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PubMed2005

HCMV-encoded G-protein-coupled receptors as constitutively active modulators of cellular signaling networks.

Several herpesviruses encode G-protein-coupled receptor (vGPCR) proteins that are homologous to human chemokine receptors. In contrast to chemokine receptors, many vGPCRs signal in a ligand-independent (constitutive) manner. Such constitutive signaling is of major significance because various pathologies are associated with activating GPCR mutations. Constitutive activity of the human herpesvirus 8-encoded GPCR (ORF74), for example, is essential for its oncogenic potential to cause angioproliferative Kaposi's sarcoma-like lesions. The human cytomegalovirus (HCMV) encodes four GPCRs, of which US28 and UL33 display constitutive activity in transfected, but also HCMV-infected, cells. In addition, US28 is activated by a broad spectrum of chemokines. Furthermore, both US28 and UL33 show promiscuous G-protein coupling, whereas chemokine receptors activate primarily G(i/o) proteins. Thus, these vGPCRs are versatile signaling devices, reprogramming cellular signaling networks to modulate cellular function after infection. By these means, these HCMV-encoded receptors might contribute to HCMV-related pathologies.

Amino Acid Sequence↗
PubMed2004

Conserved cytoplasmic domain sequences mediate the ER export of VZV, HSV-1, and HCMV gB.

Glycoprotein B (gB) is conserved among the herpesviruses and participates in both virus entry and cell-cell spread. The ER export of VZV gB is mediated by two cytoplasmic domain regions, aa 818-826, which contains a YXXphi motif, and the C-terminal 17 aa. The current study examines whether related sequences in the cytoplasmic domains of HSV-1 and HCMV gB similarly influence the ER export of their gB homologs. Directed mutations were introduced into the cytoplasmic domains of HSV-1 and HCMV gB, and the efficiencies with which the mutated proteins acquired Golgi-dependent modifications were determined. Sequences homologous to VZV gB aa 818-826 were required for normal ER export of both HSV-1 gB and HCMV gB. However, the C-terminal regions of HSV-1 and HCMV gB had no impact on ER export. Therefore, alpha- and betaherpesvirus gB homologs share conserved ER export signals, but species-specific differences in the ER export of gB also exist.

Amino Acid Sequence↗
PubMed1999

The development of a quantitative PCR ELISA to determine HCMV DNAaemia levels in heart, heart/lung and lung transplant recipients.

The adaptation of the polymerase chain reaction (PCR) enzyme-linked immunosorbent assay (ELISA) using a co-amplified DNA standard to quantitate the human cytomegalovirus (HCMV) glycoprotein B (gB) gene in clinical samples is described. The PCR ELISA is a solution hybridisation system with colorimetric end stage detection of amplicons. A DNA internal standard (IS) was designed by replacing a probe sequence used currently within the gB region with a heterogeneous sequence, allowing co-amplification with the same oligonucleotide primer sets and differentiation by probe hybridisation. Two DNA fragments homologous to the gB and IS sequences were generated and used for co-amplification studies to construct a standard curve. From this the copy number of the gB gene present in clinical samples could be interpolated. Co-amplification with 1000 IS copies allowed quantitation of 10-1000000 gB DNA copies in a single PCR. This assay was validated subsequently using blood samples tested by the HCMV antigenaemia assay and showed a trend of increasing HCMV DNAaemia with increasing antigenaemia levels. This rapid assay avoids using gel electrophoresis and cumbersome quantitative systems. It has the potential for early identification of patients at high risk of developing HCMV disease, and for therapeutic monitoring.

Base Sequence↗
PubMed1994

Human neural xenografts: progress in developing an in-vivo model to study human immunodeficiency virus (HIV) and human cytomegalovirus (HCMV) infection.

Human immunodeficiency virus type 1 (HIV-1) infection is highly specific for its human host. In order to study HIV-1 infection of the human nervous system, we have established a small animal model in which second-trimester (11-17.5 weeks) human fetal brain or neural retina is transplanted into the anterior chamber of the eye of immunosuppressed adult rats (Epstein et al., 1992; Cvetkovich et al., 1992), and more recently in immunodeficient (SCID) mice. The human xenografts survive for many months, vascularize and form a blood-brain barrier. Immunohistochemistry with PGP 9.5 identified neuronal cell bodies and neuritic processes. Electron microscopy revealed axonal growth cones and synaptic junctions. Infection of these xenografts with cell-free HIV-1 proved difficult, however co-engraftment with HIV-1-infected human monocytes resulted in characteristic pathological changes, including the formation of syncytial giant cells, neuronal loss, and astroglial proliferation, supporting the hypothesis that these cells can mediate neurotoxicity. In other studies, xenografts of human fetal retinal tissue were readily infected with cell-free human cytomegalovirus (HCMV) strain AD169. These grafts contained cells with intracytoplasmic and intranuclear inclusions typical of HCMV infection. Productive infection within these grafts was demonstrated by the presence of immediate early, and late (capsid) HCMV antigens, by recovery of HCMV on human fibroblast cultures, and by serial passage of virus to additional retinal xenografts (DiLoreto et al., 1994).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Benzothiadiazine dioxides (BTD) derivatives as non-nucleoside human cytomegalovirus (HCMV) inhibitors. study of structural requirements for biological activity.

Two new series of BTD derivatives have been synthesised allowing to explore the steric requirements for their biological activity. The N3-alkylBTD compounds have shown antiviral activity in the same order or lower than previously prepared compounds. However, the cytotoxicity values observed prevent this new series of BTD derivatives from its potential therapeutic application. Concerning BTD derivatives with the modified linker attached to N1 position, we have obtained new non-nucleoside anti-HCMV derivatives. The activity against HCMV is shown at concentrations that were 10-fold lower than the concentration that was toxic for the host cells, which confirm that these derivatives show a specific antiviral effect against HCMV. SAR conclusions derived from these last compounds have provided new knowledge about the structural requirements of BTD showing certain positions that could be modified for enhancing the anti-HCMV action.

Antiviral Agents↗
PubMed2000

The possible role of human cytomegalovirus (HCMV) in the origin of atherosclerosis.

BACKGROUND: The biological properties of some herpesviruses such as the ability of latent persistency in the host cells and the presence of viral DNA in atherosclerotic lesions, suggest the possible role of herpesviruses in the development of atherosclerosis. Although many authors proved the presence of viral DNA in arterial wall tissue, the role of herpesviruses in the origin and progress of atherogenesis still remains unclear. OBJECTIVES: The aim of this study was to confirm the presence of viral DNA in arterial wall and to associate the presence of these viruses with the development of atherosclerosis in patients with ischemic heart disease (IHD). STUDY DESIGN: A possible role of HCMV, EBV and HHV6 in the development of atherosclerosis was tested in 244 IHD patients and 87 coronarographically negative controls. The presence of viral DNA in aortic and venous walls, as well as in a peripheral blood samples was tested by the use of polymerase chain reaction (PCR) accompanied by, immunological tests for anti-virus antibodies IgM and IgG types for all experimental groups. RESULTS: The genomic DNA of HCMV was found in 76 and 59%, DNA of EBV in 59 and 50%, and DNA of HHV6 in 0.08 and 0.0%, of arterial walls of IHD patients and non-ischemic control group, respectively. No viral DNA was found in venous samples. Significant association (P < 0.01) has been proved between CMV infection and IHD. CONCLUSIONS: Our results suggest that HCMV and EBV can be found in the arterial wall, so that the arterial wall could be a potential site of persistency of those viruses. We also proved a significant association between the presence of HCMV DNA in aortic walls and atherosclerosis. Despite of the high genetic and biological similarity between CMV and HHV6 no substantial role of HHV6 in atherosclerosis has been proved.

Aorta↗
PubMed2001

Syntheses and structure--activity relationships of novel apio and thioapio dideoxydidehydronucleosides as anti-HCMV agents.

On the basis of the fact that apio dideoxynucleosides, in which the furanose oxygen and the C2 of the 2,3-dideoxyribose are transposed, exhibited potent anti-HIV activity and 2',3'-dideoxy-2',3'-didehydronucleosides also showed potent anti-HIV activity, we synthesized apio dideoxydidehydronucleosides in which the oxygen atom and the double bond of the 2,3-dideoxy-2,3-didehydroribose are exchanged. The thioapio dideoxydidehydronucleosides were also synthesized since sulfur serves as a bioisostere of oxygen. Apio dideoxydidehydronucleosides 13a--f were synthesized starting from 1,3-dihydroxyacetone, utilizing phenylselenenyl chemistry as a key step. The ratio of the anomeric mixture was variable from 1:1 to 5:1 during the condensation of nucleosidic bases with the phenylselenyl acetate 11 in the presence of a Lewis acid. This is in contrast with other glycosyl donors such as 5-O-(tert-butyldiphenylsilyl)-2-phenylselenenyl-2,3-dideoxyribosyl acetate which shows excellent neighboring group effect (alpha:beta = 1:99). Thioapio dideoxydidehydronucleosides 22a,b were synthesized from the lactone 9 via thiolactone 17 as a key intermediate which was synthesized from dicyclohexylcarbodiimide coupling of the mercapto acid produced from the basic hydrolysis of thioacetate 16. The majority of apio analogues synthesized in this study exhibited moderate to potent anti-HCMV activity, among which the 5-fluorouracil derivative 13c was found to be the most potent against HCMV, while thioapio analogues showed no activity against HCMV. However, all synthesized compounds did not exhibit any significant activities against HIV-1, HSV-1, and HSV-2. The fact that apio dideoxydidehydronucleosides were active against HCMV suggests that the apio dideoxydidehydro sugar moiety can serve as a novel template for the development of new antiviral agents.

Antiviral Agents↗
PubMed2002

Preeclampsia: a multifactorial disease resulting from the interaction of the feto-maternal HLA genotype and HCMV infection.

PROBLEM: To clarify the possible influence of human leukocyte antigen (HLA) mother-child genotypes and human cytomegalo virus (HCMV) presence on the development of preeclampsia. METHODS OF STUDY: One hundred and four DNA samples from mothers with preeclampsia, mothers with a normal history of pregnancies and their neonates were tested by polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) for HLA-A, -G, -DRB1, -DQA1, -DQB1 alleles. The HCMV sequences were analyzed using a PCR-SSOP method and the four primers described by Chou (Chou S: J Clin Microb 1992; 30:2307-2310). RESULTS: Compared with their respective controls, a significant increase of DRB1*07 among neonates (P(c) = 0.05) and of DRB1*07 and/or DRB1*06 among pre-eclamptic mothers (P(c) = 0.003, RR = 8,5) was found. When HCMV sequences were detected in pre-eclamptic mothers carrying those phenotypes the RR increased up to 40. Furthermore, the fetal inheritance of a maternal HLA-G*0104 increased the risk for the appearance of the disease (RR = 30; P = 0.025). CONCLUSION: The results suggest that the presence of alleles HLA-G*0104, DRB1*07/06, HCMV sequences and the fetal inheritance of maternal G*0104, should be considered as conditioning factors for the development of preeclampsia.

Alleles↗
PubMed2004

[Breast feeding of very preterm infants of HCMV-seropositive mothers].

Preterm infants can be infected with human cytomegalovirus (HCMV) transmitted via breast milk of their HCMV-seropositive mothers, 96 % of whom reactivate the virus during lactation. 38 % of exposed VLBW infants become infected, with 48 % of these developing at least one symptom. Whether priority should be given to the multiple advantages of breast milk feeding or to the avoidance of a possible HCMV infection by exclusive formula feeding still cannot be decided due to insufficient data on the long-term outcome of infected infants. Inactivation of HCMV in breast milk can be achieved safely only via heat treatment, but the clinical consequences resulting from the use of pasteurized breast milk are unknown. Given the above situation, the authors decided to continue breast-feeding of VLBW and ELBW infants in their units after obtaining informed parenteral consent, until data for an evidence-based decision become available.

Breast Feeding↗
PubMedDate not supplied

HCMV infection: modulating the cell cycle and cell death.

Human cytomegalovirus (HCMV) is a member of the Herpesviridae family and is recognized as a significant pathogen to certain subgroups of the human population. It has become apparent that HCMV manipulation of the host cell cycle as well as the immune response promotes the replication and propagation of the virus. The ability of HCMV to modulate components of the host immune system and the response to infection most likely contributes to the pathology associated with this virus. This review will address the mechanisms HCMV has adapted to modulate the cell cycle to promote viral replication as well as the different ways it can prevent the "death" of an infected cell.

Apoptosis↗
PubMed1999

Role of interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma) in the control of the infection of monocyte-like cells with human cytomegalovirus (HCMV).

The role of cytokines in the control of HCMV infection has been studied in THP-1 cells, a macrophage-like cell model and in MRC-5 cells. HCMV replication was studied by immune detection of viral immediate-early antigens (IEA) and virus yield was evaluated in MRC-5 cells by immunoperoxidase staining. Pretreatment of MRC-5 and phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells with IFN-alpha or IFN-gamma for 24 hr prior to the infection reduced the number of infected cells and virus yield. A synergistic anti-CMV activity in synthesis of early proteins was obtained with these cytokines in combination with TNF-alpha in differentiated THP-1 cells only. Treatment of HCMV-infected differentiated THP-1 cells or MRC-5 cells with IFN-alpha or IFN-gamma alone had no inhibitory effect on virus replication, however the virus yield was reduced with ganciclovir. A synergistic anti-CMV activity in virus yield was obtained only when infected differentiated THP-1 cells were treated with ganciclovir in combination with IFN-gamma. The current study shows that IFN-alpha and IFN-gamma can play a role in the reduction of HCMV replication in macrophage-like cells and in the efficiency of therapies with ganciclovir in this cell type and that the anti-CMV effect of cytokines may be different in fibroblasts and in macrophage-like cells.

Antiviral Agents↗
PubMed1996

Inactivation of the very strong HCMV immediate early promoter by DNA CpG methylation in vitro.

The influence of DNA methylation in vitro on the activity of the very strong human cytomegalovirus (HCMV) major immediate early (IE) modulator/enhancer/promoter region was investigated by transient transfection experiments of premonocytic HL-60 cells. While sequence-specific methylation of the major IE enhancer and/or modulator with the cytosine methyl-transferases FnuDII, HhaI and HaeIII had no significant effect, the promoter activity was completely repressed by methylation of the cytosine in 5'-CpG sites with the Spiroplasma methyltransferase SssI. Addition of TNF-alpha or PMA which are strong stimulators of HCMV major IE enhancer/promoter activity in premonocytic HL-60 cells had no effect on repression. Inactivation of the IE enhancer/promoter via methylation by M.SssI could be partially alleviated by co-transfection with an excess of untranscribable highly methylated DNA. These results indicate that a methyl-CpG binding factor is involved as mediator in the inhibitory effect of HCMV enhancer/promoter methylation. Taken together, the HCMV major IE enhancer/ promoter has been shown to be susceptible to transcriptional inactivation by methylation of the cytosines in CpG dinucleotides, a process that is proposed to play a modulatory role in viral latency.

Antigens, Viral↗
PubMed1999

Epidemiological studies of HCMV infection in children by restriction analysis of long-PCR products.

Sequences of MIE, pol, gB gene longer fragments (2.0-2.6 kb) were amplified in two stage PCR (nested PCR) from 46 PEG-urine extracts. Restriction of particular amplicons with selected endonucleases identified 19 distinct HCMV genotypes: 8 for MIE, 6 for gB and 5 for pol. MIE profiling revealed highest differentiation power. Our data showed the correlation among MIE, pol, and gB genotypes and clinical disease, indicating that genotypes may contribute the course of HCMV infection. For newborns with symptomatic infection, the highest level of variability among three genes analysed was obtained in comparison to samples of newborns with asymptomatic infection. Long PCR technique coupled with restriction analysis may be successfully applied in HCMV genotypes differentiation in samples taken directly from HCMV infected individuals, thus may be useful in prognosis of clinical infection.

Antigens, Viral↗
PubMed2002

HCMV pp67-mRNA detection by nucleic acid sequence-based amplification in renal transplant patients.

CMV infection is a major cause of morbidity and mortality following renal transplantation. Clinical diagnosis is difficult, and rapid and sensitive diagnostic methods are needed since antiviral therapy is available. The determination of the presence of viral transcripts is considered a direct marker of HCMV replication in vivo. In particular, it seems that the expression of late transcripts might better reflect active HCMV replication, dissemination and disease, and should cease upon effective blockage of viral polymerase by antiviral agents, such as gancyclovir. The unspliced pp67-mRNA can be specifically amplified using nucleic acid sequence-based amplification (NASBA) in a background of DNA. In the present study blood samples of forty-two renal transplant patients with active HCMV infection, demonstrated by pp65-antigenaemia, were investigated to detect pp67-mRNA using the NASBA technique. Thirty-one pp65-antigenaemia positive patients resulted NASBA positive (73.8%) also in case of very low levels of antigenaemia; in 9/42 (21.4%) pp67-m-RNA was detected between 6 and 15 days before antigenaemia. Our results indicate that pp67-mRNA NASBA is a useful tool for the early diagnosis of active HCMV infection and for starting and modulating antiviral therapy, in addition to quantitative techniques such as antigenaemia, in renal transplant patients.

Cytomegalovirus↗
PubMed2002

Expression of mRNA for cytokines (TNF-alpha and IL-1alpha) in human cytomegalovirus (HCMV) and hepatitis B virus (HBV) infections.

The study was aimed at detecting cellular sources of transcripts for two cytokines, TNF-alpha and IL-1alpha in infection with human cytomegalovirus (HCMV) or hepatitis B virus (HBV). The studies were performed on paraffin sections of organs (liver, pancreas, spleen, lungs) obtained upon autopsy from a child deceased due to acute inborn HCMV infection, on paraffin sections of liver biopsy, obtained from a child with HCMV-induced chronic hepatitis, and of liver biopsies obtained from children with chronic type B hepatitis (n = 13). The classical in situ hybridization was applied with digoxygenin-labeled probes and amplification by the ImmunoMax technique. In HCMV infection, the most pronounced expression of mRNA for TNF-alpha and Il-1alpha was detected in pancreatic islets (mainly in beta cells) and, then, in a decreasing sequence, in liver (in macrophages and sinusoidal endothelial cells) and in lungs (in alveolar macrophages). No expression of the two cytokines was detected in the spleen. In HBV infection, weak expression of TNF-alpha and more intense expression of IL-1alpha in the liver were observed, mainly in sinusoidal endothelial cells and in macrophages as well as in hepatocytes. These results were confirmed by immunocytochemical experiments.

Child↗
PubMed1998

[Study on HCMV replication in gene transtecfed cells].

Five gene transfected cells (GTC: A5, B3, D3, G8 and H3) were generated by DNA (from HEP-2) transfer (into HEL). Chromosome number of the transfectants fell between that of HEL and the combined chromosome number of the two cell lines. D3 showed more positive fluorescence cells than A5, B3, G8 and H3 by 4d after infection of HCMV. As HCMV infection dose was increased from 0.1 to 100 PFU/ml, significant increase of viral production was observed. The similar susceptibility to HCMV was shown in different passages of D3. The immortal D3 may provide a tool to analyze host cell factors controlling the transcription and replication of HCMV.

Cell Line↗
PubMed2005

[Effects of HCMV on phenotypes of parotid duct epithelial cells and its mechanisms].

OBJECTIVE: To investigate the effects of HCMV infection on phenotypes of parotid duct epithelial cells and relative mechanisms. METHODS: The expressions of immediate early antigen of HCMV, pan cytokeratin and cathepsin D etc. were detected by immunohistochemical staining in tissues of parotid cytomegalic inclusion disease. RESULTS: Cytokeratin which acts as an epithelial marker became negative while staining of Cathepsin D was intensified in parotid duct epithelial cells after infected by HCMV. CONCLUSION: It demonstrated that cytokeratin was lost through over-expression of Cathepsin D in parotid duct epithelial cells infected by HCMV.

Animals↗
PubMed1998

[Molecular diagnosis of HCMV infection].

Active HCMV infection is diagnosed by isolation of the virus or by demonstrating its presence of viral genome or viral antigens. The viral genome can be directly detected by molecular biological techniques. The two most popular techniques are polymerase chain reaction (PCR) and in situ hybridization (ISH). The sensitivity of PCR is superior to the detection of viral antigens in infected cells or isolation of viruses in culture. HCMV-DNA in peripheral leukocytes is often positive in healthy people. To discriminate a latent infection from an active infection may be done by reducing the number of amplification cycles, by testing in cell free blood samples (serum or plasma), by amplification of viral mRNA transcripts, or by quantification of HCMV DNA. ISH is the method for diagnosis by demonstrating the viral genome in cells of involved organs and is more sensitive and specific than histology or immunohistochemistry. The viral genome can be detected even in formalin fixed paraffin-embedded sections. In situ PCR (IS-PCR) is a new molecular technique, that combines the extreme sensitivity of the PCR with the cellular localization provided by ISH, and that can detect even one copy of viral DNA per cell. And also other procedures for quantitative HCMV DNA detection, Hybrid Capture system, and serodiagnosis using the recombinant antigens are described.

Cytomegalovirus↗