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PubMed2006

Characterization of human cytomegalovirus (HCMV) UL97 mutations found in a valganciclovir/oral ganciclovir prophylactic trial by use of a bacterial artificial chromosome containing the HCMV genome.

A method based on manipulation of the human cytomegalovirus genome in a bacterial artificial chromosome was developed to determine the role played by 6 UL97 mutations of unknown significance. These mutations were found in blood samples from solid-organ transplant recipients in a trial comparing valganciclovir and oral ganciclovir prophylaxis. Recombinant viruses containing UL97 mutations P405L, A427V, M550I, A582V, Y617H, and A674T were generated in a bacterial system. Viral stocks were subsequently reconstituted in human fibroblasts, and ganciclovir susceptibilities were tested using a plaque-reduction assay. All recombinant viruses containing these unknown mutations were found to be susceptible to ganciclovir.

Amino Acid Substitution↗
PubMed1995

Humoral immune response against human cytomegalovirus (HCMV)-specific proteins after HCMV infection in lung transplantation as detected with recombinant and naturally occurring proteins.

The humoral immune response to four intracellularly located cytomegalovirus (CMV) proteins was studied in 15 lung transplant recipients experiencing active CMV infections. Five patients had primary infections, and 10 had secondary infections. Antibodies of the immunoglobulin M (IgM) and IgG classes were measured in an enzyme-linked immunosorbent assay (ELISA) system in which procaryotically expressed recombinant proteins were used as a substrate and also in a monoclonal antibody-based capture ELISA which uses naturally occurring proteins as a substrate. The proteins investigated were the lower matrix protein pp65 (ppUL83), the major DNA-binding protein p52 (ppUL44), and the two immediate early proteins IE1 and IE2 (different splicing products of UL123). Higher levels of antibodies were found to pp65 and especially to p52 than to the immediate early antigens. Antibody levels detected in the recombinant protein-based ELISAs were generally lower than antibody responses detected with the matching antigen capture ELISA. Moreover, some patients appeared to have antibodies mainly to epitopes present on naturally occurring proteins. The antibody responses detected in both assays were related to the viral load during infection as assessed by the CMV antigenemia test, which is a quantitative marker for CMV load. It was found that although epitopes on naturally occurring proteins induce higher antibody responses and responses in more patients, antibodies directed to epitopes present on the recombinant proteins were inversely related to the viral load during a CMV infection. Therefore, antibodies to epitopes on the recombinant proteins might be more clinically relevant in this group of lung transplant recipients.

Antibodies, Viral↗
PubMed1996

Human cytomegalovirus (HCMV) smallest capsid protein identified as product of short open reading frame located between HCMV UL48 and UL49.

The capsid of cytomegalovirus contains an abundant, low-molecular-weight protein whose coding sequence within the viral genome had not been identified. We have used a combination of biochemical and immunological techniques to demonstrate that this protein, called the smallest capsid protein in human cytomegalovirus, is encoded by a previously unidentified 225-bp open reading frame (ORF) located between ORFs UL48 and UL49. This short ORF, called UL48/49, is the positional homolog of herpes simplex virus ORF UL35 (encoding capsid protein VP26) and shows partial amino acid sequence identity to positional homologs in human herpes viruses 6 and 7.

Amino Acid Sequence↗
PubMed2001

Diagnosis and prognostic markers of HCMV infection.

Human cytomegalovirus (HCMV) infections are frequently observed as well in immunocompetent as in immunocompromised patients. Diagnostic techniques for HCMV detection have greatly improved during the recent years. Detection of HCMV by culture has been bettered by centrifugating samples in a shell vial and by using monoclonal antibody to the immediate early antigen. Detection of antigens in leucocytes was facilitated by using whole blood instead of leucocytes separated by dextran sedimentation. Detection of HCMV recently sharpened by using molecular biology methods mainly based on the detection of the genome. Under certain circumstances, and especially in pregnant women, diagnosis of HCMV infection is essentially based on the detection of IgG and IgM antibodies. However, as IgM antibody is not a marker of primary infection, complementary tests are needed to help in the datation of the infection. Among them, the measurement of IgG avidity greatly improved the diagnosis of primary infections. In immunocompromised patients, very sensitive techniques are needed to diagnose HCMV infections. Detection of antigenemia and HCMV DNA are the methods of choice for an early detection of the infection. Diagnosis of HCMV-organ diseases largely depends on the infected organ and the presence of HCMV in the organ is, sometimes, difficult to interpret. Today, diagnosis of congenital infections is possible by detecting HCMV in the amniotic fluid. However, in order to reliably detect HCMV, amniocentesis must be performed after 21 week's gestation and at least 6 weeks after seroconversion. As all HCMV infections do not induce disease, prognostic markers are needed, as well in immunocompromised patients as in fetuses. Many studies were conducted in immunocompromised patients to find prognostic markers of HCMV infection in order to introduce preemptive therapy when needed. It seems that quantitative determination of HCMV DNA could be very useful to predict HCMV disease. Qualitative determination of mRNA could also be useful as a prognostic marker of HCMV disease. Determination of viral genotypes is more controversial. As for the infected fetuses, little was published about the prediction of sequelae. Some factors, such as viral load in amniotic fluid or in fetal blood or level of IgM antibody in fetal blood, may be predictive of sequelae, but these data require further studies.

Biomarkers↗
PubMed1999

Mechanisms of human cytomegalovirus (HCMV) (re)activation and its impact on organ transplant patients.

Human cytomegalovirus (HCMV) infection plays an important role in transplant patients. Its impact is both direct and indirect. This review focuses on new aspects of HCMV (re)activation and HCMV related pathology, particularly HCMV-associated renal allograft injury. During the last two years we have learned that HCMV is more frequently (re)activated, even in healthy people, than previously expected. Inflammatory as well as stress mediators and some drugs may (re)activate the virus by using distinct intracellular pathways. Commonly, HCMV (re)activation is accompanied by HCMV antigenemia/DNAemia, suggesting that precursor cells in the bone marrow play an important role as a reservoir of latent virus. However, local HCMV (re)activation (colon, lung) without detection of active HCMV infection in the peripheral blood is possible. In healthy people a sufficient type 1 T-cell response controls the active HCMV infection, while in patients with severe immune deficiency (AIDS, high-dose immunosuppression) the virus can spread in an uncontrolled fashion and induce 'classic' HCMV disease. In patients with moderate immune deficiency (e.g. long-term transplant patients on low-dose immunosuppression) virus spreading is controlled but the elimination of cells harboring the active virus may be insufficient. The resulting persistent HCMV antigenemia may induce chronic inflammatory processes leading to tissue injury, particularly in the allograft. Therefore, antiviral therapy may be useful in patients suffering from graft deterioration with otherwise clinically symptomless HCMV infection. HCMV-related immune deficiency with an increased risk of developing bacterial/fungal superinfections is frequently seen in patients with symptomatic HCMV disease but not in asymptomatic CMV antigenemia. The risk of developing superinfections can be predicted by flow-cytometric monitoring of peripheral blood monocytes.

Biomarkers↗
PubMed2001

Early diagnosis and monitoring of active HCMV infection in children with systemic lupus erythematosus.

OBJECTIVE: To investigate the prevalence and features of active human cytomegalovirus (HCMV) infection in children with systemic lupus erythematosus (SLE) and evaluate the diagnostic value of the HCMV using antigenemia assay, serum polymerase chain reaction (PCR) and serology test. METHODS: Twenty-one SLE children undergoing immunosuppressive therapy were enrolled in this study. Immunofluorescence assay, PCR and serology tests were used to determine HCMV pp65 and p72 antigens in leukocytes, HCMV DNA in sera, and HCMV specific IgM and IgG antibodies, respectively. As a control group, twenty-one immunocompetent children with skeletal malformation were involved in this study. Statistical analysis was performed using Chi-square test or Fisher's exact test (Systat, USA), P values less than 0.05 were considered significant. RESULTS: Active HCMV infection was diagnosed in 28.6% (6/21) of SLE patients, with none in the control group; the difference between the two groups was significant (P = 0.027). Two out of 6 SLE patients developed active HCMV infection before immunosuppressive therapy and the remaining 4 patients developed SLE after immunosuppressive therapy. Among the 21 SLE children, HCMV pp65 antigenemia was detected in 5 patients, p72 antigenemia in 3 patients, serum HCMV DNA in 9 patients, serum HCMV-specific IgM in 2 patients, and IgG in 19 patients. The sensitivity and specificity for diagnosis of active HCMV infection were 83.3% and 100%, respectively for pp65 antigenemia; 50% and 100% for p72 antigenemia; 100% and 80% for serum PCR; 33.3% and 100% for HCMV IgM serology; 50% and 100% for HCMV IgG serology. CONCLUSIONS: Compared with the control group, active HCMV infection is much more frequent in SLE children, and can occur before treatment with immunosuppressive agents, but most often occur after immunosuppressive therapy. In comparison with the other techniques used in this study, the pp65 antigenemia assay seems to be a better method for the early diagnosis and monitoring of active HCMV infection in children with SLE.

Adolescent↗
PubMed2001

[Cellular expression of human cytomegalovirus (HCMV) in children with chronic hepatitis B].

OBJECTIVE: The study aimed at detection tissue expression of human cytomegalovirus (HCMV) in children with chronic type B hepatitis. MATERIAL AND METHODS: The studies were performed on liver biopsies obtained from 26 children with active HBV replication after excluding infection with other hepatotropic viruses. Control group consisted of liver biopsies obtained from 5 children with chronic hepatitis of other aetiology (HCV, HCMV, autoimmune hepatitis). The studies were performed employing immunocytochemical techniques of detecting the early viral antigen (HCMV-EA) and the in situ hybridisation to detect HCMV-mRNA and HCMV-DNA. MAIN OBSERVATIONS: Among 26 children with chronic type B hepatitis, presence of HCMV-DNA and HCMV-EA was demonstrated in one child. In the case, no HCMV-mRNA was detected in the tissue. In the control group, immunoreactivity for EA was noted in one child with HCMV-induced chronic hepatitis. Neither DNA nor mRNA of--HCMV could be noted in the tissue. In another child of the control group pronounced (in over 60% cells) expression of HCMV-DNA was demonstrated, in the absence of HCMV-mRNA and EA-HCMV. CONCLUSIONS: As shown by our studies, active HCMV infection in the liver in children with chronic HBV infection is a rare event and it does not deteriorate further histological pattern of the liver. However, effects of incomplete HCMV replication of extrahepatic localisation of viral particles on subsequent course of chronic hepatitis cannot be excluded. High effectiveness of the ImmunoMax technique should be stressed: the technique permitted to demonstrate even scanty amounts of the virus in the organ and in conditions of its incomplete replication.

Adolescent↗
PubMed1998

[Utility of quantitation of human cytomegalovirus(HCMV) DNA in plasma and cerebrospinal fluid by quantitative competitive PCR in AIDS patients].

Persons with advanced HIV infection may have active HCMV infection for months before clinically recognized HCMV disease. The qualitative detection of HCMV-DNA in plasma by PCR is more useful than either urine or blood culture in identifying over time those persons with advanced HIV disease who will develop HCMV disease. Quantitation of HCMV DNA in plasma has identified an association between levels of HCMV DNA in plasma and risk for development of HCMV disease. Thus, quantitative competitive PCR has potential as a marker for the identification of persons who are at highest risk of developing HCMV disease and in helping to guide decisions regarding prophylaxis for HCMV disease. AIDS patients with HCMV-related central nervous system(CNS) disease have high quantities of HCMV DNA in their cerebrospinal fluid(CSF), and quantities of HCMV DNA in CSF are higher in persons with HCMV-related polyradiculopathy than encephalitis. Additionally, quantitation of HCMV DNA can be a useful marker for monitoring the antiviral efficacy of therapies of HCMV-related CNS disease.

AIDS-Related Opportunistic Infections↗
PubMed2003

Quantitation of cytomegalovirus (hCMV) DNA and beta-actin DNA by duplex real-time fluorescence PCR in solid organ (liver) transplant recipients.

Even now rare human cytomegalovirus (hCMV) reactivation is still a life-threatening complication after solid organ transplantation. Although PCR techniques are regarded as the most sensitive detection methods for hCMV, their accuracy and reproducibility are limited. This is a major disadvantage with quantitative PCR assays, which are thought to provide valuable information about hCMV latency or active viral replication in transplant patients. To enhance the diagnostic safety of quantitative hCMV PCR, we developed a duplex real-time fluorescence PCR that is capable of quantifying hCMV DNA and beta-actin DNA as internal control simultaneously within one reaction. By the use of 6-carboxyfluorescein and hexa-chloro-6-carboxyfluorescein as reporter fluorophores and 4-(4'-dimethylamino-phenylazo) benzoic acid as dark quencher dye, hCMV DNA and beta-actin DNA could be quantified in parallel in a wide linear range from 10(1) to 10(7) copies, each. To test the clinical applicability of this approach, we investigated hCMV DNA kinetics in peripheral leukocytes of three hCMV antigen-positive and four antigen-negative patients after liver transplantation, as assessed by intracellular hCMV pp65 alkaline phosphate-anti-alkaline phosphate (APAAP) complex. While all APAAP-negative individuals remained PCR negative, kinetics of HCMV DNA in leukocyte DNA samples of APAAP-positive patients correlated closely with hCMV antigen tests. Here, comparison of separate and simultaneous target quantitation revealed identical results. It is of interest that, while single hCMV antigen positivity is commonly not regarded as a reliable parameter of viral reactivation, in our study a viral load greater than 10(4) copies/2x10(5) beta-actin DNA copies clearly indicated a subsequent increase in APAAP-positive leukocytes. We conclude that with the presented method the reliability of hCMV quantitation via real-time PCR can be substantially increased and may be used to monitor hCMV kinetics in vivo.

Actins↗
PubMed1998

Discordant detection of human cytomegalovirus DNA from peripheral blood mononuclear cells, granulocytes and plasma: correlation to viremia and HCMV infection.

BACKGROUND: There exist only few data about the HCMV infection of single positive leukocyte subtypes in immunosuppressed patients. Most reports describe HCMV coinfection of cells of the myelomonocytic line or even T- and B-cell populations. Correlation of positive PCR findings from two major leukocyte fractions and plasma to viremia and HCMV infection in general should contribute to select suitable sources of HCMV DNA for diagnostic purposes. OBJECTIVE: The diagnostic value of qualitative leukoDNAemia of simultaneously isolated peripheral blood mononuclear cells (PBMC), granulocytes as well as plasmaDNAemia was evaluated by comparing the positive results of nested PCR from blood with virus isolation either from leukocytes or from any other sources, with serology and the clinical status of immunosuppressed patients. STUDY DESIGN: PBMC, granulocytes and plasma were prepared of a total of 220 blood samples of 75 immunosuppressed patients with clinically suspected primary or recurrent HCMV infection. In a collective of 35 patients consisting mainly of recipients of marrow or solid organ transplants positive results of leuko- or plasmaDNAemia were correlated with data from HCMV screening and the clinical status. For standardization, HCMV IE Exon 4 DNA was amplified from 100 ng cellular DNA of each leukocyte population. Cross contamination can be excluded. DNA from plasma was extracted by phenol/chloroform. Using this experimental design, HCMV DNA was not detectable in PBMC, granulocytes and plasma of 23 healthy HCMV seropositive blood donors. RESULTS: Leukocyte separation in a collective of 30 patients with positive leukoDNAemia revealed in only 12 cases (40%) double infection of PBMC and granulocytes. In the majority of cases (18 patients, 60%) however, HCMV DNA was detectable in only one leukocyte fraction, either in PBMC or granulocytes. LeukoDNAemia did not correlate to viremia. HCMV DNA amplified from plasma was shown to be cell free. Infectious virus from plasma was not isolated. The predictive value of qualitative nested PCR from blood to detect HCMV infection was high for plasma and decreased in the following sequence: plasma (0.92) > PBMC (0.83) > granulocytes (0.65). CONCLUSIONS: Qualitative nPCR from plasma and PBMC seems to be sufficient to detect (an ongoing) HCMV infection of immunosuppressed patients. However, the rate of single positive leukocyte fractions is approximately 60%. Therefore, viral leukoDNAemia in 40% of cases seems to be restricted to either PBMC or granulocytes. For diagnostic purposes the whole leukocyte population should be used for PCR analysis.

Bone Marrow Transplantation↗
PubMed2006

Human retinal and brain cell lines: A model of HCMV retinitis and encephalitis.

Although HIV is accepted as the etiologic agent in AIDS, other factors have been implicated in accelerating the disease. Human cytomegalovirus (HCMV) in particular has been implicated as a cofactor in the progression from AIDS-related complex (ARC) to AIDS. HCMV infection of the central nervous system (CNS) (brain, retina) has been reported in at least 50% of AIDS patients, and has been implicated in producing encephalitis and sight-threatening retinitis. HCMV exhibits strict species specificity and animal models for human HCMV are conspicuous by their absence. We have developed a human brain cell line (mixed glial/neuronal) and a multipotential human retinal precursor cell line (neuronal in nature). We have tested the suitability of these cell lines as models for the study of HCMV infectibility. In this study, we report that these cell lines are optimal for the study of HCMV infectibility and pathogenesis in tissues of neural origin and appropriate to study HIV-HCMV interaction. Immortalized human brain and retinal cell lines were infected with a laboratory strain of HCMV (AD 169, Towne) at a multiplicity of infection moi (1-5) and viral infectibility and cell specificity monitored by: (a) phenotypic analysis (multinucleate cells, syncytium formation, etc.), (b) antigen expression (IE, E, late) by immunohistochemistry, Western blot analysis, (c) presence of viral particles by TEM, and (d) expression of indicator plasmids (HIV-LTR-CAT). We report that both human retinal and brain cell lines are permissive for HCMV infectibility. Cell specificity was not seen; both cells expressing glial/neuronal cell markers were positive for the presence of HCMV early/late antigens. Formation of multinucleate giant cells with nuclear inclusion bodies and syncytia were seen. Productive viral infection was confirmed by the ability of cell-free supernatant from the third passage of infected cells to produce pathogenicity and express viral particles, when added to fresh cultures. Using indicator plasmids, HIV-LTR, and CAT, we have shown that HIV and HCMV interact at the cellular level. We have also shown that HIV production in retinal and brain cell lines transfected with cloned HIV was enhanced by HCMV-IE genes. We did not see any differences in HCMV. AD 169, Towne isolate, and data from both strains is presented in this paper. This model could prove extremely useful for the study of cell specificity/cellular and molecular interaction between HIV/HCMV and to test antiviral therapies.

Animals↗
PubMed2002

[Detection of human cytomegalovirus infection by FQ-PCR technique and its application in the diagnosis and treatment of HCMV infected children].

BACKGROUND: To detect quantitatively HCMV DNA in peripheral blood leukocytes to monitor the status of HCMV infection, evaluate the effectiveness of antiviral treatment with ganciclovir (GCV) combined with intravenous immunoglobulin (IVIG) and find out the relationship among the HCMV DNA levels, the state of infection and the clinical outcome.The long-term goal of the study was to establish a molecular diagnostic standard for HCMV infection in children. METHODS: 45 cases of suspected HCMV-infected children were examined by PCR, ELISA and fluorescent quantitative (FQ)-PCR, respectively. Twenty five HCMV hepatitis cases of the 45 were randomly assigned to a treated group or a control group. Both groups were treated with prednisone, glucurone, Luminal and Xiaoyanlidanpian. But the treated group was given with GCV+IVIG in addition. Each infant of the two groups was checked with FQ-PCR at the five time points. RESULTS: The positive rates of PCR, ELISA and FQ-PCR were 60.00%, 33.33% and 66.67%,their sensitivities were 84.38%, 46.88% and 93.75%, respectively. There was no significant difference in viral DNA copy numbers between the two groups before being treated (P>0.05), but there was significant difference between HCMV hepatitis and normal infants (P<0.001). Although viral load of both groups decreased in both groups, the viral load of the treated group decreased more significantly. The level of HCMV DNA fell to 103 copies/ml at second time point while that of the control group fell to the same level after third time point. The differences between the two groups at each time point were statistically significant (P<0.001). The results of 135 person times testing indicated that 103 copies/ml of FQ-PCR can be taken as a critical value for prediction of active HCMV infection. CONCLUSIONS: FQ-PCR may be one of the effective methods for diagnosis of HCMV disease; it can offer a key index in the diagnosis of HCMV active infection; dynamic detection of HCMV viral load can play a role not only in monitoring antiviral therapy, but also in evaluating the development and prognosis of HCMV disease.

Antiviral Agents↗
PubMed2001

[Study on molecular epidemiology of HCMV infection in mothers and their newborns in Changsha].

The detection of HCMV-IgG, IgM in plasma by ELISA and DNA in plasma and P(C) BMCs from mothers and their newborns by PCR was carried out. Positive HCMV-IgG, HCMV-IgM, P(C)BMCs HCMV DNA and plasma HCMV DNA were demonstrated in 119(95.2%), 7(5.6%), 27(21.6%) and 14(11.2%) in 125 mothers and 117(93.6%), 1(0.8%), 18(14.4%) and 7(5.6%) in their mewborns, respectively. There were significant differences among the positive rate of newborn's HCMV-IgM, plasma HCMV DNA and CBMCs HCMV DNA (P < 0.05), but the difference between HCMV-IgM and plasma HCMV DNA had no statistic significance (P > 0.05). This study suggests that HCMV-IgG and CBMCs HCMV PCR are preferable epidemiological index of HCMV infection of pregnant women and newborns respectively.

Adult↗
PubMed2006

hCMV induced IL-6 release in trophoblast and trophoblast like cells.

BACKGROUND: Human cytomegalovirus (hCMV) infection of the trophoblasts is a crucial event in virus transmission from mother to child, being one responsible factor for intrauterine infection of the unborn. Differences of virus replication in trophoblasts depending on time point of pregnancy and degree of differentiation of trophoblasts might influence this transmission. Furthermore, immunological reactions of the trophoblasts to hCMV infection might be important defence mechanisms too. OBJECTIVES: hCMV replication and interleukin-6 release in trophoblasts and trophoblast like cells (choriocarcinoma cells) was investigated. STUDY DESIGN: Trophoblasts from term and 1st trimester placentas were isolated and infected with hCMV. hCMV production and release to the supernatant as well as interleukin-6 release and interleukin-6 mRNA production by these infected cells was measured. Choriocarcinoma cell lines (JEG-3, JAR) were treated the same. Non-infected trophoblasts were used as controls. RESULTS: In 1st trimester trophoblast, term trophoblasts and JEG-3 permissive hCMV replication was observed, although with different kinetics and efficiency. In JAR no complete virus replication was seen. High levels of interleukin-6 were measured in the supernatants of all hCMV infected cells immediately after infection. IL-6 mRNA upregulation was seen 48 h after infection in those cell types replication of hCMV occurred (1st trimester trophoblasts, term trophoblasts, JEG-3). At that time-point hCMV immediate early proteins appeared. In JARs no virus production and no IL-6 mRNA upregulation was seen, and IL-6 levels in the supernatant of these hCMV infected cells declined significantly until day 6 after infection compared to mock infected cells. CONCLUSION: These observations show that hCMV replication is influenced by the degree of trophoblast differentiation. Interleukin-6 is upregulated by hCMV infection, but is independent of complete virus replication.

Cell Differentiation↗
PubMed2001

In vitro transmission of HCMV between fibroblasts and peripheral blood leukocytes in the presence of IL-4.

We demonstrated transmission of human cytomegalovirus (HCMV) from the human lung fibroblast MRC-5 to peripheral blood leukocytes (PBLs). mRNA of the HCMV immediately-early (IE) antigen was detected in PBLs cultured with IL-2 or IL-2 + IL-4 that made direct contact with HCMV-infected MRC-5, whereas it was not detected in PBLs prevented from making cell-to-cell contact. However, mRNA of HCMV IE was not detected in PBLs cultured with IL-2 and IFN-gamma that made direct contact with HCMV-infected MRC-5. Transmission of the pp65 antigen was increased in culture medium containing IL-4. At a higher viral infection titer, cell-free HCMV infected adherent PBLs cells. The subset, which did not adhere, did not infect cell-free viruses even at a very high multiplicity of infection. Moreover, the adhered subset of PBLs infected with HCMV was able to transmit HCMV to non-infected fibroblasts. Our results suggest that cell-to-cell contact (when PBLs make direct contact with HCMV-infected cells) is important in the mechanism of HCMV transmission and that the adherent cells of PBLs are one of the most important vehicles for HCMV infection. Moreover, we suggest that type 2 cytokines such as IL-4 enhance the transmission of HCMV to PBLs.

Antigens, Viral↗