Cytomegalovirus High-risk Kidney Transplant Recipients Show No Difference in Long-term Outcomes Following Preemptive Versus Prophylactic Management.

BACKGROUND: Following kidney transplantation (KT), cytomegalovirus (CMV) infection remains an important challenge. Both prophylactic and preemptive antiviral protocols are used for CMV high-risk kidney recipients (donor seropositive/recipient seronegative; D+/R-). We performed a nationwide comparison of the 2 strategies in de novo D+/R- KT recipients accessing long-term outcomes. METHODS: A nationwide retrospective study was conducted from 2007 to 2018, with follow-up until February 1, 2022. All adult D+/R- and R+ KT recipients were included. During the first 4 y, D+/R- recipients were managed preemptively, changing to 6 mo of valganciclovir prophylaxis from 2011. To adjust for the 2 time eras, de novo intermediate-risk (R+) recipients, who received preemptive CMV therapy throughout the study period, served as longitudinal controls for possible confounders. RESULTS: A total of 2198 KT recipients (D+/R-, n = 428; R+, n = 1770) were included with a median follow-up of 9.4 (range, 3.1-15.1) y. As expected, a greater proportion experienced a CMV infection in the preemptive era compared with the prophylactic era and with a shorter time from KT to CMV infection ( P < 0.001). However, there were no differences in long-term outcomes such as patient death (47/146 [32%] versus 57/282 [20%]; P = 0.3), graft loss (64/146 [44%] versus 71/282 [25%]; P = 0.5), or death censored graft loss (26/146 [18%] versus 26/282 [9%]; P = 0.9) in the preemptive versus prophylactic era. Long-term outcomes in R+ recipients showed no signs of sequential era-related bias. CONCLUSIONS: There were no significant differences in relevant long-term outcomes between preemptive and prophylactic CMV-preventive strategies in D+/R- kidney transplant recipients.

Maternal cytomegalovirus infection and delayed language development in children at 3 years of age-a nested case-control study in a large population-based pregnancy cohort.

INTRODUCTION: Maternal cytomegalovirus (CMV) infection in pregnancy may result in vertical transmission of CMV to the child. Long-term effects of congenital CMV infection include visual, cognitive as well as neurological impairment. The aim of this study was to estimate the odds ratios for CMV seropositivity and seroconversion in mothers, with and without delayed language development in 3 year old children, nested within a large cohort. MATERIAL AND METHODS: The Norwegian Mother, Father and Child Cohort Study (MoBa) is a prospective population-based pregnancy cohort that includes 95 200 mothers and 114 500 children. Blood samples were obtained from mothers during pregnancy weeks 17 or 18 in pregnancy and after birth. We included 300 women from MoBa with children suffering from delayed language development at three years of age, based on validated questionnaires. Within the cohort, 1350 randomly selected women were included as controls to perform a nested case-control study. The cases and controls were tested for CMV IgG antibodies by an enzyme-linked immunosorbent assay. RESULTS: Among mothers of cases, 63.2% were CMV-IgG positive in the sample at birth, as compared to 55.9% among controls; OR 1.36, (95% CI; 1.05 to 1.76). Also, among case mothers, 8/118 (6.8%) initially seronegative cases, seroconverted. Among initially seronegative controls, seroconversion occurred in 23/618 (3.7%) mothers. The OR for seroconversion in cases as compared to control mothers was 1.88 (CI; 0.82 to 4.31), thus not statistically significant different. CONCLUSION: This study shows a higher risk of delayed language development at three years of age in children born by mothers seropositive for CMV, compared to children born from seronegative mothers.

Parvovirus B19 DNAemia in pregnant women in relation to perinatal death: A nested case-control study within a large population-based pregnancy cohort.

INTRODUCTION: Parvovirus B19 (B19V) is the infectious cause of exanthema infectiosum. In Europe around 40% of pregnant women are susceptible to infection. Having small children at home is the main risk factor for contracting an infection during pregnancy. The association between B19V-infection and perinatal death is not yet settled. The aims of the study were to estimate the association between maternal parvovirus B19 infection in pregnancy and perinatal death, and to assess the significance of a positive B19V PCR in pregnancy. MATERIAL AND METHODS: The study population consists of women included in the Norwegian Mother and Child Cohort Study, a prospective population-based pregnancy cohort of nearly 100 000 women. Blood samples were obtained during weeks 17-18 in pregnancy (M1), at birth, and in umbilical cord blood. Within participants in the pregnancy cohort, 138 cases of perinatal death and 1350 controls with live-born children were included in a nested case-control study. Samples were analyzed with B19V serology and B19V PCR according to a predefined test algorithm. For cases, medical records and laboratory results from hospitals were combined with the results of B19V serology and PCR. The reported causes of perinatal death were categorized using the classification system: Causes Of Death and Associated Conditions (CODAC). RESULTS: The B19V seroconversion rates were 9.8% for cases and 6.8% for control mothers. The odds ratio for maternal B19V infection in cases compared with controls was 1.28 (95% CI 0.35-4.70), adjusted for age, parity, body mass index and tobacco use. B19V-PCR-positive samples were detected at weeks 17-18 of gestation in both cases and controls. The proportion of positive samples was similar in cases and controls, 24% and 28.2%, respectively. Mothers with PCR-positive M1 samples transmitted B19V vertically in 9.1% of cases and in 11.9% of the controls. Of all perinatal deaths, 53% were attributed to placental pathology or unknown causes. CONCLUSIONS: B19V PCR positivity was high and similar in both cases and controls. In our study B19V DNAemia was not seen to be associated with fatal outcome of pregnancy. The clinical significance of B19V DNA detection during pregnancy is uncertain. Caution is needed when diagnosing a B19V infection based only on B19V DNAemia.

Maternal and congenital cytomegalovirus infections in a population-based pregnancy cohort study.

CMV is the most common cause of congenital infection. During the past few decades, there has been a change in behaviour that possibly has affected the CMV infection rate of mother and child. We investigated 1350 randomly selected pregnant women from the Norwegian Mother and Child Cohort Study using an algorithm for detection of maternal and congenital CMV (cCMV) infection including both serology and nucleic acid amplification assay. The CMV IgG seroprevalence was 54% and 23 (3.7%) mothers seroconverted. Three (0.22%) children had a positive CMV PCR in the umbilical cord blood. The transmission rate was lower than reported in previous studies, probably due to lower sensitivity in plasma compared to saliva and urine. The prevalence of cCMV in the present study was compared with the number registered with the ICD-10 code P.35.1-congenital CMV infection in the Norwegian Patient Register. The number registered was lower than the number of estimated infections. Factors like lower level of education and parity were associated with higher CMV IgG seroprevalence, but no significant difference could be linked to age. In conclusion, in this cohort of pregnant women, a high CMV IgG seroconversion rate was found, while the vertical transmission rate was low.

High incidence of maternal parvovirus B19 infection in a large unselected population-based pregnancy cohort in Norway.

BACKGROUND: Around 40% of pregnant women in Norway are parvovirus B19 (B19V) seronegative and thus at risk for B19 V infection. Studies on samples from women with symptomatic disease or known exposure have shown that nucleic acid amplification assays combined with serology increase the sensitivity and improves the diagnostic procedure. OBJECTIVES: The aim was to investigate the seroprevalence of B19V infection, the occurrence of new infections and vertical transmission in a population-based pregnancy cohort, with special emphasis on the diagnostic methods. STUDY DESIGN: We randomly selected 1350 pregnant women from the Norwegian Mother and Child Cohort Study (MoBa), using an algorithm for the detection of B19V infection, including both serology and PCR. RESULTS: Maternal infection was confirmed in 50 subjects (3.7% of 1349 women), of which 35(70%) were viremic. Of the initially seronegative 33(6.8%) seroconverted. The estimated average annual seroconversion rate was 15.5%, with the highest estimated annual seroconversion rate of 31.6%. The rates of yearly seroconversion followed the pattern found in reports from Norwegian microbiology laboratories. Among all women, 31 (2.3%) had an inconclusive serological profile and 17 (54.8%) had detectable virus. Of the 16 women with virus detectable at gestational week 17-18, seven were still seronegative with absent seroconversion in the second sample taken at birth. All together 10 children were vertically infected. CONCLUSIONS: High incidence of viremic B19V infections and high estimated annual seroconversion rates were found. Lack of seroconversion despite longstanding viremia emphasizes the importance of including PCR when testing for B19V infection during pregnancy.

Low level of MAp44, an inhibitor of the lectin complement pathway, and long-term graft and patient survival; a cohort study of 382 kidney recipients.

BACKGROUND: Higher incidence of malignancy and infectious diseases in kidney transplant recipients is related to immunosuppressive treatment after transplantation and the recipient's native immune system. The complement system is an essential component of the innate immunity. The aim of the present study was to investigate the association of effector molecules of the lectin complement pathway with graft and patient survival after kidney transplantation. METHODS: Two mannan-binding lectin (MBL) associated proteases, MASP-2 and MASP-3 (activators of the lectin pathway) and two MBL-associated proteins, MAp44 and MAp19 (inhibitors of the lectin pathway) were measured at the time of transplantation in 382 patients (≥17 years old) transplanted in 2000-2001. The cohort was followed until December 31, 2014. Data on patient and graft survival were obtained from the Norwegian Renal Registry. Cox proportional hazard regression models were performed for survival analyses. RESULTS: Low MAp44 level (1st versus 2-4 quartile) was significantly associated with overall mortality; HR 1.52, 95 % CI 1.08-2.14, p = 0.017. In the sub analyses in groups below and above median age (51.7 years), low MAp44 as a predictor of overall mortality was statistically significant only in recipients of ≤51.7 years; HR 2.57, 95 % CI 1.42-4.66, p = 0.002. Furthermore, low MAp44 was associated with mortality due to infectious diseases; HR 2.22, 95 % CI 1.11-4.41, p = 0.023. There was no association between MASP-2, MASP-3 or MAp19 levels and patient mortality. No association between any measured biomarkers and death censored graft loss was found. CONCLUSIONS: Low MAp44 level at the time of transplantation was associated with increased overall mortality in kidney recipients of median age of 51.7 years or below and with mortality due to infectious diseases in the whole patient cohort after nearly 14-years of follow up after transplantation. No associations between other effector molecules; MASP-2, MASP-3 or MAp19 and recipient mortality were found, as well as no association of any biomarker with death censored graft loss.

Lessons Learned From a Randomized Study of Oral Valganciclovir Versus Parenteral Ganciclovir Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients: The VICTOR Trial.

The VICTOR study showed comparable efficacy of treatment with intravenous ganciclovir and oral valganciclovir for cytomegalovirus (CMV) disease in solid organ transplant recipients. Oral therapy is now recommended treatment in clinical practice and guidelines. The VICTOR biobank was used in a series of post hoc analyses that yielded unique and clinically valuable insights into CMV treatment and pathogenesis. For example, the importance of tailoring therapy to initial viral load, the effect of immunosuppression on outcomes, and the need to continue therapy until undetectable viral load to prevent recurrence and emergence of resistant strains. Data were also used to validate the use of international units (IU) in quantitative measurements of CMV DNAemia, which may help future studies to define relevant cutoffs for treatment guidance. The analyses also showed the importance of inflammation on viral outcomes and identified potential targets for future studies. Here we summarize the valuable lessons learned from analysis of the VICTOR data set and sample repository.

Polyclonal Expansion of NKG2C(+) NK Cells in TAP-Deficient Patients.

Adaptive natural killer (NK) cell responses to human cytomegalovirus infection are characterized by the expansion of NKG2C(+) NK cells expressing self-specific inhibitory killer-cell immunoglobulin-like receptors (KIRs). Here, we set out to study the HLA class I dependency of such NKG2C(+) NK cell expansions. We demonstrate the expansion of NKG2C(+) NK cells in patients with transporter associated with antigen presentation (TAP) deficiency, who express less than 10% of normal HLA class I levels. In contrast to normal individuals, expanded NKG2C(+) NK cell populations in TAP-deficient patients display a polyclonal KIR profile and remain hyporesponsive to HLA class I-negative target cells. Nonetheless, agonistic stimulation of NKG2C on NK cells from TAP-deficient patients yielded significant responses in terms of degranulation and cytokine production. Thus, while interactions with self-HLA class I molecules likely shape the KIR repertoire of expanding NKG2C(+) NK cells during adaptive NK cell responses in normal individuals, they are not a prerequisite for NKG2C(+) NK cell expansions to occur. The emergence of NKG2C-responsive adaptive NK cells in TAP-deficient patients may contribute to antiviral immunity and potentially explain these patients' low incidence of severe viral infections.

Increased osteoprotegerin predicts poor virological outcome during anticytomegalovirus therapy in solid organ transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection involves interaction between endothelial cells and leukocyte subsets that may promote vascular inflammation and lead to treatment failure in infected individuals. Osteoprotegerin is a marker of vascular and systemic inflammation but has not been investigated in relation to treatment outcome during CMV infection. METHODS: We investigated whether circulating levels of osteoprotegerin are related to features of CMV disease and treatment outcomes during CMV infection in 291 solid organ transplant recipients receiving valganciclovir or ganciclovir in an international multicenter trial of CMV disease treatment (the VICTOR study). RESULTS: Elevated plasma osteoprotegerin was associated with (i) certain disease characteristics including presence of tissue invasive disease (P<0.05) and increased viral load at baseline (P<0.05), (ii) poor virological outcome at day 49 after anti-CMV therapy, (iii) increased plasma levels of markers of inflammation (pentraxin 3 and C-reactive protein) and endothelial cell activation (von Willebrand factor) both at baseline and during follow-up. CONCLUSION: Our finding indicates that elevated osteoprotegerin levels in solid organ transplant recipients with CMV infection may reflect vascular inflammation and is associated with late virological outcome in these patients.

Viral infection in placenta relevant cells--a morphological and immunohistochemical cell culture study.

Viral infections in pregnancy are known to cause fetal malformation, growth restriction, and even fetal death. Macroscopic placental examination usually shows slight and unspecific changes. Histology may show secondary, non-specific tissue reaction, i.e. villitis with lymphocytic invasion. Primary specific morphology characteristics are known for some virus, like cytomegalovirus, parvovirus, and herpes simplex, however many viral infections show non-specific changes. Placenta relevant cells as human first trimester trophoblasts HTR8/SVneo, primary human umbilical vein endothelial cells (HUVEC), and primary human embryonic fibroblasts were examined following infection with commonly occurring virus like adenovirus and enterovirus. Morphology in routine stained sections and virus-specific immunostains were studied 4, 8, 24, 48, 72 h after infection. Nuclear enlargement was seen in the infected cells. A specific diagnosis of adenovirus or enterovirus infection, however, was not possible without specific immunostains.

High ficolin-3 level at the time of transplantation is an independent risk factor for graft loss in kidney transplant recipients.

BACKGROUND: Recent studies have shown that activation of the complement system may be associated with long-term graft function. The aim of this retrospective study was to assess the impact of the pattern recognition molecules of the lectin pathway on long-term graft survival after kidney transplantation. METHODS: Patients transplanted in 2000 to 2001 were included. Mannose-binding lectin, Ficolin-1, and Ficolin-3 were measured in serum at the time of transplantation. Data on death-censored graft loss were obtained from the Norwegian Renal Registry. Competing risks regression was used to investigate the association between time to graft loss and the explanatory variables. The variables were: high Ficolin-3 (upper quartile, ≥33.3 µg/mL) versus low Ficolin-3 (<33.3 µg/mL), acute rejection (time-dependent), age, basiliximab induction, sex, donor age, human leukocyte antigen mismatches, human leukocyte antigen antibodies, cold ischemia time, living donor, and preemptive transplantation. RESULTS: A total of 382 patients with a median follow-up of 9.8 years were included. Sixty-six patients (17%) had death-censored graft loss, and 116 (30%) patients died. In a final competing risks model, high Ficolin-3 (subhazard ratio [SHR] = 1.95, P = 0.009), acute rejection (one vs. none) (SHR = 1.93, P = 0.033), acute rejection (two vs. none) (SHR = 5.45, P < 0.001), and age (SHR = 0.98, P = 0.006) were associated with death-censored graft loss. Basiliximab induction was associated with improved graft survival (SHR = 0.50, P = 0.016). No associations between mannose-binding lectin or Ficolin-1 and graft loss were found. CONCLUSION: High Ficolin-3 level at the time of transplantation was an independent significant risk factor for shorter graft survival, even when adjusted for other covariates.

[Allogeneic stem-cell transplantation in adults 1985-2012: results and development]. / Allogen stamcelletransplantasjon hos voksne 1985-2012.

BACKGROUND: Allogeneic stem cell transplantation (ASCT) has been a treatment option for patients with serious diseases of the blood and haematopoietic organs in Norway since 1985. Such treatment is potentially curative for selected patients who have a relatively short predicted survival with other treatment modalities. This article summarises the experience and results from ASCT at Oslo University Hospital Rikshospitalet. MATERIAL AND METHOD: The study included all of the 734 adult patients who had undergone allogeneic stem cell transplantation at the Department of Haematology, Rikshospitalet, later Oslo University Hospital Rikshospitalet, from November 1985 to October 2012. RESULTS: At the time of analysis, altogether 384 patients were alive, and the five and ten-year survival rates were 54% and 48% respectively. The median follow-up time was six years. A total of 339 patients (46%) had developed acute graft-versus-host disease (GvHD), and 250 (73%) of these had GvHD ≥ grade II. Altogether 280 out of 602 patients who lived ≥ 100 days after the transplantation (46.5%) developed chronic GvHD. The most frequent causes of death included recurrence of the initial disease in 116 patients (33.1 %), multi organ failure after transplantation in 88 patients (25.4%), infections in 54 patients (16%) and GvHD in 33 patients (9.4%). INTERPRETATION: ASCT is a treatment option with a curative potential for patients with serious haematological diseases when other forms of treatment provide few prospects for recovery. The total survival rate in our study is in accordance with international results for the same time period, and the indications have consistently been in line with what is accepted internationally.

The impact of early cytomegalovirus infection after kidney transplantation on long-term graft and patient survival.

This prospective observational cohort study is an extension of a previous study reporting effects of cytomegalovirus (CMV) on graft and patient survival in 471 patients who underwent kidney transplantation between 1994 and 1997. CMV pp65 antigen was measured every 7-14 d during the first three months after transplantation, given as number of CMV pp65-positive cells per 10(5) leukocytes. A positive test was defined as CMV infection. None of the patients received CMV prophylaxis or preemptive treatment. During a median of 13.7 (7.1-14.9) yr, the number of death-censored graft losses was 118 (25%) and of patient deaths 224 (48%). CMV infection was an independent significant risk factor for mortality in multivariate analysis (HR = 1.453, 95% CI 1.033-2.045, p = 0.032), adjusting for patient and donor age, preemptive transplantation, HLA-DR and -AB mismatches, living donor, acute rejection during the first three months, donor-recipient CMV IgG antibody status and diabetic nephropathy. In univariate analysis, CMV infection was significantly associated with death-censored graft loss but the association was not significant in multivariate model. CMV infection early after kidney transplantation is a predictor of overall mortality but not of death-censored graft loss after a median observation period of 13.7 yr.

Characterization of cytomegalovirus disease in solid organ transplant recipients by markers of inflammation in plasma.

BACKGROUND: While several studies have examined the general inflammatory responses in relation to cytomegalovirus infection, the identification of the various inflammatory mediators as well as their relative importance is far from clear. PATIENTS AND METHODS: Solid organ recipients enrolled in an international multicenter trial of cytomegalovirus disease treatment (the VICTOR study) were analyzed (n = 289) (ClinicalTrials.gov NCT00431353). Plasma markers of inflammation and endothelial cell activation were assessed at baseline by enzyme immunoassays. RESULTS: The major findings were: (i) Plasma levels of the CXC-chemokine interferon-inducible protein-10 (P<0.001) and C-reactive protein (P = 0.046) were independently associated with the presence of cytomegalovirus DNAemia above lower level of quantification. (ii) High levels of CC-chemokine ligand 21 (P = 0.027) and pentraxin 3 (P = 0.033) were independently associated with tissue invasive cytomegalovirus disease as opposed to cytomegalovirus syndrome. CONCLUSION: Our findings illustrate the complex interaction between cytomegalovirus and the immune system, involving a wide range of inflammatory mediators that could be associated to disease manifestations in cytomegalovirus related disease.

Virologic suppression measured by a cytomegalovirus (CMV) DNA test calibrated to the World Health Organization international standard is predictive of CMV disease resolution in transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) load measurement is used to assess the efficacy of treatment of CMV disease, but lacks standardization. Using the World Health Organization (WHO) international standard for reporting, we correlated viral load with CMV disease resolution. METHODS: CMV load was quantified in plasma using a test calibrated to the WHO standard. Three predictive rules were predefined to determine association between CMV DNAemia and outcome: (1) pretreatment CMV DNA of <18,200 (4.3 log(10)) IU/mL; (2) viral load declines of 1.0, 1.5, 2.0, and 2.5 log(10) IU/mL from baseline to days 7, 14, and 21 of treatment, respectively; and (3) viral suppression <137 (2.1 log(10)) IU/mL at days 7, 14, and 21. Analysis was performed using Cox proportional hazard models. RESULTS: Of 267 patients, 251 had CMV disease resolution by day 49 of treatment. Patients with pretreatment CMV DNA of <18,200 (4.3 log(10)) IU/mL had faster time to disease resolution (adjusted hazard ratio [AHR], 1.56; P = .001). Patients with CMV load suppression (<137 IU/mL [<2.1 log(10)]) at days 7, 14, and 21 had faster times to clinical disease resolution (AHRs, 1.61, 1.73, and 1.64, and P = .005, <.001, and <.001, respectively). Relative CMV load reductions from baseline were not significantly associated with faster resolution of CMV disease. CONCLUSIONS: Patients with pretreatment CMV DNA of <18,200 (4.3 log(10)) IU/mL are 1.5 times more likely to have CMV disease resolution. CMV suppression (<137 [2.1 log(10)] IU/mL), as measured by a test calibrated to the WHO Standard, is predictive of clinical response to antiviral treatment. CLINICAL TRIALS REGISTRATION: NCT00431353.

Cytomegalovirus viremia in dried blood spots is associated with an increased risk of death in HIV-infected patients: a cohort study from rural Tanzania.

OBJECTIVES: The objectives of the study were to assess the utility of dried blood spots (DBS) for the detection of cytomegalovirus (CMV) antibody and viremia in a resource-poor setting, to study the prevalence of CMV antibody and viremia in HIV-infected patients with access to antiretroviral therapy (ART) in Tanzania, and to relate CMV viremia to outcome. METHODS: DBS were prepared from 168 ART-naïve patients at baseline. Demographic, clinical, and laboratory data were obtained from patient records. CMV antibody was analyzed by chemiluminescent microparticle immunoassay and viremia by quantitative PCR. RESULTS: All patients were CMV-seropositive. At baseline 38 (22.6%) had detectable CMV viremia and 14 (8.3%) had a CMV viral load ≥ 200 copies/ml. In 135 patients available for follow-up, CMV ≥ 200 copies/ml was an independent risk factor for death with a hazard ratio of 5.0 (95% confidence interval 2.1-11.9) after adjusting for confounders. Symptoms compatible with CMV disease were common with viremia ≥ 200 copies/ml and CD4+ T cell counts <100 cells/mm(3), but confirmatory diagnostic procedures were unavailable. CONCLUSIONS: DBS are suitable for the detection of CMV antibody and viremia in HIV patients in resource-poor areas. CMV viremia was frequent and associated with an increased risk of death. Improved diagnosis and treatment of CMV may improve the prognosis for HIV-infected patients in developing countries and should be addressed in future studies.

Treatment of cytomegalovirus disease in solid organ transplant recipients: markers of inflammation as predictors of outcome.

BACKGROUND: Treatment failure or relapse is common in solid organ transplant recipients treated for cytomegalovirus (CMV) disease. Because CMV infections induce a vigorous inflammatory response, we investigated whether pretreatment levels of inflammatory markers were associated with virologic and clinical outcomes. METHODS: Solid organ transplant recipients enrolled in an international multicenter trial of CMV disease treatment (the VICTOR study) were studied (n=248). Plasma levels of markers of inflammation and endothelial cell activation were assessed at baseline and during follow-up by enzyme immunoassays. RESULTS: Baseline values for the chemokine CXCL16 was an independent predictor of clinical outcome (P=0.003) and was a weak independent predictor of suppression of viral load below level of detection (LOD) (P=0.013) at day 21 after initiation of treatment. Baseline levels of the long pentraxin 3 (PTX3) was an independent predictor of suppression of viral load below LOD at day 21 (P=0.002), whereas baseline levels of von Willebrand factor (vWF) was an independent predictor of clinical outcome at day 21 (P=0.008), and vWF levels at day 21 was a weak independent inflammatory predictor of viral recurrence (P=0.018). CONCLUSIONS: The present study shows that the plasma levels of CXCL16, PTX3 and vWF at the start of treatment are independently associated with virologic and clinical treatment failure during anti-CMV therapy in solid organ transplant recipients. These findings suggest a link between CMV infection and inflammation that also may influence the outcome of anti-CMV therapy.

The chromatin remodeling factor SMARCB1 forms a complex with human cytomegalovirus proteins UL114 and UL44.

BACKGROUND: Human cytomegalovirus (HCMV) uracil DNA glycosylase, UL114, is required for efficient viral DNA replication. Presumably, UL114 functions as a structural partner to other factors of the DNA-replication machinery and not as a DNA repair protein. UL114 binds UL44 (HCMV processivity factor) and UL54 (HCMV-DNA-polymerase). In the present study we have searched for cellular partners of UL114. METHODOLOGY/PRINCIPAL FINDINGS: In a yeast two-hybrid screen SMARCB1, a factor of the SWI/SNF chromatin remodeling complex, was found to be an interacting partner of UL114. This interaction was confirmed in vitro by co-immunoprecipitation and pull-down. Immunofluorescence microscopy revealed that SMARCB1 along with BRG-1, BAF170 and BAF155, which are the core SWI/SNF components required for efficient chromatin remodeling, were present in virus replication foci 24-48 hours post infection (hpi). Furthermore a direct interaction was also demonstrated for SMARCB1 and UL44. CONCLUSIONS/SIGNIFICANCE: The core SWI/SNF factors required for efficient chromatin remodeling are present in the HCMV replication foci throughout infection. The proteins UL44 and UL114 interact with SMARCB1 and may participate in the recruitment of the SWI/SNF complex to the chromatinized virus DNA. Thus, the presence of the SWI/SNF chromatin remodeling complex in replication foci and its association with UL114 and with UL44 might imply its involvement in different DNA transactions.