scholarly journals Intrinsic Immune Mechanisms Restricting Human Cytomegalovirus Replication

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 179
Author(s):  
Eva-Maria Schilling ◽  
Myriam Scherer ◽  
Thomas Stamminger
Keyword(s):  
Human Cytomegalovirus ◽  
Viral Entry ◽  
Hcmv Infection ◽  
Current Knowledge ◽  
Cytidine Deaminase ◽  
Regulatory Protein ◽  
Detailed Knowledge ◽  
Restriction Factors ◽  
Immune Mechanisms ◽  
Early Protein

Cellular restriction factors (RFs) act as important constitutive innate immune barriers against viruses. In 2006, the promyelocytic leukemia protein was described as the first RF against human cytomegalovirus (HCMV) infection which is antagonized by the viral immediate early protein IE1. Since then, at least 15 additional RFs against HCMV have been identified, including the chromatin regulatory protein SPOC1, the cytidine deaminase APOBEC3A and the dNTP triphosphohydrolase SAMHD1. These RFs affect distinct steps of the viral replication cycle such as viral entry, gene expression, the synthesis of progeny DNA or egress. This review summarizes our current knowledge on intrinsic immune mechanisms restricting HCMV replication as well as on the viral strategies to counteract the inhibitory effects of RFs. Detailed knowledge on the interplay between host RFs and antagonizing viral factors will be fundamental to develop new approaches to combat HCMV infection.

scholarly journals Host Cell Restriction Factors of Bunyaviruses and Viral Countermeasures

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 784
Author(s):  
Solène Lerolle ◽  
Natalia Freitas ◽  
François-Loïc Cosset ◽  
Vincent Legros
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
Current Knowledge ◽  
Restriction Factors ◽  
Antiviral State ◽  
Cellular Factors ◽  
Pathogenic Viruses ◽  
Genome Transcription ◽  
Infected Cells ◽  
Molecular Patterns

The Bunyavirales order comprises more than 500 viruses (generally defined as bunyaviruses) classified into 12 families. Some of these are highly pathogenic viruses infecting different hosts, including humans, mammals, reptiles, arthropods, birds, and/or plants. Host cell sensing of infection activates the innate immune system that aims at inhibiting viral replication and propagation. Upon recognition of pathogen-associated molecular patterns (PAMPs) by cellular pattern recognition receptors (PRRs), numerous signaling cascades are activated, leading to the production of interferons (IFNs). IFNs act in an autocrine and paracrine manner to establish an antiviral state by inducing the expression of hundreds of IFN-stimulated genes (ISGs). Some of these ISGs are known to restrict bunyavirus infection. Along with other constitutively expressed host cellular factors with antiviral activity, these proteins (hereafter referred to as “restriction factors”) target different steps of the viral cycle, including viral entry, genome transcription and replication, and virion egress. In reaction to this, bunyaviruses have developed strategies to circumvent this antiviral response, by avoiding cellular recognition of PAMPs, inhibiting IFN production or interfering with the IFN-mediated response. Herein, we review the current knowledge on host cellular factors that were shown to restrict infections by bunyaviruses. Moreover, we focus on the strategies developed by bunyaviruses in order to escape the antiviral state developed by the infected cells.

scholarly journals Foamy Viruses, Bet, and APOBEC3 Restriction

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 504
Author(s):  
Ananda Ayyappan Jaguva Vasudevan ◽  
Daniel Becker ◽  
Tom Luedde ◽  
Holger Gohlke ◽  
Carsten Münk
Keyword(s):  
Current Knowledge ◽  
Regulatory Protein ◽  
Host Population ◽  
Life Cycles ◽  
Restriction Factors ◽  
Host Restriction ◽  
Open Questions ◽  
Foamy Viruses ◽  
Natural Hosts ◽  
Hiv 1

Non-human primates (NHP) are an important source of viruses that can spillover to humans and, after adaptation, spread through the host population. Whereas HIV-1 and HTLV-1 emerged as retroviral pathogens in humans, a unique class of retroviruses called foamy viruses (FV) with zoonotic potential are occasionally detected in bushmeat hunters or zookeepers. Various FVs are endemic in numerous mammalian natural hosts, such as primates, felines, bovines, and equines, and other animals, but not in humans. They are apathogenic, and significant differences exist between the viral life cycles of FV and other retroviruses. Importantly, FVs replicate in the presence of many well-defined retroviral restriction factors such as TRIM5α, BST2 (Tetherin), MX2, and APOBEC3 (A3). While the interaction of A3s with HIV-1 is well studied, the escape mechanisms of FVs from restriction by A3 is much less explored. Here we review the current knowledge of FV biology, host restriction factors, and FV–host interactions with an emphasis on the consequences of FV regulatory protein Bet binding to A3s and outline crucial open questions for future studies.

scholarly journals Anti-IE1 CD4+ T-cell clones kill peptide-pulsed, but not human cytomegalovirus-infected, target cells

2007 ◽  
Vol 88 (9) ◽  
pp. 2441-2449 ◽  
Author(s):  
Sandra Delmas ◽  
Pierre Brousset ◽  
Danièle Clément ◽  
Emmanuelle Le Roy ◽  
Jean-Luc Davignon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Cytomegalovirus ◽  
Antigen Processing ◽  
Hcmv Infection ◽  
Target Cells ◽  
T Cell Clones ◽  
Early Protein ◽  
Cell Clones ◽  
Precise Role

Cellular immunity plays a major role in the control of human cytomegalovirus (HCMV) infection. CD4+ T lymphocytes have been shown to contribute to this function but their precise role is a matter of debate. Although CD4+ T cells have been shown to kill target cells through the perforin/granzyme pathway, whether HCMV-specific CD4+ T cells are capable of killing HCMV-infected targets has not yet been documented. In the present paper, we have taken advantage of well established cellular reagents to address this issue. Human CD4+ T-cell clones specific for the major immediate-early protein IE1 were shown to perform perforin-based cytotoxicity against peptide-pulsed targets. However, when tested on infected anitgen presenting cell targets, cytotoxicity was not detectable, although gamma interferon (IFN-γ) production was significant. Furthermore, cytotoxicity against peptide-pulsed targets was inhibited by HCMV infection, whereas IFN-γ production was not modified, suggesting that antigen processing was not altered. Remarkably, degranulation of CD4+ T cells in the presence of infected targets was significant. Together, our data suggest that impaired cytotoxicity is not due to failure to recognize infected targets but rather to a mechanism specifically related to cytotoxicity.

scholarly journals The role of human cytomegalovirus in atherosclerosis: a systematic review

2020 ◽  
Vol 52 (4) ◽  
pp. 339-353
Author(s):  
Wenbo Zhu ◽  
Shuangquan Liu
Keyword(s):  
Human Cytomegalovirus ◽  
Molecular Mechanisms ◽  
Hcmv Infection ◽  
Vascular Endothelial Cells ◽  
Current Knowledge ◽  
Modern Society ◽  
Underlying Mechanism ◽  
Mirna Regulation ◽  
Diverse Range ◽  
Infected Cells

Abstract Atherosclerosis is a progressive vascular disease with increasing morbidity and mortality year by year in modern society. Human cytomegalovirus (HCMV) infection is closely associated with the development of atherosclerosis. HCMV infection may accelerate graft atherosclerosis and the development of transplant vasculopathy in organ transplantation. However, our current understanding of HCMV-associated atherosclerosis remains limited and is mainly based on clinical observations. The underlying mechanism of the involvement of HCMV infection in atherogenesis remains unclear. Here, we summarized current knowledge regarding the multiple influences of HCMV on a diverse range of infected cells, including vascular endothelial cells, vascular smooth muscle cells, monocytes, macrophages, and T cells. In addition, we described potential HCMV-induced molecular mechanisms, such as oxidative stress, endoplasmic reticulum stress, autophagy, lipid metabolism, and miRNA regulation, which are involved in the development of HCMV-associated atherogenesis. Gaining an improved understanding of these mechanisms will facilitate the development of novel and effective therapeutic strategies for the treatment of HCMV-related cardiovascular disease.

scholarly journals Proteasome Subunits Relocalize during Human Cytomegalovirus Infection, and Proteasome Activity Is Necessary for Efficient Viral Gene Transcription

2009 ◽  
Vol 84 (6) ◽  
pp. 3079-3093 ◽  
Author(s):  
Karen Tran ◽  
Jeffrey A. Mahr ◽  
Deborah H. Spector
Keyword(s):  
Dna Replication ◽  
Dna Synthesis ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Proteasome Activity ◽  
Late Gene ◽  
Viral Dna ◽  
Rna Transcription ◽  
Viral Dna Replication ◽  
Early Protein

ABSTRACT We have continued studies to further understand the role of the ubiquitin-proteasome system (UPS) in human cytomegalovirus (HCMV) infection. With specific inhibitors of the proteasome, we show that ongoing proteasome activity is necessary for facilitating the various stages of the infection. Immediate-early protein 2 expression is modestly reduced with addition of proteasome inhibitors at the onset of infection; however, both early and late gene expression are significantly delayed, even if the inhibitor is removed at 12 h postinfection. Adding the inhibitor at later times during the infection blocks the further accumulation of viral early and late gene products, the severity of which is dependent on when the proteasome is inhibited. This can be attributed primarily to a block in viral RNA transcription, although DNA synthesis is also partially inhibited. Proteasome activity and expression increase as the infection progresses, and this coincides with the relocalization of active proteasomes to the periphery of the viral DNA replication center, where there is active RNA transcription. Interestingly, one 19S subunit, Rpn2, is specifically recruited into the viral DNA replication center. The relocalization of the subunits requires viral DNA replication, but their maintenance around or within the replication center is not dependent on continued viral DNA synthesis or the proteolytic activity of the proteasome. These studies highlight the importance of the UPS at all stages of the HCMV infection and support further studies into this pathway as a potential antiviral target.

scholarly journals Positive Expression of Human Cytomegalovirus Phosphoprotein 65 in Atherosclerosis

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Zhe Wang ◽  
Jun Cai ◽  
Mingming Zhang ◽  
Xiaojing Wang ◽  
Hongjie Chi ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Foam Cell ◽  
Collagen Fibers ◽  
High Rate ◽  
Early Protein ◽  
Formalin Fixed Paraffin Embedded ◽  
Masson Trichrome Staining

Previous studies showed that human cytomegalovirus (HCMV) is associated with atherosclerosis. However, local vascular atherosclerosis related HCMV infection and protein expression remain unclear. This study aimed to assess the relationship between HCMV infection and atherosclerosis. Formalin-fixed, paraffin-embedded peripheral artery specimens were obtained from 15 patients with atherosclerosis undergoing vascular surgery from 2008 to 2010 at Zhongnan Hospital, Wuhan University. Pathological analyses were carried out after hematoxylin and eosin (H&E) and Masson trichrome staining. In situ hybridization and immunohistochemistry with two different monoclonal antibodies were employed to detect HCMV nucleic acids and proteins, respectively. H&E and Masson trichrome staining showed homogeneous extracellular matrix in femoral artery, while smooth muscle fibers were interlaced with collagen fibers; in carotid artery, inflammatory cell infiltration, foam cell vascular change, cholesterol crystals, and layered collagen fibers were observed. In situ hybridization showed no expression of HCMV nucleic acids in all 15 cases. Immunohistochemical staining for protein immediate-early protein (IE1 72) was negative in all cases, while phosphoprotein 65 (pp65) expression was detected in 14 cases. A high rate of positive pp65 signals was found in patients with atherosclerosis, suggesting that local HCMV infection may be associated with the pathogenesis of atherosclerosis. Further studies on this relationship are warranted.

scholarly journals Human Cytomegalovirus Stimulates the Synthesis of Select Akt-Dependent Antiapoptotic Proteins during Viral Entry To Promote Survival of Infected Monocytes

2016 ◽  
Vol 90 (6) ◽  
pp. 3138-3147 ◽  
Author(s):  
Megan A. Peppenelli ◽  
Kyle C. Arend ◽  
Olesea Cojohari ◽  
Nathaniel J. Moorman ◽  
Gary C. Chan
Keyword(s):  
Life Span ◽  
Human Cytomegalovirus ◽  
Viral Entry ◽  
Peripheral Blood ◽  
Primary Infection ◽  
Hcmv Infection ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Viral Dissemination ◽  
Antiapoptotic Proteins

ABSTRACTPrimary peripheral blood monocytes are responsible for the hematogenous dissemination of human cytomegalovirus (HCMV) following a primary infection. To facilitate viral spread, we have previously shown HCMV to extend the short 48-h life span of monocytes. Mechanistically, HCMV upregulated two specific cellular antiapoptotic proteins, myeloid leukemia sequence 1 (Mcl-1) and heat shock protein 27 (HSP27), to block the two proteolytic cleavages necessary for the formation of fully active caspase 3 and the subsequent initiation of apoptosis. We now show that HCMV more robustly upregulated Mcl-1 than normal myeloid growth factors and that Mcl-1 was the only myeloid survival factor to rapidly induce HSP27 prior to the 48-h cell fate checkpoint. We determined that HCMV glycoproteins gB and gH signal through the cellular epidermal growth factor receptor (EGFR) and αvβ3 integrin, respectively, during viral entry in order to drive the increase of Mcl-1 and HSP27 in an Akt-dependent manner. Although Akt is known to regulate protein stability and transcription, we found that gB- and gH-initiated signaling preferentially and cooperatively stimulated the synthesis of Mcl-1 and HSP27 through mTOR-mediated translation. Overall, these data suggest that the unique signaling network generated during the viral entry process stimulates the upregulation of select antiapoptotic proteins allowing for the differentiation of short-lived monocytes into long-lived macrophages, a key step in the viral dissemination strategy.IMPORTANCEHuman cytomegalovirus (HCMV) infection is endemic within the human population. Although primary infection is generally asymptomatic in immunocompetent individuals, HCMV is a significant cause of morbidity and mortality in the immunocompromised. The multiorgan inflammatory diseases associated with symptomatic HCMV infection are a direct consequence of the monocyte-mediated systemic spread of the virus. In order for peripheral blood monocytes to facilitate viral dissemination, HCMV subverts the short 48-h life span of monocytes by inducing the expression of cellular antiapoptotic proteins Mcl-1 and HSP27. Here, we demonstrate that the rapid and simultaneous upregulation of Mcl-1 and HSP27 is a distinctive feature of HCMV-induced monocyte survival. Moreover, we decipher the signaling pathways activated during viral entry needed for the robust synthesis of Mcl-1 and HSP27. Identifying the virus-specific mechanisms used to upregulate select cellular factors required for the survival of HCMV-infected monocytes is important to the development of new classes of anti-HCMV drugs.

scholarly journals Detection of Human Cytomegalovirus in Patients with Epithelial Ovarian Cancer and its Impacts on Survival

2020 ◽  
Author(s):  
Min Yin ◽  
Aiping Chen ◽  
Fei Zhao ◽  
Xuechao Ji ◽  
Chuan Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Epithelial Ovarian Cancer ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Benign Tumors ◽  
Early Protein ◽  
Viral Carcinogenesis ◽  
Formalin Fixed Paraffin Embedded

Abstract Background: The cause of epithelial ovarian cancer(EOC) is not elucidated. Viral infection may induce chronic inflammatory infection and play a role in the pathogenesis of cancers. Some viruses are considered to be oncomodulatory, modulating cellular pathways such as cell proliferation, tumor progression, vascular disease development, and immune evasion. Human cytomegalovirus (HCMV) has been detected in several types of cancers including ovarian cancer. However, the role of HCMV in ovarian carcinogenesis remains controversial. Objective: To investigate the potential role of HCMV infection in EOC, we evaluated the prevalence of HCMV proteins in EOC tissue and its impacts on patients’ survival. Methods: Formalin-fixed, paraffin-embedded tissues from 66 patients with EOC and 30 patients with benign ovarian cystadenoma were studied. Specimens were detected for expression of HCMV immediate-early protein (IE) and HCMV tegument protein (pp65) by immunohistochemistry. Results: HCMV-IE protein expression was detected in 82% of EOC and 36% of benign tumors; pp65 was detected in 97% of EOC and 63% of benign tumors. Extensive expression of HCMV-IE protein was associated with higher stage of EOC. Reactivation of latent HCMV within the tumor at interval debulking surery may be induced by neoadjuvant chemotherapy before surgery. Extensive HCMV-IE expression was associated with shorter median overall survival than focal or negative expression (39 versus 41 months, P=0.03). Multivariate analysis indicated that HCMV-IE expression was an independent prognostic factor for overall survival (P = 0.034). Conclusions: This study demonstrate a high prevalence of HCMV proteins in tissue sections from patients with EOC. HCMV infection can be potential risk factor for EOC development. Extensive HCMV-IE expression indicated a poor prognosis. The relationship between HCMV and clinical outcomes highlight the need for further researches on the oncomodulatory of HCMV in ovarian cancer. Keywords: Epithelial ovarian cancer, Human cytomegalovirus, Viral carcinogenesis, Survival

scholarly journals Detection of Human Cytomegalovirus in Patients with Epithelial Ovarian Cancer and its Impacts on Survival

2020 ◽  
Author(s):  
Min Yin ◽  
Aiping Chen ◽  
Fei Zhao ◽  
Xuechao Ji ◽  
Chuan Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Protein Expression ◽  
Epithelial Ovarian Cancer ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Benign Tumors ◽  
Early Protein ◽  
Formalin Fixed Paraffin Embedded

Abstract Background: The cause of epithelial ovarian cancer(EOC) is not elucidated. Viral infection may induce chronic inflammatory infection and play a role in the pathogenesis of cancers. Some viruses are considered to be oncomodulatory, modulating cellular pathways such as cell proliferation, tumor progression, vascular disease development, and immune evasion. Human cytomegalovirus (HCMV) has been detected in several types of cancers including ovarian cancer. However, the role of HCMV in ovarian carcinogenesis remains controversial.Objective: To investigate the potential role of HCMV infection in EOC, we evaluated the prevalence of HCMV proteins in EOC tissue and its impacts on patients’ survival.Methods: Formalin-fixed paraffin-embedded tissues from 66 patients with EOC and 30 patients with benign ovarian cystadenoma were studied. Specimens were analyzed for expression of HCMV immediate early protein (IE) and HCMV tegument protein (pp65) by immunohistochemistry. Results: HCMV-IE protein expression was detected in 82% of EOC and 36% of benign tumors; pp65 was detected in 97% of EOC and 63% of benign tumors. Extensive HCMV-IE protein expression was associated with higher stage of EOC. Reactivation of latent HCMV within the tumor at interval debulking surgery may be induced by neoadjuvant chemotherapy before surgery. Extensive HCMV-IE expression was associated with shorter median overall survival than focal or negative expression (39 versus 41 months, P=0.03). Multivariate analysis indicated that HCMV-IE expression was an independent prognostic factor for overall survival (P = 0.034). Conclusions: This study demonstrate a high prevalence of HCMV proteins in tissue sections from patients with EOC. HCMV infection can be potential risk factor for EOC development. Extensive HCMV-IE expression indicated a poor prognosis. The relationship between HCMV and clinical outcomes highlight the need for further researches on the oncomodulatory role of HCMV in ovarian cancer.

scholarly journals E2F mediates dihydrofolate reductase promoter activation and multiprotein complex formation in human cytomegalovirus infection.

1992 ◽  
Vol 12 (10) ◽  
pp. 4364-4374 ◽  
Author(s):  
M Wade ◽  
T F Kowalik ◽  
M Mudryj ◽  
E S Huang ◽  
J C Azizkhan
Keyword(s):  
Human Cytomegalovirus ◽  
Dihydrofolate Reductase ◽  
Hcmv Infection ◽  
Cyclin A ◽  
Immediate Early Gene ◽  
Early Gene ◽  
Immediate Early ◽  
Gene Promoters ◽  
Cellular Gene ◽  
Early Protein

The adenovirus immediate-early protein E1A activates the adenovirus E2 promoter and several cellular gene promoters through transcription factor E2F. The immediate-early proteins of human cytomegalovirus (HCMV) can complement an E1A-deficient adenovirus mutant and activate the adenovirus E2 promoter. HCMV also has been shown to activate the adenovirus E2 promoter. On the basis of these findings, we have investigated whether HCMV can activate the promoter of the cellular dihydrofolate reductase (DHFR) gene, which requires E2F binding for maximal promoter activity. We show that HCMV activates the DHFR promoter and that products of the HCMV major immediate-early gene region mediate the activation of the promoter specifically through the E2F site. We used gel mobility shift assays to search for potential molecular mechanisms for this activation and found an "infection-specific" multimeric complex that bound to the E2F sites in the DHFR and E2 promoters in extracts from HCMV-infected cells but not in extracts from uninfected cells. Several antibodies against HCMV immediate-early gene products had no effect on this infection-specific complex. Subsequently, the complex was found to contain E2F, cyclin A, p33cdk2, and p107 and to be similar to S-phase-specific complexes that recently have been identified in several cell types. A functional role for the binding of the cyclin A-p33cdk2 complex to cellular gene promoters has yet to be demonstrated; however, HCMV infection causes the induction of both cellular DNA replication and transcription of growth-related genes containing E2F sites in their promoters. The findings described above therefore may relate to both of these effects of HCMV infection. We also provide evidence that some of the molecular events associated with adenovirus infection are different from those associated with HCMV infection.

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