Modulation of host cell signaling during cytomegalovirus latency and reactivation
20
Citation
168
Reference
10
Related Paper
Citation Trend
Abstract:
Abstract Background Human cytomegalovirus (HCMV) resides latently in cells of the myeloid compartment, including CD34 + hematopoietic progenitor cells and circulating monocytes. Healthy hosts maintain the virus latently, and this infection is, for the most part, asymptomatic. However, given the proper external cues, HCMV reactivates from latency, at which point the virus disseminates, causing disease. The viral and cellular factors dictating the balance between these phases of infection are incompletely understood, though a large body of literature support a role for viral-mediated manipulation of host cell signaling. Main body To establish and maintain latency, HCMV has evolved various means by which it usurps host cell factors to alter the cellular environment to its own advantage, including altering host cell signaling cascades. As early as virus entry into myeloid cells, HCMV usurps cellular signaling to change the cellular milieu, and this regulation includes upregulation, as well as downregulation, of different signaling cascades. Indeed, given proper reactivation cues, this signaling is again altered to allow for transactivation of viral lytic genes. Conclusions HCMV modulation of host cell signaling is not binary, and many of the cellular pathways altered are finely regulated, wherein the slightest modification imparts profound changes to the cellular milieu. It is also evident that viral-mediated cell signaling differs not only between these phases of infection, but also is myeloid cell type specific. Nonetheless, understanding the exact pathways and the means by which HCMV mediates them will undoubtedly provide novel targets for therapeutic intervention.Keywords:
Cytomegalovirus
There are no specific ways to prevent and cure human cytomegalovirus (HCMV) infection to date. We investigate the effect and mechanism of baicalein (BAI) and genistein (GEN) used as a drug to inhibit HCMV infection in human astrocyte(AS). RT-qPCR was used to detect the expression changes of viral IE1,IE2 genes. Chromatin immunoprecipitation assay (ChIP) was used to detect the expression change of major immediate early promoter (MIEP). RT-qPCR results showed that compared with HCMV group, 20 μmol/L BAI+HCMV,HCMV+BAI group, and 10 μmol/L GEN+HCMV,HCMV+GEN group can down-regulate the IE1,IE2 genes expressions. ChIP results showed that compared with HCMV group, 20 μmol/L BAI+HCMV,HCMV+BAI group, and 10 μmol/L GEN+HCMV and HCMV+GEN group can reduce histone acetylation of MIEP. A certain concentration of BAI or GEN can inhibit the human astrocyte’s IE1 and IE2 to some extent. The inhibiting mechanism may be that BAI and GEN can decrease the expression of IE1,IE2 genes and also inhibit histone acetylation of MIEP, thus decrease the expression of IE1,IE2 genes, which makes BAI and GEN inhibit viral proliferation.
Baicalein
Chromatin immunoprecipitation
Immediate early gene
Cite
Citations (1)
ヒトサイトメガロウイルス (human cytomegalovirus: HCMV) の治療薬として，現在ガンシクロビル (GCV) とホスカルネット (PFA) が使用されているが，易感染性宿主の HCMV 感染症には，抗 HCMV 薬の長期投与が必要なため，薬物耐性 HCMV の出現が問題となっており，作用機序の異なる新たな治療薬の開発が求められている． 現在我々は，代替医療薬を中心に抗 HCMV 薬の探索を行っている．今回は，防腐作用や殺菌作用などがあることが知られているクマザサを用い，その抽出物に，抗 HCMV 効果があるか否かについて検討した．クマザサ抽出液をウイルス感染細胞に添加したところ，濃度依存的にウイルスの細胞変性効果が抑制され，ウイルス粒子産生にも抑制がみられた．また，リアルタイム RT-PCR 法および，ウエスタンブロット法による解析の結果，クマザサ抽出液によりウイルスの複製，増殖に重要な Major immediate early (IE) 遺伝子の発現に抑制がみられたことから，クマザサ抽出液は GCV とは異なる作用機序により抗 HCMV 効果をもつ可能性が示された．
Sasa
Cytomegalovirus
Cite
Citations (2)
Despite the researchers’ efforts, the cause and development of breast cancer is still incompletely understood. Currently, in some reports, human cytomegalovirus has been referred as a risk factor for breast cancer. This study aimed to determine relative frequency of cytomegalovirus in tissue samples of women with breast cancer in Sanandaj County. In this study, to determine the relative frequency of the human cytomegalovirus (CMV) 50 formalin-fixed tissues of breast cancer, which all were invasive ductal carcinoma, were studied using the nested-polymerase chain reaction. In 26 cases of breast cancer tissues (26/50), human cytomegalovirus was detected. Seventeen cases of breast cancer tissues were in a moderately differentiated stage, and nine cases had poor-differentiated stage tissues that were positive for viral DNA. At older ages (>45 years) the prevalence rate of human cytomegalovirus DNA was higher, but no significant association was seen (p=0.16). In general, due to the high prevalence of the DNA of human cytomegalovirus (58%), in this study it is assumed that human cytomegalovirus (HCMV) has a contributing role in breast cancer; although more study is required to clearly define its part in this type of cancer.
Cytomegalovirus
Cite
Citations (4)
The possible correlation between cytomegalovirus, human herpesvirus types 6, 7 and cytomegalovirus-related clinical symptoms was studied in kidney transplant patients in Kuwait. Cytomegalovirus infection was diagnosed using the pp65 antigenemia assay. DNA of cytomegalovirus was detected by nested polymerase chain reaction (nested-PCR). PCR was also used to amplify the genes coding for structural proteins of human herpesvirus-6 (240 bp) and human herpesvirus-7 (186 bp). Glycoprotein B genotypes of cytomegalovirus were determined by restriction fragment length polymorphism. The average number of cells positive for cytomegalovirus pp65 antigen showed a steady increase with the severity of the cytomegalovirus-related symptoms. Furthermore, cytomegalovirus pp65 antigen positivity was significantly more frequent among recipients of cadaver kidney (45.5%) than among those who received live related kidneys (22.6%). Cytomegalovirus gB genotype 1 was detected more frequently (P<0.036) in recipients with live related donor kidney (38%) than in patients of cadaver kidney (13%). The genome of human herpesvirus-6 was detected at the same rate in patients with or without cytomegalovirus-related symptoms. However, the genome of human herpesvirus-7 was detected significantly more frequently (P<0.0001) in asymptomatic patients (41.7%) than in recipients with symptomatic cytomegalovirus infection (17%). We conclude that cytomegalovirus gB genotypes are not associated with the outcome of a cytomegalovirus infection in kidney transplant patients, that human herpesvirus-6 does not play a role in cytomegalovirus pathogenesis and that the role of human herpesvirus-7 in cytomegalovirus-related morbidity in kidney recipients remains unclear.
Cytomegalovirus
Betaherpesvirinae
Cite
Citations (20)
Since murine cytomegalovirus (MCMV) was first described in 1954, it has been used to model human cytomegalovirus (HCMV) diseases. MCMV is a natural pathogen of mice that is present in wild mice populations and has been associated with diseases such as myocarditis. The species-specific nature of HCMV restricts most research to cell culture-based studies or to the investigation of non-invasive clinical samples, which may not be ideal for the study of disseminated disease. Initial MCMV research used a salivary gland-propagated virus administered via different routes of inoculation into a variety of mouse strains. This revealed that the genetic background of the laboratory mice affected the severity of disease and altered the extent of subsequent pathology. The advent of genetically modified mice and viruses has allowed new aspects of disease to be modeled and the opportunistic nature of HCMV infection to be confirmed. This review describes the different ways that MCMV has been used to model HCMV diseases and explores the continuing difficulty faced by researchers attempting to model HCMV congenital cytomegalovirus disease using the mouse model.
Cytomegalovirus
Betaherpesvirinae
Cite
Citations (37)
Abstract Background: Human cytomegalovirus (HCMV) is a beta-hersvirinae that has a high latent infection rate worldwide and can cause serious consequences in immunocompromised patients when reactivation; however, the mechanism of how HCMV convert from latent to reactivation has rarely been investigated. In the present study, we aimed to perform a comprehensive analysis of the HCMV-encoded microRNA (miRNA) profile in serum of patients upon HCMV reactivation from latency and to further evaluate its clinical significance for the disease monitoring and preventing usefulness. Methods: Serum samples from 59 viremia patients and 60 age-gender matched controls were enrolled in this study for screening and validation of different expression of HCMV miRNAs. Serum concentrations of 22 known HCMV miRNAs were determined by a hydrolysis probe-based stem-loop quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay. HCMV DNA was measured by quantitative real-time PCR (qPCR) with the whole blood sample. Serum HCMV IgG and IgM were assessed using enzyme linked immunosorbent assay (ELISA). Another 47 samples from 5 patients at different time points were collected to evaluate the monitoring effectiveness and disease prediction ability of differential expression HCMV-miRNAs during the antiviral treatment. Results: The RT-qPCR analysis revealed that the serum levels of 16 of the 22 examined HCMV miRNAs were elevated in HCMV viremia patients compared with controls, and a profile of 8 HCMV miRNAs including hcmv-miR-US25-2-3p, hcmv-miR-US4-5p, hcmv-miR-US25-2-5p, hcmv-miR-US25-1-3p, hcmv-miR-US25-1, hcmv-miR-UL36, hcmv-miR-UL148D, hcmv-miR-US29-3p were markedly elevated (fold change > 2, P < 0.01). Receiver operating characteristic curve (ROC) analysis were performed on the selected HCMV-miRNAs in all of the patients and controls that enrolled in this study, and which ranged from 0.72 to 0.80 in the autoimmune patients. In addition, hcmv-miR-US25-1-3p levels were significantly correlated with HCMV DNA load (r = 0.349，P = 0.007), and were obviously higher in the reactivation set than the latency set in the autoimmune patients, which could be a predictor for the monitoring of the antiviral treatment. Conclusions: HCMV miRNAs profile showed markedly shift-switch from latency to reactivation in circulation from HCMV infected patients and hcmv-miR-US25-1-3p may be served as a predictor for the switch upon reactivation from latency in patients suffered with autoimmune diseases.
Viremia
Virus latency
Cite
Citations (0)
ABSTRACT We identified a 6-aminoquinolone compound, WC5, that inhibits human cytomegalovirus (HCMV) replication with a selectivity index of ∼500. WC5 also showed activity against drug-resistant HCMV strains. In contrast, it did not significantly affect the replication of human herpesvirus 6 and 8 and was ∼10-fold less active against murine cytomegalovirus. Thus, WC5 may represent a lead for the development of new, potent, and selective anti-HCMV compounds.
Cytomegalovirus
Cite
Citations (25)
背景人的 cytomegalovirus (HCMV ) 在 vivo 感染很多个机关和纸巾。不同症状和 HCMV 感染的织物向性也许源于基因多型性。包含至少 19 个开的读物框架(ORF )( 到 151 的表示 UL133 ) 的 DNA 的一个新区域在低经过的 HCMV 临床的种类， Toledo，和几其它被发现低经过临床孤立，然而并非在 HCMV 实验室种类在场， AD169。这些基因之一， UL143 ，被学习在 HCMV 探索 UL143 ORF 的顺序可变性临床孤立并且检验在基因可变性和 HCMV infection.Methods 的结果之间的可能的协会从怀疑的天生地 感染HCMV 的婴儿获得的种类的 UL143 基因被聚合酶链反应( PCR )和 sequenced.Results 放大种类的十九个序列被划分成 2 个主要的组， G1 ( n=16 )和 G2 ( n=3 )。所有与 Toledo 相比序列有框架移动变化。核苷酸多型性授与实质的氨基酸替换什么时候与 Toledo 相比。在 G1 的种类的所有 16 UL143 通常认为的蛋白质由于错误感觉变化有一个新 myristylation 地点和二个 PKC 地点的损失。没有有说服力的关系在 HCMV 疾病的存在之间被观察， UL 143 顺序 group.Conclusions HCMV-UL143 在低经过存在孤立。框架移动变化引起的顺序可变性在所有 HCMV 临床的种类被发现。没有明显的连接在 UL143 多型性和怀疑的先天的 HCMV 感染的结果之间被观察。
Cytomegalovirus
Cite
Citations (0)
Human cytomegalovirus (HCMV) is a common pathogen that causes persistent infections in immune deficient patients and results in significant morbidity and mortality, particularly among transplant recipients and children. Different HCMV glycoprotein H (gH) genotypes may cause different diseases and affect the severity of these diseases. To develop a sensitive quantitative real-time PCR assay that could rapidly distinguish between two HCMV gH genotypes, primers were designed to target the conserved region of the gH gene. gH1 and gH2 probes were designed to target the two variable regions. Standard HCMV strains (AD169 and TOWNE) and 203 clinical urine samples from HCMV infected children were used for the present study. Based on the primer-probe set used to detect the target gH gene segment of HCMV, our quantitative real-time PCR assay specifically discriminated between HCMV gH1 and gH2 with a detection limit of approximately 10(2) viral copies/ml. Among the 203 clinical urine samples tested, 145 were gH1 positive, 56 were gH2 positive, and 2 were positive for both. Thus, we developed a gH gene-based real time-PCR method that could rapidly, stably, and specifically distinguish between two HCMV gH genotypes. We found HCMV gH1 to be common among children examined in Zhejiang, China.
Betaherpesvirinae
Cytomegalovirus
Primer (cosmetics)
Cite
Citations (7)
Abstract Human cytomegalovirus (HCMV) is a prevalent herpesvirus, infecting the majority of the human population. Like other herpesviruses, it causes lifelong infection through the establishment of latency. Although reactivation from latency can cause significant morbidity and mortality in immunocompromised hosts, our understanding of HCMV latency and how it is maintained remains limited. Here, we discuss the characterized latency reservoir in hematopoietic cells in the bone marrow and the gaps in our knowledge of mechanisms that facilitate HCMV genome maintenance in dividing cells. We further review clinical evidence that strongly suggests the tissue origin of HCMV reactivation, and we outline similarities to murine cytomegalovirus where latency in tissue‐resident cells has been demonstrated. Overall, we think these observations call for a rethinking of HCMV latency reservoirs and point to potential sources of HCMV latency that reside in tissues.
Cytomegalovirus
Betaherpesvirinae
Cite
Citations (15)