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PubMed2004

HCMV activates PI(3)K in monocytes and promotes monocyte motility and transendothelial migration in a PI(3)K-dependent manner.

Human cytomegalovirus (HCMV) is a leading cause of morbidity and mortality in immunocompromised hosts. In immunocompetent hosts, HCMV is associated with chronic inflammatory diseases including atherosclerosis. Monocytes and macrophages are proposed to play key roles in HCMV dissemination to host tissue, and their infection provides a biological link between the lifecycle of HCMV and disease pathology. We hypothesize that viral spread occurs via a mechanism in which infected peripheral blood monocytes, which are nonpermissive for viral replication, extravasate into host tissue and subsequently differentiate into permissive macrophages. Supporting this hypothesis, we recently showed that HCMV specifically induced the differentiation of monocytes into macrophages that become permissive for viral replication. To expand our understanding of HCMV pathogenesis, we next examined monocyte activation and migration, the first events in viral pathogenesis. We show here that HCMV up-regulates phosphatidylinositol 3,4,5 triphosphate kinase [PI(3)K] activity and that this increased PI(3)K activity is essential for infected monocyte-transendothelial migration. This increase in migration occurs through the up-regulation of cell motility in a PI(3)K-dependent process. Last, we show that these activated monocytes express a number of inflammatory mediators via PI(3)K signaling. We propose that the up-regulation of monocyte migration and immune mediators by HCMV infection is required for the hematogenous dissemination of the virus and as a consequence, could promote chronic inflammatory diseases associated with HCMV infection.

Animals↗
PubMed2003

[An experimental study on the effect of allitridin on inhibiting the expression of HCMV immediate-early antigens in vitro].

OBJECTIVE: To investigate the prophylactic, blocking and therapeutic effects of Allitridin on inhibiting HCMV proliferation by measuring the expression level of HCMV IEA in vitro and explore the mechanism of Allitridin anti-HCMVactivity. METHODS: The cytotocity of Allitridin was evaluated through MTT colorimetry and cell morphology. HCMV IEA levels were quantitatively detected by Flow Cytometry respectively under the following conditions: Allitridin was given before (pretreated for 24 h), during, or after viral inoculation in which serial doses (maximum tolerant concentration, MTC for human embryo lung cells, HEL) of Allitridin was used to treat HCMV infected HLE cells for different durations (24, 48, 72, 96 h) after viral infection. RESULT: The MTC of Allitridin was 9.60 mg x L(-1). Allitridin remarkably inhibited the expression of HCMV IEA in vitro. Within MTC, the inhibitory rate had a significant correlation with its dosage (r = 0.96). At the time of IEA highest expression (72 h after infection), inhibitory effect was the greatest (inhibitory rate: 89.3%). With pretreatment of Allitridin, the inhibitory rate was 28.6%. When Allitridin was used together with HCMV inoculation, IEA inhibitory rate was only 10.3%. CONCLUSION: Allitridin can inhibit HCMV, IEA expression in vitro remarkably which is probably one of the major mechanisms of Allitridin anti-HCMV activity because IEAs are the very important regulatory factors for the expression of all HCMV genes. Its therapeutic effect is the best at the peak stage of IE1 gene expression (72 h after infection) but it has low prophylactic and little blocking effect.

Allyl Compounds↗
PubMed2006

[Effect of HCMV on p38MAPK, apoptosis and cell cycle of human glioma U251 cells].

OBJECTIVE: To study the changes of p38MAPK expressions, the frequency of apoptosis and the distribution of cell cycle of hunan Glioma U251 cells after HCMV infection. METHODS: The expression of total p38 (both phosphorylated and nonphosphorylated p38) and phosphorylated p38 in U251 cells were detected by Western blotting at 15 min, 30 min, 1 h, 6 h, 10 h, 16 h, 24 h, 36 h and 48 h after HCMV infection. The apoptosis percentage and the cell cycle distribution of U251 cells at 2 d, 5 d and 7 d after HCMV infection were detected by flow cytometry (FCM). RESULTS: The results of Western blotting demonstrated that a strong increase in phosphorylated p38 was detected from 6 h to 10 h after HCMV infection, with mean gray scales 186.33 +/- 7.51 (t = 5.37, P < 0.01) and 188.00 +/- 7.02 (t = 5.26, P < 0.01 for all) at 6 h and 10 h, respectively, and p38 phosphorylation decreased to the basic level at 16 h after HCMV infection. But the overall levels of p38 protein were not significantly altered during the course of infection. FCM analysis showed that HCMV could significantly increase the apoptotic rates of U251 cells compared with controls (t = 10.84, P < 0.01), and the apoptotic percentages of the cells reached to peak [(10.18 +/- 1.24)%] at 5 d after HCMV infection. The data of FCM showed that HCMV could decrease the number of U251 cells in G1 phase and arrest the cells in S and G2 phase. The numbers of G1 phase U251 cells were significantly lowered to (56.50 +/- 2.57)% (t = 26.45, P < 0.01), (62.33 +/- 2.64)% (t = 21.20, P < 0.01) and (67.45 +/- 4.44)% (t = 10.61, P < 0.01), respectively at 2 d, 5 d and 7 d after infection. CONCLUSION: HCMV could activate p38MAPK pathway and trigger apoptosis and interfere cell cycle in U251 cells.

Apoptosis↗
PubMed1992

On the association of human beta 2 microglobulin with cell culture-grown human cytomegalovirus (HCMV).

We studied the production of human beta 2 microglobulin (beta 2m) in mock-infected or human cytomegalovirus (HCMV) infected human embryonic lung fibroblasts (HEL) and the association of human beta 2m with HCMV virions. Titration of beta 2m by two-step sandwich enzyme immunoassay revealed that HEL released considerable amounts of human beta 2m into the culture medium and that the production of beta 2m was significantly enhanced by HCMV infection. The concentration of human beta 2m in the culture medium of HCMV-infected HEL reached 500 to 600 ng/ml, which corresponded to 7- to 12-fold of levels found in healthy adult urine. Immunoprecipitation assays showed that HEL-grown HCMV bound a significant amount of endogenous beta 2m, but the viruses were efficiently neutralized by either human hyperimmune anti-HCMV globulin or anti-HCMV monoclonal antibody even when treated with a large amount of human beta 2m or with dialysed urine. Thus it seems unlikely that the binding of beta 2m by HCMV is involved in masking the viral antigenic site necessary for neutralization.

Cells, Cultured↗
PubMed1988

Rapid (24h) neutralization assay for the detection of antibodies to human cytomegalovirus using a monoclonal antibody to an HCMV early nuclear protein.

Neutralizing antibodies to human cytomegalovirus (HCMV) may play an important role during the course of an HCMV infection but yet detection with conventional methods remains difficult and time consuming. A new neutralization test has been developed basically corresponding to the known microtitre technique. A monoclonal antibody to an HCMV early nuclear protein is utilized to detect HCMV (AD169) infected fibroblasts by biotin/streptavidin-enhanced immunoperoxidase staining. The test procedure was thereby confined to only 24 h. Evaluation of the new neutralization test (24h-NT) was done in comparison to the conventional method (NT). Preselected serum samples (n = 217), of which n = 169 were HCMV-seropositive in ELISA (reciprocal titre greater than or equal to 40), were tested for neutralizing antibodies (NAbs) to HCMV. ELISA titres were measured by a commercially available kit (Behring, F.R.G.). NAbs could be detected in 107 sera by 24h-NT (reciprocal titre greater than or equal to 5) and in 110 sera determined by NT (reciprocal titre greater than or equal to 5). Those sera were exclusively positive in ELISA. ELISA negative sera (n = 48; reciprocal titre less than 40) yielded no detectable neutralizing titres. This specific and rapid test should facilitate HCMV-NAbs detection for a wide variety of applications including routine virology diagnostics, evaluation of HCMV hyperimmunoglobulins and medical research.

Antibodies, Monoclonal↗
PubMed2004

Quantitative analysis of HCMV DNA load in whole blood of renal transplant patients using real-time PCR assay.

BACKGROUND: Preemptive antiviral treatment of Human Cytomegalovirus (HCMV) disease is a major goal in the management of organ transplant patients. It requires sensitive diagnostic methods. Automated real-time PCR systems have been recently proposed to monitor HCMV infection in such patients. OBJECTIVE: Objectives of this study was to compare a real-time quantitative PCR on whole blood with the HCMV pp65 antigenemia assay in renal transplant recipients, and also to evaluate two different DNA extraction methods. STUDY DESIGN: A total of 248 specimens from 21 patients were tested by quantitative pp65 antigenemia and quantitative real-time PCR. DNA was extracted from whole blood samples using two different methods: a conventional column manual assay and an automated system. RESULTS: Quantification of HCMV DNA using the two extraction methods showed highly similar results (Spearman rank test, r=0.863). We found a significant correlation between DNA quantification by real-time PCR in whole blood and pp65 antigenemia test (Spearman rank test, r=0.767). This correlation was not modified when the HCMV DNA results were normalized by quantification of the albumin cellular gene. In eight patients, HCMV infection was detected earlier with quantitative PCR than with the antigenemia test (mean delay of 11.25 days). HCMV DNA load equivalent of 50 pp65 positive cells/200,000 polymorphonuclear leukocytes (PMNLs) is log4.095 copies per ml of blood. CONCLUSIONS: Real-time PCR in whole blood is a sensitive method for estimating the HCMV genome load in renal transplant patients, and is more rapid and practicable than using PMNLs for pp65 antigenemia tests.

Cytomegalovirus↗
PubMed1995

[Correlation of PCR results to detect HCMV with clinical course of kidney transplant recipients].

Peripheral blood leukocyte (PBL) specimens and urine specimens of 18 renal transplant patients were examined weekly or biweekly for the presence of human cytomegalovirus (HCMV), using polymerase chain reaction (PCR) technique, shell vial procedure and culture. In 11 out of 18 patients, HCMV was detected from either or both of PBL and urine within one to three months after transplantation. HCMV DNA was detected by PCR for a longer period of time, in comparison to the shell vial procedure, showing that PCR was more sensitive. However, only 3 patients showed symptomatic HCMV infection with pyrexia leukocytopenia and liver dysfunction, whose PBL and urine specimens were positive for HCMV by both of the methods. In these 3 patients, HCMV was detected for a longer period of time, whereas in the other asymptomatic patients, it was detectable for only one or two weeks. Moreover, using DNA obtained from PBL in symptomatic phase, HCMV major immediate early (MIE) gene was detected by PCR after amplification for fewer cycles, whereas DNA obtained from these 3 patients in the asymptomatic period or at the end to active HCMV infection, and from other asymptomatic patients, it was detectable after 30 cycles of amplification.

Cytomegalovirus↗
PubMed2000

Little role of anti-gB antibodies in neutralizing activity of patient's sera with human cytomegalovirus (HCMV) infection.

Human cytomegalovirus (HCMV) gB is known to play important roles in cell surface attachment, virion penetration, spread of infection from cell to cell, and provocation of neutralizing antibody. This study was performed to determine the role of anti-HCMV gB antibody in overall neutralizing response in patients with HCMV infection and healthy control with past infection. HCMV gB was stably expressed in 293 cells. With the stable cell line expressing gB as a specific immunosorbent, anti-gB antibody was removed from the current and past HCMV-infected sera and the remaining neutralizing activity was measured by plaque assay. It was shown that 19-50% of the total virus-neutralizing activity of sera with past HCMV infections was derived from anti-gB antibody, but anti-gB antibody had little effect on the total serum virus-neutralizing activity in patients currently infected with HCMV. This result suggests that neutralizing antibody to HCMV gB may reflect disease status.

Adult↗
PubMed1996

Recognition of human cytomegalovirus gene products by HCMV-specific cytotoxic T cells.

The antigen specificity of HCMV-specific cytotoxic T cells (CTL) was investigated in healthy adult seropositive donors by analyzing the frequency of CTL precursors (CTLp) against six different HCMV-encoded proteins. HCMV-specific, CD8+ CTL clones from two donors were also characterized. Thje precursor frequency analysis showed that a major phosphoprotein of HCMV, pp65 (UL83), was the immunodominant CTL target antigen in healthy seropositive adults. The frequency of CTLp specific for different HCMV proteins ranged from 1/12,000 for pp65 to > 1/100,000 for gB (UL55), gH (UL75), pp50 (UL44), and pp28 (UL98). Characterization of the HCMV-specific CTL clones from two donors revealed that the majority of clones lysed targets expressing pp65 and that none of the clones recognized other HCMV proteins.

Antigens, Viral↗
PubMed2005

PCR detection of viral DNA in serum as an ancillary analysis for the diagnosis of acute mononucleosis-like syndrome due to human cytomegalovirus (HCMV) in immunocompetent patients.

BACKGROUND: Serologic tests are occasionally inconclusive for the diagnosis of mononucleosis-like syndrome due to human cytomegalovirus (HCMV). OBJECTIVES: To determine the value of viral DNA detection in serum by PCR as an ancillary test for the diagnosis of HCMV mononucleosis. STUDY DESIGN: Sera from 34 previously healthy individuals with HCMV mononucleosis, obtained within 1 month after the onset of symptoms, were assayed for viral DNA by three commercial PCRs (QCA gB, QCA MIE and Amplicor CMV Monitor). Sera from 30 patients with evidence of past HCMV infection served as controls. RESULTS: Viral DNA was detected in 20% of the samples from patients with HCMV mononucleosis by both QCA procedures, but in none of the controls. All samples tested negative by the Amplicor CMV Monitor. CONCLUSION: Analysis of sera for the presence of HCMV DNA is of limited value for the diagnosis of HCMV mononucleosis.

Adolescent↗
PubMed1997

Human cytomegalovirus DNA kinetics using a novel HCMV DNA quantitative assay in white blood cells of immunocompromised patients under Ganciclovir therapy.

The clearance of human cytomegalovirus (HCMV) was evaluated in infected patients under Ganciclovir (GCV) treatment, using a novel HCMV DNA quantitation assay (HCMV DNA hybrid capture system, Murex Diagnostics). Peripheral white blood cells (WBC) from whole blood specimens of seven AIDS patients, three kidney and two allogeneic bone marrow transplant (BMT) recipients suffering from HCMV disease, were assessed by this method. HCMV DNA 50 and 90% mean clearances were observed at 2.11 +/- 1.97 and 6.22 +/- 4.31 days, respectively, after initial GCV treatment. The viral DNA kinetics were correlated with positive and negative pp65 antigenaemia and viral blood culture. Two-fold higher clearances and initial DNA levels were observed in the AIDS group compared to the transplant group. Neither clinical nor virological relapses were observed under GCV treatment. HCMV DNA quantitation in WBC appears well adapted for a therapeutic follow up of patients with HCMV disease.

Antigens, Viral↗
PubMed2006

Evaluation of the COBAS Amplicor HCMV Monitor for early detection and monitoring of human cytomegalovirus infection after allogeneic stem cell transplantation.

Early diagnosis of human cytomegalovirus (HCMV) infection and the introduction of preemptive antiviral therapy have reduced HCMV-related mortality after allogeneic stem cell transplantation. A critical goal remains stratifying risk profiles and minimizing potential harm owing to antiviral overtreatment. We compared the commercially available standardized COBAS Amplicor CMV Monitor (CACM) to an in-house PCR assay, for the monitoring of HCMV infection. Seventy-two patients were surveyed by an in-house PCR of whole blood, quantitative viral load assessment by CACM and virus culture assays in a prospective and a retrospective study. A high concordance between CACM and PCR was documented. The viral load at onset correlated with the peak viral load (Spearman rank correlation R=0.634, P=0.0004). In patients developing HCMV disease, both viral loads were in trend higher (P=0.823, respectively P=0.053), and the viremic episodes longer (P=0.015), as compared to asymptomatically HCMV-infected patients. The serological pre-transplant status was the major risk factor for the development of HCMV disease, showing highest risk for seropositive patients receiving a seronegative graft, whereas donor type (related or unrelated) and graft type (bone marrow or peripheral blood mobilized stem cells) did not have an influence. HCMV infection proved to be a risk factor for the development of non-viral opportunistic infections (P=0.002).

Adult↗
PubMed2007

Late human cytomegalovirus (HCMV) proteins inhibit differentiation of human neural precursor cells into astrocytes.

Human cytomegalovirus (HCMV) is the most common cause of congenital infections in developed countries, with an incidence varying between 0.5-2.2%. Such infection may be the consequence of either a primary infection or reactivation of a latent infection in the mother and the outcome may vary from asymptomatic to severe brain disorders. Moreover, infants that are asymptomatic at the time of birth may still develop neurologic sequelae at a later age. Our hypothesis is that infection of stem cells of the central nervous system by HCMV alters the proliferation, differentiation or migration of these cells, and thereby gives rise to the brain abnormalities observed. We show that infection of human neural precursor cells (NPCs) with the laboratory strain Towne or the clinical isolate TB40 of HCMV suppresses the differentiation of these cells into astrocytes even at an multiplicity of infection (MOI) as low as 0.1 (by 33% and 67%, respectively). This inhibition required active viral replication and the expression of late HCMV proteins. Infection as late as 24 hr after the onset of differentiation, but not after 72 hr, also prevented the maturation of infected cultures. Furthermore, in cultures infected with TB40 (at an MOI of 1), approximately 54% of the cells were apoptotic and cell proliferation was significantly attenuated. Clearly, HCMV can reduce the capacity of NPCs to differentiate into astrocytes and this effect may provide part of the explanation for the abnormalities in brain development associated with congenital HCMV infection.

Abortion, Induced↗
PubMed2000

Physical and functional interaction between the HCMV IE2 protein and the Wilms' tumor suppressor WT1.

Human cytomegalovirus (HCMV) is a major renal pathogen in congenitally infected infants and renal allograft recipients. It has been shown that human kidney cells of glomerular, tubular, and vascular origin were all infected by HCMV in vitro. It has previously been demonstrated that the IE2 protein of HCMV directly associates with the zinc finger domain of Egr-1. The zinc finger region of WT1 is a sequence-specific DNA-binding domain which also recognizes the consensus DNA binding site (5'-CGCCCCCGC-3') of Egr-1, thus suggesting a possible interaction between WT1 and IE2. Here we demonstrate that HCMV IE2 binds to the C-terminal region of WT1 containing zinc finger domain in vivo as well as in vitro and that WT1 can inhibit IE2-driven transactivation of the responsive promoter. Our results suggest that WT1 may be able to regulate the functional activity of HCMV IE2. Furthermore, these data may provide new insights into the possible involvement of HCMV in WT1-related pathogeneses.

Animals↗
PubMed1998

The acidic domain of pUL37x1 and gpUL37 plays a key role in transactivation of HCMV DNA replication gene promoter constructions.

Transient complementation of human cytomegalovirus (HCMV) oriLyt DNA replication in permissive human diploid cells expressing replication genes under native promoters requires its UL36-38 gene products. Two of the immediate early (IE) proteins encoded by this locus, pUL37x1 and, to a lesser extent, gpUL37, activated expression of HCMV early gene promoter constructions. The other IE protein encoded by the UL36-38 locus, pUL36, and the early product, pUL38, did not transactivate the HCMV early promoter constructions under similar conditions. The acidic domain, common to both pUL37x1 and gpUL37, is required for activation of HCMV early promoter constructions. Conversely, gpUL37 sequences downstream of amino acid 199 are not required for transactivation of viral early promoters. Taken together, these results suggest that the requirement for UL36-38 products for HCMV DNA replication results, at least in part, from the requirement of the transactivation of HCMV early DNA replication promoters by pUL37x1 and, to a lesser extent, by gpUL37 and that the acidic domain is critical for this activity.

Binding Sites↗
PubMed2003

Dendritic cells and HCMV cross-presentation.

The outcome of a viral infection is the result of an endless fight between the organism whose task is to mount an antiviral response and the virus that adapts strategies to circumvent the host response. Human cytomegalovirus (HCMV), a latent herpesvirus, can be considered as a spearhead in exploiting co-existence with the host to develop numerous immuno-evasion mechanisms. The ability of the organism to initiate a primary immune response against viruses such as HCMV is highly dependent on the capacity of professional antigen-presenting cells (APCs), namely dendritic cells (DCs), to prime and activate specific effector T cells. Recent findings emerging from the murine cytomegalovirus (MCMV) animal model demonstrated that infection of murine DCs with MCMV impaired their capacity to prime an effective T cell response. Even though data on interference of HCMV with DC functions are still limited, immunosuppressive effects identical to those reported for MCMV can be suspected and we may then ask how a cytotoxic T lymphocyte (CTL) response is generated in these unfavourable conditions. In response to this question, cross-presentation of HCMV antigens by uninfected DCs to CD8+ T cells could be considered a key process in initiating an immune response. In this chapter we discuss the mechanisms through which DCs could acquire HCMV antigens and how cross-presentation could be modulated throughout infection. Moreover, further knowledge of DC functions is key for the development of DC-based immunotherapy against HCMV.

Antigen Presentation↗
PubMed1995

Cell membrane bound N-acetylneuraminic acid is involved in the infection of fibroblasts and phorbol-ester differentiated monocyte-like cells with human cytomegalovirus (HCMV).

We focused on the role of membrane bound sugar residues in the infection of fibroblasts and monocyte-like cells with human cytomegalovirus (HCMV). Treatment of phorbol 12-myristate 13-acetate (PMA) differentiated monocyte-like cells THP-1 or human fibroblasts MRC-5 with lectins specific for N-acetylneuraminic acid (NeuAc) blocked infection with HCMV. HCMV failed to infect sialidase-treated differentiated THP-1 cells or MRC-5 cells. By using NeuAc, N-glycolylneuraminic acid (NeuGl) and alpha 2-3, but not alpha 2-6, sialyl-oligosaccharide, the infection of cells was less efficient. NeuAc was more potent inhibitor than NeuGl. These observations suggest that the sialic acid specificity and the nature of the interglycosidic linkage at the end of the complex carbohydrates may play an important role. Analogous experiments indicated that HCMV binds to N-acetylglucosamine (GlcNAc) in addition to NeuAc. Human cytomegalovirus infection in differentiated THP-1 cells and in human fibroblasts was inhibited by incubation of the virus with 20 micrograms/ml of heparin before and during the adsorption period. Treatment of the cells with heparinase or heparitinase inhibited infection with HCMV. We emphasized the role of NeuAc and GlcNAc and heparan sulfate proteoglycans at the surface of the cells, in the early steps of infection of both human fibroblasts and PMA differentiated monocyte-like cells with HCMV.

Acetylglucosamine↗
PubMedDate not supplied

Detection of cytomegalovirus in bronchial lavage and urine using a monoclonal antibody to an HCMV early nuclear protein.

Laboratory diagnosis of 24 cases of human cytomegalovirus (HCMV) infection in patients with the acquired immunodeficiency syndrome, renal transplant recipients and premature infants was achieved. These results were obtained by a rapid, sensitive and versatile HCMV-antigen detection method, which combined cell culture and immunoperoxidase staining with a monoclonal antibody to an HCMV "early" nuclear protein. The results were compared with HCMV isolation by the conventional cell culture method. While some of these immunocompromised patients lacked a significant antibody response, infective HCMV could be detected in the patients' urine and bronchial lavage fluid. The diagnostic procedure took no longer than 24 h. The usefulness of this antigen test for an effective diagnosis in immunocompromised individuals was demonstrated. We recommend routine analysis of various specimens, since recent developments in chemotherapy of HCMV infection and the risks of long-term damage demand immediate management of the patients concerned.

Adult↗