permanent damage to the central nervous system. The mouse model of CMV infection is most commonly used to study mechanisms of infection and pathogenesis. While essential to limit mouse CMV (MCMV) replication, the [...] Read more.

Congenital human cytomegalovirus (HCMV) infection may cause life-threatening disease and permanent damage to the central nervous system. The mouse model of CMV infection is most commonly used to study mechanisms of infection and pathogenesis. While essential to limit mouse CMV (MCMV) replication, the inflammatory responses, particularly IFNγ and TNFα, cause neurodevelopmental abnormalities. Other soluble mediators of the immune response in most tissues remain largely unexplored. To address this gap, we quantified 48 soluble mediators of the immune response, including 32 cytokines, 10 chemokines, 3 growth factors/regulators, and 3 soluble receptors in the spleen, liver, lungs, and brain at 9 and 14 days postinfection (dpi). Our analysis found 25 induced molecules in the brain at 9 dpi, with an additional 8 showing statistically elevated responses at 14 dpi. Specifically, all analyzed CCL group cytokines (CCL2, CCL3, CCL4, CCL5, CCL7, and CCL11) were upregulated at 14 dpi in the brain. Furthermore, data revealed differentially regulated analytes across tissues, such as CCL11, CXCL5, and IL-10 in the brain, IL-33/IL-33R in the liver, and VEGF-a and IL-5 in the lungs. Overall, this study provides an overview of the immune dynamics of soluble mediators in congenital CMV. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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21 pages, 83361 KiB

Open AccessArticle

Subconfluent ARPE-19 Cells Display Mesenchymal Cell-State Characteristics and Behave like Fibroblasts, Rather Than Epithelial Cells, in Experimental HCMV Infection Studies

by Preethi Golconda, Mariana Andrade-Medina and Adam Oberstein

Viruses 2024, 16(1), 49; https://doi.org/10.3390/v16010049 - 28 Dec 2023

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Abstract

Human cytomegalovirus (HCMV) has a broad cellular tropism and epithelial cells are important physiological targets during infection. The retinal pigment epithelial cell line ARPE-19 has been used to model HCMV infection in epithelial cells for decades and remains a commonly used cell type [...] Read more.

Human cytomegalovirus (HCMV) has a broad cellular tropism and epithelial cells are important physiological targets during infection. The retinal pigment epithelial cell line ARPE-19 has been used to model HCMV infection in epithelial cells for decades and remains a commonly used cell type for studying viral entry, replication, and the cellular response to infection. We previously found that ARPE-19 cells, despite being derived from an epithelial cell explant, express extremely low levels of canonical epithelial proteins, such as E-cadherin and EpCAM. Here, we perform comparative studies of ARPE-19 and additional epithelial cell lines with strong epithelial characteristics. We find that ARPE-19 cells cultured under subconfluent conditions resemble mesenchymal fibroblasts, rather than epithelial cells; this is consistent with previous studies showing that ARPE-19 cultures require extended periods of high confluency culture to maintain epithelial characteristics. By reanalyzing public gene expression data and using machine learning, we find evidence that ARPE-19 cultures maintained across many labs exhibit mesenchymal characteristics and that the majority of studies employing ARPE-19 use them in a mesenchymal state. Lastly, by performing experimental HCMV infections across mesenchymal and epithelial cell lines, we find that ARPE-19 cells behave like mesenchymal fibroblasts, producing logarithmic yields of cell-free infectious progeny, while cell lines with strong epithelial character exhibit an atypical infectious cycle and naturally restrict the production of cell-free progeny. Our work highlights important characteristics of the ARPE-19 cell line and suggests that subconfluent ARPE-19 cells may not be optimal for modeling epithelial infection with HCMV or other human viruses. It also suggests that HCMV biosynthesis and/or spread may occur quite differently in epithelial cells compared to mesenchymal cells. These differences could contribute to viral persistence or pathogenesis in epithelial tissues. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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11 pages, 1621 KiB

Open AccessArticle

Genetic Variants Associated with Drug Resistance of Cytomegalovirus in Hematopoietic Cell Transplantation Recipients

by Seungwan Chae, Hoon Seok Kim, Sung-Yeon Cho, Dukhee Nho, Raeseok Lee, Dong-Gun Lee, Myungshin Kim and Yonggoo Kim

Viruses 2023, 15(6), 1286; https://doi.org/10.3390/v15061286 - 30 May 2023

Cited by 3 | Viewed by 2443

Abstract

Cytomegalovirus (CMV) infection is a serious complication in hematopoietic cell transplantation (HCT) recipients. Drug-resistant strains make it more challenging to treat CMV infection. This study aimed to identify variants associated with CMV drug resistance in HCT recipients and assess their clinical significance. A [...] Read more.

Cytomegalovirus (CMV) infection is a serious complication in hematopoietic cell transplantation (HCT) recipients. Drug-resistant strains make it more challenging to treat CMV infection. This study aimed to identify variants associated with CMV drug resistance in HCT recipients and assess their clinical significance. A total of 123 patients with refractory CMV DNAemia out of 2271 HCT patients at the Catholic Hematology Hospital between April 2016 and November 2021 were analyzed, which accounted for 8.6% of the 1428 patients who received pre-emptive therapy. Real-time PCR was used to monitor CMV infection. Direct sequencing was performed to identify drug-resistant variants in UL97 and UL54. Resistance variants were found in 10 (8.1%) patients, and variants of uncertain significance (VUS) were found in 48 (39.0%) patients. Patients with resistance variants had a significantly higher peak CMV viral load than those without (p = 0.015). Patients with any variants had a higher risk of severe graft-versus-host disease and lower one-year survival rates than those without (p = 0.003 and p = 0.044, respectively). Interestingly, the presence of variants reduced the rate of CMV clearance, particularly in patients who did not modify their initial antiviral regimen. However, it had no apparent impact on individuals whose antiviral regimens were changed due to refractoriness. This study highlights the importance of identifying genetic variants associated with CMV drug resistance in HCT recipients for providing appropriate antiviral treatment and predicting patient outcomes. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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14 pages, 2730 KiB

Open AccessArticle

Human Cytomegalovirus UL23 Antagonizes the Antiviral Effect of Interferon-γ by Restraining the Expression of Specific IFN-Stimulated Genes

by Hankun Wang, Weijian Peng, Jialin Wang, Chunling Zhang, Wangchun Zhao, Yanhong Ran, Xiaoping Yang, Jun Chen and Hongjian Li

Viruses 2023, 15(4), 1014; https://doi.org/10.3390/v15041014 - 20 Apr 2023

Cited by 3 | Viewed by 2203

Abstract

Interferon-γ (IFN-γ) is a critical component of innate immune responses in humans to combat infection by many viruses, including human cytomegalovirus (HCMV). IFN-γ exerts its biological effects by inducing hundreds of IFN-stimulated genes (ISGs). In this study, RNA-seq analyses revealed that HCMV tegument [...] Read more.

Interferon-γ (IFN-γ) is a critical component of innate immune responses in humans to combat infection by many viruses, including human cytomegalovirus (HCMV). IFN-γ exerts its biological effects by inducing hundreds of IFN-stimulated genes (ISGs). In this study, RNA-seq analyses revealed that HCMV tegument protein UL23 could regulate the expression of many ISGs under IFN-γ treatment or HCMV infection. We further confirmed that among these IFN-γ stimulated genes, individual APOL1 (Apolipoprotein-L1), CMPK2 (Cytidine/uridine monophosphate kinase 2), and LGALS9 (Galectin-9) could inhibit HCMV replication. Moreover, these three proteins exhibited a synergistic effect on HCMV replication. UL23-deficient HCMV mutants induced higher expression of APOL1, CMPK2, and LGALS9, and exhibited lower viral titers in IFN-γ treated cells compared with parental viruses expressing full functional UL23. Thus, UL23 appears to resist the antiviral effect of IFN-γ by downregulating the expression of APOL1, CMPK2, and LGALS9. This study highlights the roles of HCMV UL23 in facilitating viral immune escape from IFN-γ responses by specifically downregulating these ISGs. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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15 pages, 3589 KiB

Open AccessArticle

Immunohistochemistry Staining-Proven Cytomegalovirus Colitis in Living Donor Liver Transplantation

by Shu-Hsien Lin, Kun-Ta Wu, Chih-Chi Wang, Ting-Ting Liu, Hock-Liew Eng and King-Wah Chiu

Viruses 2023, 15(1), 115; https://doi.org/10.3390/v15010115 - 30 Dec 2022

Cited by 2 | Viewed by 2392

Abstract

Background and Aims: Cytomegalovirus (CMV) infection is a common occurrence in liver transplantation (LT) even in an era of preventive strategies. However, the diagnosis of CMV colitis remains challenging. This study aimed to focus on the clinical significance of endoscopic biopsy-proven CMV colitis [...] Read more.

Background and Aims: Cytomegalovirus (CMV) infection is a common occurrence in liver transplantation (LT) even in an era of preventive strategies. However, the diagnosis of CMV colitis remains challenging. This study aimed to focus on the clinical significance of endoscopic biopsy-proven CMV colitis in patients following living donor liver transplantation (LDLT). Methods: From January 2007 to December 2021, a total of 55 CMV colitis cases were retrospectively enrolled and divided into a non-LDLT group in 53 and an LDLT group in 2 cases. Clinical demographics, diagnostic measurement, histopathology, and anti-viral therapy were investigated. Results: There were 1630 cases undergoing LDLT in the period 2007–2021, with only 2 recipients being confirmed to have CMV colitis in 2021 (2/114, 1-year incidence: 1.75%). Comparisons between the 53 non-LDLT cases and 2 LDLT cases are as follows: Serum anti-CMV immunoglobulin M (IgM) was shown to be positive (n = 3, 5.5% vs. n = 0, p = 1.0) and negative (n = 20, 37.7% vs. n = 2, 100%, p = 0.16); anti-CMV immunoglobulin G (IgG) was positive (n = 19, 35.8% vs. n = 2, 100%, p = 0.14) and none were negative; CMV DNAemia was shown to be detectable (n = 14, 26.4% vs. n = 1, 50%, p = 0.47) and undetectable (n = 14, 26.4% vs. n = 1, 50%, p = 0.47). Among the two recipients with CMV colitis, one had CMV DNAemia and the other had no CMV DNAemia upon the development of symptoms; negative anti-CMV-IgM and positive anti-CMV-IgG were observed both pre-transplant and post-transplant; finally, CMV colitis was documented based on the presence of inclusion bodies and positive immunohistochemistry (IHC) staining in histology. Conclusion: Patients with immunocompromised status, in particular organ transplantation, may have positive serum anti-CMV IgM/IgG antibodies both before and after transplantation. This study emphasized the fact that endoscopic biopsy with IHC staining may be a more powerful tool for making an accurate diagnosis of CMV colitis in the setting of living donor liver transplantation. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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8 pages, 223 KiB

Open AccessArticle

Long-Term Associations between Human Cytomegalovirus Antibody Levels with All-Cause Mortality and Cardiovascular Outcomes in an Australian Community-Based Cohort

by Silvia Lee, Nikki van den Berg, Alison Castley, Mark Divitini, Matthew Knuiman, Patricia Price, David Nolan, Frank Sanfilippo and Girish Dwivedi

Viruses 2022, 14(12), 2676; https://doi.org/10.3390/v14122676 - 29 Nov 2022

Cited by 2 | Viewed by 1759

Abstract

Human cytomegalovirus (HCMV) infection has been shown to increase the risk of cardiovascular events and all-cause death among individuals with clinically apparent cardiovascular disease (CVD). Whether this association exists in individuals with no history of CVD remains unclear. Serum levels of HCMV IgG [...] Read more.

Human cytomegalovirus (HCMV) infection has been shown to increase the risk of cardiovascular events and all-cause death among individuals with clinically apparent cardiovascular disease (CVD). Whether this association exists in individuals with no history of CVD remains unclear. Serum levels of HCMV IgG antibody were measured using an ELISA in 2050 participants aged 40–80 years from the 1994/1995 Busselton Health Survey who did not have CVD at baseline. Outcomes were all-cause death, cardiovascular death, acute coronary syndrome (ACS) and major adverse coronary and cerebrovascular events (MACCE, composite of all-cause death, ACS, stroke and coronary artery revascularisation procedures). Cox proportional hazards regression analysis was used to investigate HCMV antibody levels as a predictor of death and cardiovascular outcomes during follow-up periods of 5, 10 and 20 years. At baseline, participants had a mean age of 56 years and 57% were female. During the 20-year follow-up, there were 448 (21.9%) deaths (including 152 from CVD), 139 (6.8%) participants had ACS and 575 (28.0%) had MACCE. In the fully adjusted model, levels of HCMV antibody at 20 years was associated with all-cause death (HR 1.04; 95% CI 1.00, 1.07, p = 0.037) but not with CVD death, ACS or MACCE. Levels of HCMV antibody are associated with all-cause death but not with cardiovascular outcomes in adults without pre-existing CVD. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

Review

Jump to: Editorial, Research

15 pages, 2516 KiB

Open AccessReview

The Effects of Viral Infections on the Molecular and Signaling Pathways Involved in the Development of the PAOs

by Xiaozhou Liu, Zhengdong Zhao, Xinyu Shi, Yanjun Zong and Yu Sun

Viruses 2024, 16(8), 1342; https://doi.org/10.3390/v16081342 - 22 Aug 2024

Cited by 3 | Viewed by 1161

Abstract

Cytomegalovirus infection contributes to 10–30% of congenital hearing loss in children. Vertebrate peripheral auditory organs include the outer, middle, and inner ear. Their development is regulated by multiple signaling pathways. However, most ear diseases due to viral infections are due to congenital infections [...] Read more.

Cytomegalovirus infection contributes to 10–30% of congenital hearing loss in children. Vertebrate peripheral auditory organs include the outer, middle, and inner ear. Their development is regulated by multiple signaling pathways. However, most ear diseases due to viral infections are due to congenital infections and reactivation and affect healthy adults to a lesser extent. This may be due to the fact that viral infections affect signaling pathways that are important for the development of peripheral hearing organs. Therefore, an in-depth understanding of the relationship between viral infections and the signaling pathways involved in the development of peripheral hearing organs is important for the prevention and treatment of ear diseases. In this review, we summarize the effects of viruses on signaling pathways and signaling molecules in the development of peripheral auditory organs. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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17 pages, 707 KiB

Open AccessReview

Burden of Congenital CMV Infection: A Narrative Review and Implications for Public Health Interventions

by Cecilia Liberati, Giulia Sturniolo, Giulia Brigadoi, Silvia Cavinato, Silvia Visentin, Erich Cosmi, Daniele Donà and Osvalda Rampon

Viruses 2024, 16(8), 1311; https://doi.org/10.3390/v16081311 - 17 Aug 2024

Cited by 1 | Viewed by 1351

Abstract

Cytomegalovirus causes the most common congenital infection worldwide. With most infants asymptomatic at birth, the few affected may present with variable clinical scenarios, from isolated hearing loss to severe neurologic impairment. Public health interventions include all actions at the health system, community, and [...] Read more.

Cytomegalovirus causes the most common congenital infection worldwide. With most infants asymptomatic at birth, the few affected may present with variable clinical scenarios, from isolated hearing loss to severe neurologic impairment. Public health interventions include all actions at the health system, community, and individual levels that aim at reducing the burden of congenital Cytomegalovirus. This review examines the literature on maternal and neonatal screening programs in light of current evidence for treatment and the development of vaccines against Cytomegalovirus. Potential biases and benefits of these interventions are outlined, with the objective of increasing awareness about the problem and providing readers with data and critical tools to participate in this ongoing debate. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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10 pages, 1345 KiB

Open AccessReview

Polyploid Giant Cancer Cells: A Distinctive Feature in the Transformation of Epithelial Cells by High-Risk Oncogenic HCMV Strains

by Georges Herbein and Ranim El Baba

Viruses 2024, 16(8), 1225; https://doi.org/10.3390/v16081225 - 31 Jul 2024

Cited by 1 | Viewed by 1537

Abstract

Human cytomegalovirus (HCMV) infection is common in tumor tissues across different types of cancer. While HCMV has not been recognized as a cancer-causing virus, numerous studies hint at its potential role in cancer development where its presence in various cancers corresponds with the [...] Read more.

Human cytomegalovirus (HCMV) infection is common in tumor tissues across different types of cancer. While HCMV has not been recognized as a cancer-causing virus, numerous studies hint at its potential role in cancer development where its presence in various cancers corresponds with the hallmarks of cancer. Herein, we discuss and demonstrate that high-risk HCMV-DB and BL strains have the potential to trigger transformation in epithelial cells, including human mammary epithelial cells (HMECs), ovarian epithelial cells (OECs), and prostate epithelial cells (PECs), through the generation of polyploid giant cancer cells (PGCCs). A discussion is provided on how HCMV infection creates a cellular environment that promotes oncogenesis, supporting the continuous growth of CMV-transformed cells. The aforementioned transformed cells, named CTH, CTO, and CTP cells, underwent giant cell cycling with PGCC generation parallel to dedifferentiation, displaying stem-like characteristics and an epithelial–mesenchymal transition (EMT) phenotype. Furthermore, we propose that giant cell cycling through PGCCs, increased EZH2 expression, EMT, and the acquisition of malignant traits represent a deleterious response to the cellular stress induced by high-risk oncogenic HCMV strains, the latter being the origin of the transformation process in epithelial cells upon HCMV infection and leading to adenocarcinoma of poor prognosis. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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12 pages, 1311 KiB

Open AccessReview

Engineering of RNase P Ribozymes for Therapy against Human Cytomegalovirus Infection

by Adam Smith, Isadora Zhang, Phong Trang and Fenyong Liu

Viruses 2024, 16(8), 1196; https://doi.org/10.3390/v16081196 - 25 Jul 2024

Viewed by 1469

Abstract

Nucleic acid-based gene interference and editing strategies, such as antisense oligonucleotides, ribozymes, RNA interference (RNAi), and CRISPR/Cas9 coupled with guide RNAs, are exciting research tools and show great promise for clinical applications in treating various illnesses. RNase P ribozymes have been engineered for [...] Read more.

Nucleic acid-based gene interference and editing strategies, such as antisense oligonucleotides, ribozymes, RNA interference (RNAi), and CRISPR/Cas9 coupled with guide RNAs, are exciting research tools and show great promise for clinical applications in treating various illnesses. RNase P ribozymes have been engineered for therapeutic applications against human viruses such as human cytomegalovirus (HCMV). M1 ribozyme, the catalytic RNA subunit of RNase P from Escherichia coli, can be converted into a sequence-specific endonuclease, M1GS ribozyme, which is capable of hydrolyzing an mRNA target base-pairing with the guide sequence. M1GS RNAs have been shown to hydrolyze essential HCMV mRNAs and block viral progeny production in virus-infected cell cultures. Furthermore, RNase P ribozyme variants with enhanced hydrolyzing activity can be generated by employing in vitro selection procedures and exhibit better ability in suppressing HCMV gene expression and replication in cultured cells. Additional studies have also examined the antiviral activity of RNase P ribozymes in mice in vivo. Using cytomegalovirus infection as an example, this review summarizes the principles underlying RNase P ribozyme-mediated gene inactivation, presents recent progress in engineering RNase P ribozymes for applications in vitro and in mice, and discusses the prospects of using M1GS technology for therapeutic applications against HCMV as well as other pathogenic viruses. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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17 pages, 1001 KiB

Open AccessReview

The Interactions of the Complement System with Human Cytomegalovirus

by Eduardo Lujan, Isadora Zhang, Andrea Canto Garon and Fenyong Liu

Viruses 2024, 16(7), 1171; https://doi.org/10.3390/v16071171 - 20 Jul 2024

Cited by 1 | Viewed by 1692

Abstract

The complement system is an evolutionarily ancient component of innate immunity that serves as an important first line of defense against pathogens, including viruses. In response to infection, the complement system can be activated by three distinct yet converging pathways (classical, lectin, and [...] Read more.

The complement system is an evolutionarily ancient component of innate immunity that serves as an important first line of defense against pathogens, including viruses. In response to infection, the complement system can be activated by three distinct yet converging pathways (classical, lectin, and alternative) capable of engaging multiple antiviral host responses to confront acute, chronic, and recurrent viral infections. Complement can exert profound antiviral effects via multiple mechanisms including the induction of inflammation and chemotaxis to sites of infection, neutralization/opsonization of viruses and virally infected cells, and it can even shape adaptive immune responses. With millions of years of co-evolution and the ability to establish life-long infections, herpesviruses have evolved unique mechanisms to counter complement-mediated antiviral defenses, thus enabling their survival and replication within humans. This review aims to comprehensively summarize how human herpesviruses engage with the complement system and highlight our understanding of the role of complement in human cytomegalovirus (HCMV) infection, immunity, and viral replication. Herein we describe the novel and unorthodox roles of complement proteins beyond their roles in innate immunity and discuss gaps in knowledge and future directions of complement and HCMV research. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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21 pages, 424 KiB

Open AccessReview

Overview of Cytomegalovirus Ocular Diseases: Retinitis, Corneal Endotheliitis, and Iridocyclitis

by Reiko Kobayashi and Noriyasu Hashida

Viruses 2024, 16(7), 1110; https://doi.org/10.3390/v16071110 - 11 Jul 2024

Cited by 3 | Viewed by 2020

Abstract

Cytomegalovirus (CMV) infection is a significant clinical concern in newborns, immunocompromised patients with acquired immunodeficiency syndrome (AIDS), and patients undergoing immunosuppressive therapy or chemotherapy. CMV infection affects many organs, such as the lungs, digestive organs, the central nerve system, and eyes. In addition, [...] Read more.

Cytomegalovirus (CMV) infection is a significant clinical concern in newborns, immunocompromised patients with acquired immunodeficiency syndrome (AIDS), and patients undergoing immunosuppressive therapy or chemotherapy. CMV infection affects many organs, such as the lungs, digestive organs, the central nerve system, and eyes. In addition, CMV infection sometimes occurs in immunocompetent individuals. CMV ocular diseases includes retinitis, corneal endotheliitis, and iridocyclitis. CMV retinitis often develops in infected newborns and immunocompromised patients. CMV corneal endotheliitis and iridocyclitis sometimes develop in immunocompetent individuals. Systemic infections and CMV ocular diseases often require systemic treatment in addition to topical treatment. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

17 pages, 1135 KiB

Open AccessReview

Cytomegalovirus Diseases of the Gastrointestinal Tract in Immunocompetent Patients: A Narrative Review

by Pai-Jui Yeh, Ren-Chin Wu, Chyi-Liang Chen, Cheng-Tang Chiu, Ming-Wei Lai, Chien-Chang Chen, Cheng-Hsun Chiu, Yu-Bin Pan, Wey-Ran Lin and Puo-Hsien Le

Viruses 2024, 16(3), 346; https://doi.org/10.3390/v16030346 - 23 Feb 2024

Cited by 5 | Viewed by 2916

Abstract

Cytomegalovirus (CMV) is a potential pathogen that causes gastrointestinal (GI) tract diseases regardless of host immunity. In contrast to immunocompromised individuals, immunocompetent patients lack a comprehensive overview of the gastrointestinal manifestations. This study aims to provide a comprehensive summary of the current evidence [...] Read more.

Cytomegalovirus (CMV) is a potential pathogen that causes gastrointestinal (GI) tract diseases regardless of host immunity. In contrast to immunocompromised individuals, immunocompetent patients lack a comprehensive overview of the gastrointestinal manifestations. This study aims to provide a comprehensive summary of the current evidence regarding presentations, diagnostics, management, risk assessment, and outcomes in immunocompetent patients with CMV GI disease. A thorough literature search of English publications up to April 2022 was conducted across electronic databases to identify relevant articles, with eligible case series selected for detailed analysis. The majority of immunocompetent patients affected by CMV GI disease are typically elderly, critically ill, or burdened with comorbidities that compromise immunity. Clinical presentations range from subtle symptoms to severe surgical conditions, including instances of mortality. Specific clinical presentations, blood test results, or endoscopic features are lacking, necessitating reliance on histopathological tests such as immunohistochemistry staining for diagnosis. While antiviral therapy may offer benefits in improving outcomes, careful individual assessment is warranted due to diverse comorbidities and potential side effects. Mortality rates vary considerably based on underlying medical conditions and therapeutic approaches. It is imperative for clinicians to maintain vigilance for CMV GI disease among high-risk groups, despite their baseline immunocompetence, in order to enhance clinical outcomes. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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17 pages, 811 KiB

Open AccessReview

Exploring the Potential of Cytomegalovirus-Based Vectors: A Review

by Janine Zeng, Dabbu Kumar Jaijyan, Shaomin Yang, Shaokai Pei, Qiyi Tang and Hua Zhu

Viruses 2023, 15(10), 2043; https://doi.org/10.3390/v15102043 - 2 Oct 2023

Cited by 4 | Viewed by 3616

Abstract

Viral vectors have emerged as powerful tools for delivering and expressing foreign genes, playing a pivotal role in gene therapy. Among these vectors, cytomegalovirus (CMV) stands out as a promising viral vector due to its distinctive attributes including large packaging capacity, ability to [...] Read more.

Viral vectors have emerged as powerful tools for delivering and expressing foreign genes, playing a pivotal role in gene therapy. Among these vectors, cytomegalovirus (CMV) stands out as a promising viral vector due to its distinctive attributes including large packaging capacity, ability to achieve superinfection, broad host range, capacity to induce CD8+ T cell responses, lack of integration into the host genome, and other qualities that make it an appealing vector candidate. Engineered attenuated CMV strains such as Towne and AD169 that have a ~15 kb genomic DNA deletion caused by virus passage guarantee human safety. CMV’s large genome enables the efficient incorporation of substantial foreign genes as demonstrated by CMV vector-based therapies for SIV, tuberculosis, cancer, malaria, aging, COVID-19, and more. CMV is capable of reinfecting hosts regardless of prior infection or immunity, making it highly suitable for multiple vector administrations. In addition to its broad cellular tropism and sustained high-level gene expression, CMV triggers robust, virus-specific CD8⁺ T cell responses, offering a significant advantage as a vaccine vector. To date, successful development and testing of murine CMV (MCMV) and rhesus CMV (RhCMV) vectors in animal models have demonstrated the efficacy of CMV-based vectors. These investigations have explored the potential of CMV vectors for vaccines against HIV, cancer, tuberculosis, malaria, and other infectious pathogens, as well as for other gene therapy applications. Moreover, the generation of single-cycle replication CMV vectors, produced by deleting essential genes, ensures robust safety in an immunocompromised population. The results of these studies emphasize CMV’s effectiveness as a gene delivery vehicle and shed light on the future applications of a CMV vector. While challenges such as production complexities and storage limitations need to be addressed, ongoing efforts to bridge the gap between animal models and human translation continue to fuel the optimism surrounding CMV-based vectors. This review will outline the properties of CMV vectors and discuss their future applications as well as possible limitations. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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42 pages, 4972 KiB

Open AccessReview

Insights into the Transcriptome of Human Cytomegalovirus: A Comprehensive Review

by Janine Zeng, Di Cao, Shaomin Yang, Dabbu Kumar Jaijyan, Xiaolian Liu, Songbin Wu, Ruth Cruz-Cosme, Qiyi Tang and Hua Zhu

Viruses 2023, 15(8), 1703; https://doi.org/10.3390/v15081703 - 8 Aug 2023

Cited by 4 | Viewed by 3062

Abstract

Human cytomegalovirus (HCMV) is a widespread pathogen that poses significant risks to immunocompromised individuals. Its genome spans over 230 kbp and potentially encodes over 200 open-reading frames. The HCMV transcriptome consists of various types of RNAs, including messenger RNAs (mRNAs), long non-coding RNAs [...] Read more.

Human cytomegalovirus (HCMV) is a widespread pathogen that poses significant risks to immunocompromised individuals. Its genome spans over 230 kbp and potentially encodes over 200 open-reading frames. The HCMV transcriptome consists of various types of RNAs, including messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs), with emerging insights into their biological functions. HCMV mRNAs are involved in crucial viral processes, such as viral replication, transcription, and translation regulation, as well as immune modulation and other effects on host cells. Additionally, four lncRNAs (RNA1.2, RNA2.7, RNA4.9, and RNA5.0) have been identified in HCMV, which play important roles in lytic replication like bypassing acute antiviral responses, promoting cell movement and viral spread, and maintaining HCMV latency. CircRNAs have gained attention for their important and diverse biological functions, including association with different diseases, acting as microRNA sponges, regulating parental gene expression, and serving as translation templates. Remarkably, HCMV encodes miRNAs which play critical roles in silencing human genes and other functions. This review gives an overview of human cytomegalovirus and current research on the HCMV transcriptome during lytic and latent infection. Full article

(This article belongs to the Special Issue 65-Year Anniversary of the Discovery of Cytomegalovirus)

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