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HCMV
Terms modified by HCMV Selected AbstractsInfantile spasms and cytomegalovirus infection: antiviral and antiepileptic treatmentDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 9 2007Dorota Dunin-Wasowicz MD PhD From 1 January 1995 to 31 December 2004, 22 patients (13 males, nine females; age range 2-12mo) with infantile spasms and cytomegalovirus (CMV) infection were treated with intravenous ganciclovir (GCV) and antiepileptic drugs. GCV was given for 3 to 12 weeks with a 1-month interval (one, two, or three courses). Epileptic spasms occurred before (group A: eight patients), simultaneously (group B: eight patients), and after (group C: six patients) a diagnosis of human CMV (HCMV) infection and antiviral treatment. In 11 patients, DNA HCMV was found in cerebrospinal fluid by nested-polymerase chain reaction method (neuroinfection). All infants excreted CMV in urine. DNA HCMV and specific immunoglobulin M and immunoglobulin G antibodies were present in blood. Ten patients, including four with neuroinfection, have been seizure-free for at least the past 18 months. In two patients with neuroinfection, vigabatrin monotherapy was withdrawn after a 2 year 6 month seizure-free period. Eighteen patients required antiepileptic drugs polytherapy, four of whom required additional adrenocorticotropic hormone (ACTH). Six patients on polytherapy were seizure-free on follow-up, two of whom were treated with ACTH, but no patient with hypsarrhythmia who required ACTH treatment was seizure-free on follow-up. In five patients, psychomotor development was normal, 16 had tetraplegia (Gross Motor Function Classification System [GMFCS] Level V), and one had diplegia (GMFCS Level III). Early antiviral and antiepileptic therapy could result in the long-term cessation of seizures. [source] The study of cytopathological aspects induced by human cytomegalovirus infectionDIAGNOSTIC CYTOPATHOLOGY, Issue 5 2004B.S., C.M.I.A.C., Takako Takeuchi C.T. Abstract In cytological examination, human cytomegalovirus (HCMV) infection can not be implied unless typical HCMV-infected cells like owl's-eye cells are present. However, such cells are not always observed in HCMV-infection cases. The aim of our study is to establish the cytopathological features induced by HCMV. In vitro transfection and fluorescence in situ hybridization (FISH) were performed on human embryo lung (HEL) cells. Marked cellular aggregation was observed at 6-hr postinfection (hpi). Multinucleated cells, giant cells, and, particularly, small vacuoles were present in the nuclei or cytoplasm before the appearance of inclusion bodies. However, molding and ground glass in nuclei were absent. Cell clusters displayed round cytoplasm, dispersed later, and showed anisocytosis. All features occurred before 48 hpi when the owl's-eye cell appeared. In FISH, the positive signal highlighted viral particles that became predominant and localized in nuclei. These cytological aspects are dependent on viral replication and contribute to the cytological detection of HCMV infection. Diagn. Cytopathol. 2004;31:289,293. © 2004 Wiley-Liss, Inc. [source] Differential mutagen sensitivity of peripheral blood lymphocytes from smokers and nonsmokers: Effect of human cytomegalovirus infectionENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3 2004Thomas Albrecht Abstract We used the mutagen sensitivity assay to test the hypothesis that human cytomegalovirus (HCMV) infection modifies the sensitivity of cells to genetic damage from genotoxic agents. Chromosome aberration (CA) frequency in peripheral blood lymphocytes (PBLs) from 20 smokers who were matched with 20 nonsmokers by age (± 5 years), sex, and ethnicity was evaluated following in vitro exposure to bleomycin and/or HCMV infection. Bleomycin induced significant (P < 0.05) concentration-dependent increases in the frequency of aberrant cells, chromatid-type damage (breaks), and chromosome-type aberrations (deletions, rearrangements) in PBLs. The baseline (background) CA frequency was similar in both smokers and nonsmokers. Significantly higher frequencies of aberrant cells (P < 0.05) were observed in PBLs from smokers compared to nonsmokers at all bleomycin concentrations tested (10, 30 and 100 ,g/ml). Infection of PBLs with HCMV induced a significant (P < 0.05) twofold increase in the frequency of CA (primarily chromatid breaks) in PBLs, regardless of the smoking status. PBLs from smokers and nonsmokers infected with HCMV prior to challenge with bleomycin demonstrated significant (P < 0.05) concentration-dependent increases in the levels of aberrant cells, chromatid-type damage (breaks), and chromosome-type aberrations (deletions, rearrangements) compared to noninfected cells challenged with bleomycin. The frequency of induced CA was consistently higher for PBLs derived from smokers relative to nonsmokers (P = 0.06 and 0.002). These data indicate that, individually, both smoking and HCMV infection significantly enhance the sensitivity of PBLs to bleomycin-induced genetic damage. More importantly, the data also suggest that smoking and HCMV infection interact synergistically to enhance the sensitivity of PBLs to such damage. Environ. Mol. Mutagen. 43:169,178, 2004. © 2004 Wiley-Liss, Inc. [source] Expression and function of NKG2D in CD4+ T cells specific for human cytomegalovirusEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2006Andrea Sáez-Borderías Abstract The human NKG2D killer lectin-like receptor (KLR) is coupled by the DAP10 adapter to phosphoinositide 3-kinase (PI3,K) and specifically interacts with different stress-inducible molecules (i.e. MICA, MICB, ULBP) displayed by some tumour and virus-infected cells. This KLR is commonly expressed by human NK cells as well as TCR,,+ and TCR,,+CD8+ T lymphocytes, but it has been also detected in CD4+ T cells from rheumatoid arthritis and cancer patients. In the present study, we analysed NKG2D expression in human cytomegalovirus (HCMV)-specific CD4+ T lymphocytes. In vitro stimulation of peripheral blood mononuclear cells (PBMC) from healthy seropositive individuals with HCMV promoted variable expansion of CD4+NKG2D+ T lymphocytes that coexpressed perforin. NKG2D was detected in CD28, and CD28dull subsets and was not systematically associated with the expression of other NK cell receptors (i.e. KIR, CD94/NKG2 and ILT2). Engagement of NKG2D with specific mAb synergized with TCR-dependent activation of CD4+ T cells, triggering proliferation and cytokine production (i.e. IFN-, and TNF-,). Altogether, the data support the notion that NKG2D functions as a prototypic costimulatory receptor in a subset of HCMV-specific CD4+ T lymphocytes and thus may have a role in the response against infected HLA class II+ cells displaying NKG2D ligands. [source] Phenotypic classification of human CD8+ T,cells reflecting their function: inverse correlation between quantitative expression of CD27 and cytotoxic effector functionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2004Hiroko Tomiyama Abstract Phenotypic classification of human CD8+ T,cells using three cell surface markers, CD27, CD28 and CD45RA, was recently suggested to be useful for identification of naive, memory and effector CD8+ T,cells. However, it still remains unclear whether such classification precisely reflects functional classification of CD8+ T,cells. To clarify this, we characterized each CD27CD28CD45RA subset of total and human cytomegalovirus (HCMV)-specific CD8+ T,cells by analyzing the expression of perforin and two chemokine receptors, CCR5 and CCR7, as well as their function. An inverse correlation between perforin and CD27 expression was found in all four CD28CD45RA subsets. Therefore, to achieve a phenotypic classification of CD8+ T,cells that moreprecisely reflects their function, the CD27+ subset was divided into CD27low and CD27high subsets based on the expression level of CD27. Functional and flow cytometric analyses of CD27CD28CD45RA subsets showed that this phenotypic classification reflects functional classification of CD8+ T,cells. HCMV-specific CD8+ T,cells from healthy HCMV-seropositive individuals were predominantly found in effector and memory/effector subsets, indicating that HCMV-specific effector CD8+ T,cells are actively induced by HCMV replication in healthy HCMV carriers. Phenotypic analyses of CD8+ T,cells using this classification will enable the characterization of antigen-specific CD8+ T,cells. [source] Differential effects of US2, US6 and US11 human cytomegalovirus proteins on HLA class,Ia and HLA-E expression: impact on target susceptibility to NK cell subsetsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2003Manuel Llano Abstract We compared in an inducible expression system the individual effect of US2, US6 and US11 human cytomegalovirus (HCMV) proteins on HLA-E and HLA class,Ia surface expression, assessing in parallel their influence on target susceptibility to NK cell clones. To this end, the RPMI,8866 B,lymphoma cell line (HLA-A2, HLA-A3, HLA-B7, HLA-Cw7, HLA-ER, HLA-EG) was stably cotransfected with the ecdysone receptor, together with the US sequences under the control of an ecdysone-inducible promoter. Biosynthesis of viral proteins was turned on by incubating transfectants with Ponasterone,A. US6 down-regulated expression of all class,I molecules, hampering target resistance to NK cell clones controlled by the CD94/NKG2A, KIR2DL2 and/or CD85j (ILT2 or LIR-1) inhibitory receptors. By contrast, US11 reduced the surface levels of class,Ia molecules but preserved HLA-E; this rendered US11+ cells sensitive to NK clones under the control of KIR2DL2 and/or CD85j, while their resistance to CD94/NKG2A+KIR2DL2, effector cells was maintained. US2 preserved as well HLA-E expression but selectively targeted class,Ia molecules; in fact, HLA-A and HLA-C allotypes were down-modulated whereas HLA-B7 remained unaltered. US2+ targets became sensitive to KIR2DL2+ cells but remained resistant to CD94/NKG2A+CD85j+ NK clones. The differential effects of US proteins on HLA class,Ia and HLA-E likely reflect the evolutionary adaptation of HCMV to counteract NK-mediated surveillance. [source] Dynamics of a Transgene Expression in Acute Rat Brain Slices Transfected with Adenoviral VectorsEXPERIMENTAL PHYSIOLOGY, Issue 4 2003C. E. L. Stokes We present a quantitative account of the expression dynamics of a transgene (enhanced green fluorescent protein, EGFP) in acute brain slices transfected with an adenoviral vector (AVV) under control of the human cytomegalovirus (HCMV) promoter. Micromolar concentrations of EGFP could be detected in brainstem and hippocampal slices as early as 7 h after in vitro transfection with a viral titre of 4.4 × 109 plaque-forming units (pfu) ml,1. Although initially EGFP appeared mainly in glia, it could be detected in neurones with longer incubation times of 10-12 h. However, fluorescence was never detected within some populations of neurones, such as hippocampal pyramidal cells, or within the hypoglossal motor nucleus. The density of cells expressing EGFP peaked at 10 h and then decreased, possibly suggesting that high concentrations of EGFP are toxic. The age of the animal significantly affected the speed of EGFP accumulation: after 10 h of incubation in 30-day-old rats only 4.88 ± 0.51 cells/10 000 ,m2 were fluorescent compared to 7.28 ± 0.39 cells/10 000 ,m2 in 12-day-old rats (P < 0.05). HCMV promoter-driven transgene expression depended on the activity of protein kinase A, and was depressed with a cAMP/protein kinase A antagonist (20 ,M Rp-cAMPS; P < 0.0005). This indicates that expression of HCMV-driven constructs is likely to be skewed towards cellular populations where cAMP-dependent signalling pathways are active. We conclude that acute transfection of brain slices with AVVs within hours causes EGFP expression in micromolar concentrations and that such transfected cells may remain viable for use in physiological experiments. [source] Human cytomegalovirus and natural killer-mediated surveillance of HLA class I expression: a paradigm of host,pathogen adaptationIMMUNOLOGICAL REVIEWS, Issue 1 2001Miguel López-Botet Summary: Among various strategies to evade the host immune response, some viruses like human cytomegalovirus (HCMV) interfere with surface MHC class I expression and antigen presentation to T lymphocytes. The ability of natural killer (NK) cells to detect MHC class I molecules through inhibitory receptors can be envisaged as an adaptation of the immune system for responding to such pathological alterations. To fulfil that role, rodents use members of the Ly49 C-type lectin superfamily, whereas primates employ killer immunoglobulin-like receptors and the immunoglobulin-like transcript 2/leucocyte immunoglobulin-like receptor-1 receptor. CD94/NKG2 lectin-like heterodimers represent the most conserved receptor system for MHC class I molecules; by interacting with human HLA-E or murine Qa-1b, CD94/NKG2A inhibitory receptors broadly probe the biosynthesis pathway of other class I molecules. Reciprocally, HCMV has developed mechanisms to evade the NK response while modulating HLA class Ia expression. The ability of HCMV to maintain surface levels of HLA-E and to express an HLA class I surrogate (UL18) are herein discussed in the context of the interplay with human NKR systems. This work was supported by grants FIS 00/0181 and SAF98-0006. We thank Dr A. Angulo for helpful discussion. [source] High prevalence of an active cytomegalovirus infection in the appendix of immunocompetent patients with acute appendicitisINFLAMMATORY BOWEL DISEASES, Issue 2 2008Mensur Dzabic Abstract Background Appendicitis is a very common surgical diagnosis with unclear pathology. Human cytomegalovirus (HCMV) can modulate our immune system and has been associated with inflammatory bowel disease (IBD) and various other inflammatory diseases. Methods We investigated the association between HCMV and acute appendicitis in 14 immunocompetent patients. Tissue sections from 10 AIDS patients with verified HCMV infection were used as positive controls, and uninflamed intestinal tissue sections from 12 patients were used as negative controls. Results Cells double positive for HCMV early antigens and IL-6/IL-8 were observed in the appendices of 64.3% of appendicitis patients (9 of 14) by immunohistochemical analysis. HCMV late antigen was found in the appendices of 42.9% of the acute appendicitis patients (6 of 14). Latent HCMV appendix infection, as verified by in situ hybridization, as well as HCMV IgG, was observed in 78.6% of patients (11 of 14). The study samples from all 6 healthy appendices were negative for HCMV early and late antigens, although 50% (3 of 6) were HCMV IgG and HCMV DNA positive. Conclusions We have shown that HCMV infection of the appendix is associated with acute appendicitis (P = 0.002) and possibly with the severity of the disease. Our study identified HCMV as a pathogen to be sought for in the appendicitis patient group, possibly allowing further medical treatment of these patients. (Inflamm Bowel Dis 2007) [source] Evidence of active cytomegalovirus infection and increased production of IL-6 in tissue specimens obtained from patients with inflammatory bowel diseasesINFLAMMATORY BOWEL DISEASES, Issue 3 2003Afsar Rahbar Abstract Recent reports have focused interest on human cytomegalovirus (HCMV) in inflammatory bowel diseases (IBD). Our aim in this study was to examine the frequency of HCMV-infected intestinal cells in tissue sections obtained from patients with IBD, and to investigate if HCMV-infected intestinal cells produce the proinflammatory cytokine IL-6. We studied intestinal tissue sections from 13 patients with ulcerative colitis, 10 with Crohn's disease, 10 cancer patients without intestinal inflammation, and 10 samples from HCMV-infected AIDS patients. HCMV-DNA was detected by in situ hybridization in sections obtained from 12/13 patients with ulcerative colitis, in 10 with Crohn's disease, in 10/10 samples from HCMV-infected AIDS patients, but not in any of the 10 samples that were obtained from uninflamed tissues. HCMV-specific antigens were detected in samples from all HCMV-infected AIDS patients, in 11/13 sections from patients with ulcerative colitis, in 10/10 samples from patients with Crohn's disease, but not in sections from uninflamed tissues. Cells were double positive for an HCMV early antigen and IL-6 in 10/13 sections from patients with ulcerative colitis, in all patients with Crohn's disease, and in 4/10 samples from AIDS patients. In conclusion, these results suggest that active HCMV infection in the intestine is very frequent in patients with IBD, and may contribute to the inflammatory process through an increased production of IL-6. [source] A HCMV pp65 polypeptide promotes the expansion of CD4+ and CD8+ T cells across a wide range of HLA specificitiesJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8b 2009Maurizio Provenzano Abstract Human cytomegalovirus (HCMV) can cause life-threatening disease in infected hosts. Immunization with human leukocyte antigen (HLA)-restricted immunodominant synthetic peptides and adoptive transfer of epitope-specific T cells have been envisaged to generate or boost HCMV-specific cellular immunity, thereby preventing HCMV infection or reactivation. However, induction or expansion of T cells effective against HCMV are limited by the need of utilizing peptides with defined HLA restrictions. We took advantage of a combination of seven predictive algorithms to identify immunogenic peptides of potential use in the prevention or treatment of HCMV infection or reactivation. Here we describe a pp65-derived peptide (pp65340,355, RQYDPVAALFFFDIDL: RQY16-mer), characterized by peculiar features. First, RQY-16mer is able to stimulate HCMV pp65 specific responses in both CD4+ and CD8+ T cells, restricted by a wide range of HLA class I and II determinants. Second, RQY-16mer is able to induce an unusually wide range of effector functions in CD4+ T cells, including proliferation, killing of autologous HCMV-infected target cells and cytokine production. Third, and most importantly, the RQY-16mer is able to stimulate CD4+ and CD8+ T-cell responses in pharmacologically immunosuppressed patients. These data suggest that a single reagent might qualify as synthetic immunogen for potentially large populations exposed to HCMV infection or reactivation. [source] Herpes viruses in periodontal compromised sites: comparison between HIV-positive and -negative patientsJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 10 2008Sabrina Rosa Grande Abstract Aim: The objective of this study was to compare the frequency of herpes simplex virus type 1 (HSV-1), Epstein,Barr virus (EBV) and human cytomegalovirus (HCMV) in subgingival plaque, saliva and peripheral blood of HIV-positive and-negative patients with periodontal disease. Material and Methods: Fifty HIV-positive subjects (23 with gingivitis, 27 with periodontitis) and 50 healthy HIV-negative patients with chronic periodontitis were included in the study. Parameters of probing depth (PD), clinical attachment level (CAL), gingival index and plaque index were recorded. The samples were processed for viral identification by the nested polymerase chain reaction technique. Results: HCMV was the most prevalent virus in HIV-positive (82%) and-negative patients (84%), and the detection in the three samples was similar (p>0.05). HSV-1 was the least prevalent virus in both groups, being detected in similar frequencies in oral sites and in peripheral blood. EBV-1 was found more frequently in saliva and subgingival plaque of HIV-positive patients than in HIV-negative patients (p0.05). Conclusions: EBV-1 was more frequently recovered in oral sites of HIV-positive patients than in HIV-negative patients. [source] Does cytomegalovirus play a causative role in the development of various inflammatory diseases and cancer?JOURNAL OF INTERNAL MEDICINE, Issue 3 2006C. SÖDERBERG-NAUCLÉR Abstract. Human cytomegalovirus (HCMV) is a herpes virus that infects and is carried by 70,100% of the world's population. During its evolution, this virus has developed mechanisms that allow it to survive in an immunocompetent host. For many years, HCMV was not considered to be a major human pathogen, as it appeared to cause only rare cases of HCMV inclusion disease in neonates. However, HCMV is poorly adapted for survival in the immunosuppressed host and has emerged as an important human pathogen in AIDS patients and in patients undergoing immunosuppressive therapy following organ or bone marrow transplantation. HCMV-mediated disease in such patients has highlighted the possible role of this virus in the development of other diseases, in particular inflammatory diseases such as vascular diseases, autoimmune diseases and, more recently, with certain forms of cancers. Current research is focused on determining whether HCMV plays a causative role in these diseases or is merely an epiphenomenon of inflammation. Inflammation plays a central role in the pathogenesis of HCMV. This virus has developed a number of mechanisms that enable it to hide from the cells of the immune system and, at the same time, reactivation of a latent infection requires immune activation. Numerous products of the HCMV genome are devoted to control central functions of the innate and adaptive immune responses. By influencing the regulation of various cellular processes including the cell cycle, apoptosis and migration as well as tumour invasiveness and angiogenesis, HCMV may participate in disease development. Thus, the various drugs now available for treatment of HCMV disease (e.g. ganciclovir, acyclovir and foscarnet), may also prove to be useful in the treatment of other, more widespread diseases. [source] Analysis of mixed infections by multiple genotypes of human cytomegalovirus in immunocompromised patientsJOURNAL OF MEDICAL VIROLOGY, Issue 5 2009P. Sowmya Abstract Human cytomegalovirus (HCMV) is a significant cause of morbidity and mortality in immunocompromised patients. The present study was carried out to determine the frequency of occurrence of multiple genotypes of HCMV in immunocompromised patients, to determine if there is any discrepancy in identification of mixed infections by multiple genotypes in paired clinical specimens obtained from patients and to determine the significance of viral load differences between patients infected with single and multiple genotypes. One hundred clinical specimens from 75 patients were included in the study. Real-time PCR; Multiplex PCR and PCR-based RFLP were applied for the determination of viral load and genotyping of HCMV, respectively. Out of the 75 patients, 36 (48%) carried multiple genotypes. Discrepancy with regard to detection of genotypes were found in 17/25 patients whose paired clinical specimens were analyzed. Mixed genotypes were found more often in peripheral blood than urine or intraocular fluids collected from the same patient. There was a statistically significant difference between the median viral loads of clinical specimens carrying single genotypes and multiple genotypes. Mixed infections with multiple genotypes were found predominantly in the leukocyte fraction of peripheral blood specimens. The detection of mixed infections by multiple genotypes in the hypervariable regions of HCMV can be a surrogate marker of an increase in viral load. J. Med. Virol. 81:861,869, 2009. © 2009 Wiley-Liss, Inc. [source] Genotypic analysis of two hypervariable human cytomegalovirus genesJOURNAL OF MEDICAL VIROLOGY, Issue 9 2008Amanda J. Bradley Abstract Most human cytomegalovirus (HCMV) genes are highly conserved in sequence among strains, but some exhibit a substantial degree of variation. Two of these genes are UL146, which encodes a CXC chemokine, and UL139, which is predicted to encode a membrane glycoprotein. The sequences of these genes were determined from a collection of 184 HCMV samples obtained from Africa, Australia, Asia, Europe, and North America. UL146 is hypervariable throughout, whereas variation in UL139 is concentrated in a sequence encoding a potentially highly glycosylated region. The UL146 sequences fell into 14 genotypes, as did all previously reported sequences. The UL139 sequences grouped into 8 genotypes, and all previously reported sequences fell into a subset of these. There were minor differences among continents in genotypic frequencies for UL146 and UL139, but no clear geographical separation, and identical nucleotide sequences were represented among communities distant from each other. The frequent detection of multiple genotypes indicated that mixed infections are common. For both genes, the degree of divergence was sufficient to preclude reliable sequence alignments between genotypes in the most variable regions, and the mode of evolution involved in generating the genotypes could not be discerned. Within genotypes, constraint appears to have been the predominant mode, and positive selection was detected marginally at best. No evidence was found for linkage disequilibrium. The emerging scenario is that the HCMV genotypes developed in early human populations (or even earlier), becoming established via founder or bottleneck effects, and have spread, recombined and mixed worldwide in more recent times. J. Med. Virol. 80:1615,1623, 2008. © 2008 Wiley-Liss, Inc. [source] Molecular epidemiology of primary human cytomegalovirus infection in pregnant women and their familiesJOURNAL OF MEDICAL VIROLOGY, Issue 8 2008Maria Grazia Revello Abstract The source of human cytomegalovirus (HCMV) infection was investigated in 29 pregnant women with primary HCMV infection by comparing DNA sequences of UL146, UL144 and a portion of UL55 gene of HCMV strains circulating within each family. Thirteen families were identified in which the pregnant woman, the husband and/or a child were shedding HCMV. In three of these families, both the woman and the husband suffered from a concomitant primary HCMV infection. Phylogenetic analysis of UL146, UL144, and UL55 genes indicated that strains circulating within each family were identical, whereas strains from different families appeared to be distinct. However, identical UL146, UL144, and UL55 DNA sequences were observed sporadically among unrelated strains. A child rather than the husband was the virus source for the great majority of pregnant women. No association was observed between UL144 polymorphisms and intrauterine transmission. J. Med. Virol. 80:1415,1425, 2008. © 2008 Wiley-Liss, Inc. [source] Human cytomegalovirus (HCMV) UL139 open reading frame: Sequence variants are clustered into three major genotypesJOURNAL OF MEDICAL VIROLOGY, Issue 4 2006Ying Qi Abstract Human cytomegalovirus (HCMV) infects a number of organs and cell types, leading to the hypothesis that HCMV disease and tissue tropism may be related to specific sequence variability. This study examined the genomic variability of a new polymorphic locus in HCMV, UL139 open reading frame (ORF). Detailed analysis showed that a large number of nucleotide insertions and non-synonymous substitutions occurred in the UL139 ORF, particularly in the 5, half, using the Toledo strain as the reference sequence. The UL139 variants were not distributed randomly, but were clustered clearly into three major groups: G1 (G1a, G1b, and G1c), G2 (G2a, G2b), and G3. In this study, it was found that the predicted UL139 product shared sequence homology with human CD24, a signal transducer modulating B-cell activation responses, and the sequences in G1c contained a specific attachment site of prokaryotic membrane lipoprotein lipid. The precise definition of UL139 genotypes and its putative function would be helpful in understanding better HCMV. J. Med. Virol. 78:517,522, 2006. © 2006 Wiley-Liss, Inc. [source] Impact of human metapneumovirus and human cytomegalovirus versus other respiratory viruses on the lower respiratory tract infections of lung transplant recipientsJOURNAL OF MEDICAL VIROLOGY, Issue 3 2006Giuseppe Gerna Abstract Viral respiratory tract infections in lung transplant recipients may be severe. During three consecutive winter-spring seasons, 49 symptomatic lung transplant recipients with suspected respiratory viral infection, and 26 asymptomatic patients were investigated for presence of respiratory viruses either in 56 nasopharyngeal aspirate or 72 bronchoalveolar lavage samples taken at different times after transplantation. On the whole, 1 asymptomatic (3.4%) and 28 symptomatic (57.1%) patients were positive for human metapneumovirus (hMPV, 4 patients), influenza virus A (3 patients), and B (2 patients), respiratory syncytial virus (2 patients), human coronavirus (2 patients), human parainfluenza virus (2 patients), rhinovirus (5 patients), while 4 patients were coinfected by 2 respiratory viruses, and 5 were infected sequentially by 2 or more respiratory viruses. In bronchoalveolar lavage samples, hMPV predominated by far over the other viruses, being responsible for 60% of positive specimens, whereas other viruses were present in nasopharyngeal aspirates at a comparable rate. RT-PCR (detecting 43 positive samples/128 examined) was largely superior to monoclonal antibodies (detecting 17 positive samples only). In addition, HCMV was detected in association with a respiratory virus in 4/18 HCMV-positive patients, and was found at a high concentration (>105 DNA copies/ml) in 3/16 (18.7%) patients with HCMV-positive bronchoalveolar lavage samples and pneumonia. Coinfections and sequential infections by HCMV and respiratory viruses were significantly more frequent in patients with acute rejection and steroid treatment. In conclusion: (i) about 50% of respiratory tract infections of lung transplant recipients were associated with one or more respiratory viruses; (ii) hMPV largely predominates in bronchoalveolar lavage of symptomatic lung transplant recipients, thus suggesting a causative role in lower respiratory tract infections; (iii) RT-PCR appears to be the method of choice for detection of respiratory viruses in lung transplant recipients, (iv) a high HCMV load in bronchoalveolar lavage is a risk factor for viral pneumonia, suggesting some measure of intervention for the control of viral infection. J. Med. Virol. 78:408,416, 2006. © 2006 Wiley-Liss, Inc. [source] Complete replication of human cytomegalovirus in explants of first trimester human placentaJOURNAL OF MEDICAL VIROLOGY, Issue 4 2001Liliana Gabrielli Abstract Tissue integrity and viability of first trimester placenta explants were obtained in culture for 3 weeks. Explants were infected with human cytomegalovirus (HCMV), several cycles of HCMV replication were obtained and the progression of the infection was observed within a tissue that maintains its normal cellular organization. In agreement with recent clinical data, 3 weeks were necessary for the virus to colonize the placenta fully. Complete HCMV replication was observed in trophoblasts, followed by subsequent transmission of the infection to the stromal fibroblasts and fetal endothelial capillary cells. Viral DNA replication was monitored and the production of infectious viral progeny documented. J. Med. Virol. 64:499,504, 2001. © 2001 Wiley-Liss, Inc. [source] Late human cytomegalovirus (HCMV) proteins inhibit differentiation of human neural precursor cells into astrocytesJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2007Jenny Odeberg Abstract 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. © 2006 Wiley-Liss, Inc. [source] Herpesviruses in human periodontal diseaseJOURNAL OF PERIODONTAL RESEARCH, Issue 1 2000Adolfo Contreras Recent studies have identified various herpesviruses in human periodontal disease. Epstein,Barr virus type 1 (EBV-1) infects periodontal B-lymphocytes and human cytomegalovirus (HCMV) infects periodontal monocytes/macrophages and T-lymphocytes. EBV-1, HCMV and other herpesviruses are present more frequently in periodontitis lesions and acute necrotizing ulcerative gingivitis-lesions than in gingivitis or periodontally healthy sites. Reactivation of HCMV in periodontitis lesions tends to be associated with progressing periodontal disease. Herpesvirus-associated periodontitis lesions harbor elevated levels of periodontopathic bacteria, including Acrinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Bacteriodes forsythus, Prevotella intermedia, Prevotella nigrescens and Treponema denticola. It may be that active periodontal herpesvirus infection impairs periodontal defenses, thereby permitting subgingival overgrowth of periodontopathic bacteria. Alteration between latent and active herpesvirus infection in the periodontium might lead to transient local immunosuppression and explain in part the episodic progressive nature of human periodontitis. Tissue tropism of herpesvirus infections might help explain the localized pattern of tissue destruction in periodontitis. Absence of herpesvirus infection or viral reactivation might explain why some individuals carry periodontopathic bacteria while still maintaining periodontal health. Further studies are warranted to delineate whether the proposed herpesvirus-periodontopathic bacteria model might account for some of the pathogenic features of human periodontal disease. [source] Design of translactam HCMV protease inhibitors as potent antiviralsMEDICINAL RESEARCH REVIEWS, Issue 4 2005Alan D. Borthwick Abstract Human cytomegalovirus (HCMV) is an important pathogen for which there is a significant unmet medical need. New HCMV antivirals, active against novel molecular targets, are undoubtedly needed as the currently available drugs ganciclovir, cidofovir, and foscarnet, which are all viral DNA inhibitors, suffer from limited effectiveness, mainly due to the development of drug resistance, poor bioavailability, and toxicity. One of the newer molecular targets that has been exploited in the search for better drug candidates is HCMV protease. Our ,Ala HCMV protease (wild type variant with the internal cleavage site deleted) was cloned and expressed in E. coli. This viral enzyme was used to develop HCMV protease assays to evaluate potential inhibitors. The chirally pure (SRS)-,-methyl pyrrolidine-5,5- trans -lactam template was synthesized, which together with the natural substrate requirements of HCMV protease and detailed SAR, was used to design potent and selective mechanism based inhibitors of HCMV protease. The mechanism of action of these inhibitors of HCMV protease was investigated by ESI/MS, and the X-ray crystal structure of the HCMV protease was used to refine our selective viral enzyme inhibitors to obtain plasma stable antivirals. A novel ELISA antiviral assay was developed which, together with a cytotoxicity assay, enabled us to discover anti-HCMV drug candidates equivalent in potency to ganciclovir that had good pharmacokinetics in the dog and good brain and ocular penetration in the guinea pig. © 2005 Wiley Periodicals, Inc. Med Res Rev. [source] Recent strategies in the development of new human cytomegalovirus inhibitorsMEDICINAL RESEARCH REVIEWS, Issue 3 2001Ana Martinez Abstract Human cytomegalovirus (HCMV) is one of the most common opportunistic infections in immunucompromised individuals, such as AIDS patients and organ transplant recipients, and is the most frequent congenital viral infection in humans. Despite a reduction of the incidence of AIDS-related opportunistic infections in patients under highly active antiretroviral treatment, attention should be paid to the HCMV risk factor in these individuals. Furthermore, HCMV may have an important role in atherosclerosis. Existing antiviral treatments for the HCMV infection suffer from poor bioavailability, toxicity, and limited effectiveness, mainly due to the development of drug resistance. Fortunately there are novel and potentially very effective new compounds undergoing pre-clinical and clinical evaluation. This review provides an overview in the last five years of new HCMV inhibitors (chemical structures, SAR, and new mechanisms of action) with the aim to provide new clues for the development of future drugs against this opportunistic virus. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 3, 227,244, 2001 [source] Periodontitis lesions are the main source of salivary cytomegalovirusMOLECULAR ORAL MICROBIOLOGY, Issue 4 2009ahin Background:, Herpesviruses play causal or cooperative roles in childhood infections, tumorigenesis, ulcerogenesis, and periodontitis. Saliva is a common vehicle of herpesvirus horizontal transmission, but the source of salivary herpesviruses remains obscure. To evaluate the significance of periodontal disease in shedding of oral herpesviruses, this study determined the genome-copy counts of human cytomegalovirus (HCMV) and Epstein,Barr virus (EBV) in whole saliva of subjects with periodontitis, gingivitis, or no natural teeth. Methods:, Whole saliva was collected from 14 periodontitis patients, 15 gingivitis patients and 13 complete denture wearers. The study subjects were systemically healthy and had not received periodontal treatment in the past 3 months. Real-time TaqMan polymerase chain reaction was used to determine the salivary load of HCMV and EBV. Results:, Salivary HCMV was detected in seven (50%) periodontitis patients, but not in any gingivitis or edentulous subjects (P < 0.001). Salivary EBV was detected in 11 (79%) periodontitis patients, in five (33%) gingivitis patients, and in seven (54%) edentulous subjects (P = 0.076). Salivary samples showed copy counts of HCMV in the range of 3.3 × 103,4.2 × 104/ml and of EBV in the range of 3.6 × 102,1.6 × 109/ml. Conclusions:, HCMV and EBV are commonly present in the saliva of periodontitis patients. Periodontitis lesions of systemically healthy subjects seem to constitute the main origin of salivary HCMV, but do not comprise the sole source of salivary EBV. [source] Herpesviruses in periodontal pocket and gingival tissue specimensMOLECULAR ORAL MICROBIOLOGY, Issue 1 2000A. Contreras Human cytomegalovirus (HCMV) and Epstein-Barr virus type 1 (EBV-1) are frequently detected in crevicular fluid of deep periodontal pockets, but little or no information is available on occurence of herpesviruses in gingival tissue. This investigation studied the presence of herpesviruses in periodontal pockets and the corresponding gingival tissues from 11 periodontally healthy and 14 periodontitis sites. A nested-polymerase chain reaction was employed to identify the presence of HCMV, EBV-1, EBV-2, herpes simplex virus, human herpesvirus (HHV)-6, HHV-7 and HHV-8 in each test sample. In healthy periodontal sites, HCMV was detected in 1 (9%) and EBV-1 in 2 (18%) pocket samples, and HCMV was detected in 2 (18%) and EBV-1 in 3 (27%) gingival tissue samples. In periodontitis lesions, HCMV was detected in 9 (64%) pocket samples and in 12 (86%) gingival tissue samples, and EBV-1 was detected in 6 (43%) pocket samples and in 11 (79%) gingival tissue samples. HHV-6 and HHV-8 were detected exclusively in gingival tissue samples. The present findings confirm the frequent presence of HCMV and EBV-1 in periodontitis lesions and suggest using gingival tissue specimens for detecting periodontal HHV-6, HHV-7 and HHV-8. [source] Viruses in periodontal disease , a reviewORAL DISEASES, Issue 4 2005I Cappuyns The purpose of this review was to evaluate the evidence supporting the hypothesis that viral infection plays a role in the development of periodontitis. An involvement in periodontal diseases has been suspected specifically for human immunodeficiency virus (HIV) and herpes viruses. An association has been demonstrated between HIV infection and some distinct forms of periodontal infection, i.e. necrotizing lesions. Furthermore, reports of increased prevalence and severity of chronic periodontitis in HIV-positive subjects suggests that HIV infection predispose to chronic periodontitis. Several studies, most of them from the same research group, have demonstrated an association of herpesviruses with periodontal disease. Viral DNA have been detected in gingival tissue, gingival cervicular fluid (GCF) and subgingival plaque from periodontaly diseased sites. In addition markers of herpesviral activation have been demonstrated in the GCF from periodontal lesions. Active human cytomegalovirus (HCMV) replication in periodontal sites may suggest that HCMV re-activation triggers periodontal disease activity. Concerns regarding sampling, methods and interpretation cast doubts on the role of viruses as causes of periodontal disease. [source] Mechanisms of expression of HHV8, EBV and HPV in selected HIV-associated oral lesionsORAL DISEASES, Issue 2002JJ Hille Opportunistic DNA viruses, particularly members of the herpesvirus family, are frequently the aetiological agents of HIV-associated oral lesions. Oral lesions common to the early phase of the AIDS epidemic, including Kaposi's sarcoma (KS), oral aphthous ulceration, AIDS-associated oral lymphoma, and oral hairy leukoplakia (OHL), have been tested for the prevalence of Epstein,Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). While EBV DNA is detected by PCR in all of these lesions, abundant viral replication can only be detected in OHL. In OHL, a novel state of EBV infection has been discovered with concurrent expression of replicative and transforming proteins, with all of these proteins contributing to the development of the lesion. Activation of signalling pathways and up-regulation of the viral receptor, proliferative and antiapoptotic genes by these proteins induce several of the histological features common to OHL, such as acanthosis and hyperproliferation. In contrast to other permissive herpesvirus infections, expression of EBV transforming proteins within the permissively infected OHL tissue enables epithelial cell survival and may enhance viral replication. Detection of KSHV in these HIV-infected individuals has been localized only to their saliva. Replicative and latent KSHV gene products have been detected in association with the development of oral KS lesions. EBV, but not human cytomegalovirus (HCMV), has been detected by PCR in minor salivary gland biopsies of HIV-associated salivary gland disease. Human papillomaviruses (HPV) are associated with oral warts in HIV-positive individuals; a diagnosis that appears to be increasing in frequency in the era of highly active antiretroviral therapy. To date, there appears to be little increase in the incidence of HPV-associated oral cancer. The mechanisms of interaction between HIV and HPV are not fully understood. Expression of viral gene products is clearly important and necessary for the development of multiple AIDS-associated oral lesions. [source] HCMV seroprevalence and associated risk factors in pregnant women, Havana City, 2007 to 2008PRENATAL DIAGNOSIS, Issue 9 2010C. B. Correa Abstract Objective To prenatally identify pregnant women at risk of developing congenital infection due to human cytomegalovirus (HCMV). Methods One thousand one hundred and thirty-one pregnant women from three municipalities from Havana City were serologically screened for HCMV infection (IgM/IgG, IgG avidity) from January 2007 to January 2008. Demographical, epidemiological, and clinical variables were correlated to serologic status to identify predictors of seroconversion in pregnancy. Results The majority of women were seropositive to HCMV (92.6%); 27 women (2.4%) developed HCMV active infection during pregnancy, defined by the detection of IgG+ and IgM+ (7 women), IgM+ and IgG, (2 women), and IgG seroconversion (18 women). Susceptibility of active HCMV infection during pregnancy was associated with maternal age < 20 years and nulligravidity. Primary infection was detected in 20 pregnant women (1.8%), whereas 7 patients (0.6%) had active non-primary infection. Conclusion Although pregnant women in Cuba have high seroprevalence rates for HCMV, those younger than 20 years and nulligravidae are at risk of acquiring infection during pregnancy. Copyright © 2010 John Wiley & Sons, Ltd. [source] Enhanced monocyte binding to human cytomegalovirus-infected syncytiotrophoblast results in increased apoptosis via the release of tumour necrosis factor alphaTHE JOURNAL OF PATHOLOGY, Issue 4 2005Gary Chan Abstract We have shown that monocytes bound to intercellular adhesion molecules (ICAM-1) on syncytialized placental trophoblasts (ST) induce trophoblast apoptosis, and that ST infection by human cytomegalovirus (HCMV) up-regulates ICAM-1. We hypothesize that the focal loss of trophoblast seen in HCMV-infected placenta is mediated by increased adherence of monocytes at sites of infection. We find that ST cultures (differentiated from primary cytotrophoblasts) increase monocyte binding when infected with HCMV. Monocyte adhesion was inhibited by antibodies to ICAM-1 and its ligand leukocyte function-associated molecule (LFA-1) on monocytes. When co-cultured with adhering monocytes, infected ST cultures had higher levels of apoptosis than infected cultures alone. Although trophoblast apoptosis clustered around adhering monocytes, it occurred only in non-infected cells. Blocking monocyte binding with ICAM-1 and LFA-1 antibodies reduced the rate of apoptosis to that of the infected culture. Co-cultures incubated with TNF, antibody and EGF inhibited both monocyte- and HCMV-induced apoptosis but did not block binding. We conclude that HCMV stimulates ST culture expression of ICAM-1, which binds to LFA-1 on monocytes that release TNF,, thereby inducing apoptosis of neighbouring uninfected trophoblasts. The above data indicates that trophoblast loss associated with HCMV infection can be caused by increased monocyte adhesion to ST. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Successful Immunotherapy of HCMV Disease Using Virus-Specific T Cells Expanded from an Allogeneic Stem Cell Transplant RecipientAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2010G. R. Hill Opportunistic infection remains the principal cause of mortality in allogeneic stem cell transplant recipients with active extensive chronic graft-versus-host disease. Human cytomegalovirus (HCMV) represents an important cause of disease in this setting and the toxicity of protracted and recurrent antiviral treatment together with eventual drug resistance represents a significant limitation to therapy. Although the expansion and adoptive transfer of HCMV-specific T cells from the healthy original donor can be an effective strategy to control viral replication, this is not possible when donors are seronegative or are subsequently inaccessible. Here we demonstrate for the first time, the successful expansion of HCMV-specific T cells from a seropositive transplant recipient of a seronegative graft with active HCMV disease and the long-term reconstitution of protective antiviral immunity following their adoptive transfer back into the patient. 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