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PubMedDate not supplied

[A role of recombination in the evolution of enteroviruses].

Enteroviruses, members of the family Picornaviridae (more than 70 serotypes), are distributed throughout the world and cause a broad spectrum of clinical manifestations in man and animals. Human enteroviruses are classified into 5 species: human enteroviruses A to D, and Poliovirus. Recombination has long been known to be an important property of poliovirus genetics; however, recombination has been recently shown to be also ubiquitous in non-polio enteroviruses. Prototype enterovirus strains have complex phylogenetic relations and all currently available enterovirus strains are recombinant to prototype strains. The extremely high rate of recombination allows the fragments of the enterovirus genome to evolve independently at a microevolutionary scale. Recombination strictly takes place between the members of the same species, usually outside the capsid-encoding genome region. Therefore, it can be concluded that the species enterovirus exists as a worldwide reservoir of the genetic information that shuffles frequently to produce new virus variants. This new model of the genetics of enterovirus accounts for failures to associate the serotype of enteroviruses and the form of the disease caused. The contents of this review have been published in the Reviews in Medical Virology, 2005.

Biological Evolution↗
PubMed2003

Frequency, viral loads, and serotype identification of enterovirus infections in Scottish blood donors.

BACKGROUND: Enteroviruses are non-enveloped, frequently pathogenic RNA viruses infecting humans. Infection is potentially transmissible through blood or blood component transfusion from donor in the viremic phase before seroconversion for antibody. To investigate the threat to blood safety from enteroviruses, a large-scale survey of frequency and levels of viremia in blood donors was conducted. STUDY DESIGNS AND METHODS: Blood donations from Scotland over a period of 22 calendar months were screened for enterovirus RNA sequences by PCR. Positive samples were quantified, and serotypes were identified by nucleotide sequencing of VP1. RESULTS: From a total of 3658 pools of 95 donations tested, 73 samples that were enterovirus-positive were identified (corrected annual frequency 0.024% or 1 in 4000). The highest rates of viremia were in late summer months (e.g., 0.055%, 1 in 1800 in July) and lowest from January to May (0.009 and 0.012%). Viral loads ranged from 500 (the lower cutoff of the assay) to greater than 100,000 amplifiable enterovirus template copies per mL. Coxsackievirus A16, echoviruses 11 and 30, and enterovirus 71 were most often identified. CONCLUSIONS: The detection of enterovirus-positive blood units indicates the potential for enteroviral transmission by blood components. Although the infrastructure established for PCR-based screening for HCV RNA would allow parallel screening for enteroviruses, any decision concerning donor testing would require further information on the outcome of transfusion-acquired enterovirus infections.

Blood↗
PubMed2002

Development and evaluation of a 'real-time' RT-PCR for the detection of enterovirus and parechovirus RNA in CSF and throat swab samples.

A two-step reverse transcriptase TaqMantrade mark duplex PCR (RT-PCR) assay was developed using the ABI 7700 Sequence Detection System for the detection of enterovirus (EV) and parechovirus type 1 and 2 (PEV) RNA from samples of cerebrospinal fluid (CSF) and throat swabs. Using sequence-specific fluorescent dye labeled probes and continuous 'real-time' monitoring, PCR amplified product accumulation was measured. Based on limiting dilutions, the TaqMantrade mark enterovirus and parechovirus RT-PCR showed an increase of two orders of magnitude compared to cell culture with sensitivity of 100% (7/7) when assessed using enterovirus cell culture positive samples (CSF, TS). The assays were specific for enterovirus and parechovirus and did not amplify a wide selection of virus and bacterial isolates. RNA was amplified from 22 enterovirus serotypes: coxsackie A7, A9, A21; coxsackie B2, B3, B4, B5; echovirus 2, 4, 6, 7, 9, 11, 13, 17, 18, 19, 30, 31; poliovirus types 1, 2, and 3, and parechovirus types 1 and 2. The assay was used to assess the incidence of enterovirus and parechovirus RNA in cell culture negative CSF and throat swab samples (n = 200). An additional 33 (15.9%) enterovirus and 2 (1%) parechovirus were identified as positive by RT-PCR. Also, of 100 CSF samples from suspected cases of meningococcal meningitis submitted for meningococcal PCR testing, 59 (59%) were enterovirus and 2 (2%) parechovirus 1 and 2 were positive by RT-PCR. The TaqMantrade mark duplex assay offers a more rapid and sensitive alternative to conventional cell culture for the diagnosis of enterovirus and parechovirus infection. Closed tube real-time detection using the ABI Sequence Detection System obviates the need for post-PCR manipulation, which reduces hands on time and eliminates the risk of contamination from amplified PCR product.

Enterovirus↗
PubMed2003

Serotype-specific detection of enterovirus 71 in clinical specimens by DNA microchip array.

Enterovirus 71 is an important pathogen that causes high morbidity and mortality in children in Taiwan. Virus isolation in cell cultures has been the standard method for enterovirus 71 identification in Clinical Virology Laboratories. However, virus isolation takes 5-10 days when using cell culture. A microchip for enterovirus 71 detection was developed as an alternative diagnostic method. The novel approach is based on hybridization of amplified DNA specimens with oligonucleotide DNA probes immobilized on a microchip. Two oligonucleotides were used as detection probes, the pan-enterovirus sequence located in the 5'-noncoding region (5'-NCR) and the enterovirus 71-specific sequence located in the VP2 region. The diagnostic procedure takes 6 h. One hundred specimens identified as enteroviruses by viral cultures were tested using this microchip, including 67 enterovirus 71 specimens. The sensitivity of the novel method is 89.6% and its specificity is 90.9%. The enterovirus 71-microchip can detect the amplicon derived from viral RNA corresponding to 1-10 virions in a clinical specimen. Microchip array is a potential diagnostic method for identification of enterovirus in the future.

5' Untranslated Regions↗
PubMed2004

Enterovirus infections following T-cell depleted allogeneic transplants in adults.

Anecdotally, enteroviruses have been reported to cause serious complications post BMT, but the exact impact of these viruses in the post transplant period has not been reported. We prospectively evaluated stool, urine and throat samples for enteroviruses by viral culture together with relevant body fluids by RT-PCR in 64 allograft recipients receiving grafts T-cell depleted by Campath-1H, following both conventional and reduced-intensity conditioning. Seven patients (10.4%) developed nine episodes of enterovirus infections at a median of 146 days post transplant. Four episodes were associated with symptomatic illnesses, which could be attributable to enteroviruses. There was no mortality directly related to enteroviruses. There was no correlation between dose and mode of Campath-1H use, lymphocyte recovery, IgG and IgA levels and enterovirus isolation. Although enteroviruses tended to be more frequent in TBI-based conventional conditioning recipients, the only significant risk factor for enterovirus infection was unrelated donor graft. The low incidence of the severe enterovirus infections could have been related to a low lymphocyte count in this cohort in the absence of GVHD, particularly CD4+ count, which has been implicated in tissue damage in experimental animals. Further studies are needed to define its impact in different allograft settings.

Adolescent↗
PubMed2006

The association between rainfall rate and occurrence of an enterovirus epidemic due to a contaminated well.

AIMS: To determine the association between rainfall rate and occurrence of enterovirus infection related to contamination of drinking water. METHODS AND RESULTS: One fatality case and three cases of severe illness were observed during the enterovirus epidemic in a village in southern Taiwan from 16 September to 3 October 1998. Groundwater samples were collected from the public well in the village after heavy rainfall to test for enterovirus using the reverse transcription-polymerase chain reaction (RT-PCR) assay. The RT-PCR assay detected the enterovirus in the groundwater sample collected on 26 September 1998. The logistic regression model also revealed a statistically significant association between the rainfall rate and the observation of cases of enterovirus infection. CONCLUSIONS: According to the fitted logistic regression model, the probability of detecting cases of enterovirus infection was greater than 50% at rainfall rates >31 mm h(-1). The higher the rainfall rate, the higher the probability of enterovirus epidemic. SIGNIFICANCE AND IMPACT OF THE STUDY: Contamination of drinking water by the enterovirus may lead to epidemics that cause deaths and severe illness, and such contamination may be caused by heavy rainfall. The major finding in this study is that the enterovirus could be flushed to groundwater in an unconfined aquifer after a heavy rainfall. This work allows for a warning level so that an action can be taken to minimize future outbreaks and so protect public health.

Developing Countries↗
PubMed2004

Isolation of enterovirus strains from children with preclinical Type 1 diabetes.

AIMS: To develop methods for isolation of enterovirus strains from subjects with preclinical Type 1 diabetes and evaluate if their presence in stools is associated with beta-cell damage. METHODS: The study subjects were participants of the Finnish Type 1 Diabetes Prediction and Prevention Study (DIPP). The prospectively followed birth cohort comprised 12 children who turned positive for diabetes-associated autoantibodies during the follow-up (case children) and 53 controls matched for date of birth, sex and HLA-DQB1 alleles. Altogether, 878 stool samples were analysed for the presence of enterovirus RNA by RT-PCR followed by virus isolation and partial sequencing of viral genome. Enterovirus antibodies and RNA were simultaneously analysed from serum. RESULTS: Eleven enterovirus infections were diagnosed in case children and 42 infections in control children by the presence of viral RNA in stools. The proportion of children who were repeatedly enterovirus RNA-positive stools was higher among case than control children (42% vs. 11% of children; P=0.02). Combined serum (antibody and RT-PCR) and stool analyses indicated at least one enterovirus infection in 83% of the case children before the appearance of autoantibodies, while only 42% of the control children had infection by the same age (P=0.006). Twelve enterovirus strains were isolated from case children and 38 strains from control children. CONCLUSIONS: This protocol makes it possible to isolate a large number of enterovirus strains from prediabetic subjects. The findings suggest that enterovirus infections may be associated with the beta-cell damaging process.

Autoantibodies↗
PubMed1993

Molecular pathogenesis of enterovirus-induced myocarditis: virus persistence and chronic inflammation.

In situ hybridization studies have proved that myocardial enterovirus infections are detectable in all stages of acute and chronic enterovirus-induced myocarditis as well as in some patients with end-stage dilated cardiomyopathy, suggesting the possibility of myocardial enterovirus persistence. Possible enterovirus persistence in the human heart is supported by the discovery of enterovirus persistence in different murine models of chronic myocarditis, demonstrating that coxsackievirus B3, typically a cytolytic enterovirus, is capable of evading immunological surveillance in a host-dependent fashion. Progress is currently being made in unraveling the molecular mechanisms of enterovirus persistence, the diversity of host and virus genetics and their impact on the nature and severity of the disease. Apart from providing an etiologic diagnosis, there are therapeutic implications from the in situ demonstration of myocardial enterovirus infection. Evaluation of specific antiviral agents, for example interferons, may lead to the development of new therapeutic strategies capable of providing protection against myocardial enterovirus infection.

Animals↗
PubMed1994

Detection of enterovirus-specific total and polymeric IgA antibodies in serum using a synthetic peptide or heated virion antigen in ELISA.

The presence of enterovirus-specific total and polymeric IgA antibodies was assessed in serum from different groups of patients and healthy controls by indirect ELISA using heated virions and synthetic peptide, both enteroviral broad reactive antigens. Total IgA antibody response against a synthetic peptide, representing an enterovirus group-common epitope, was detected in 52% of the patients with an acute enterovirus infection and in 12% of the patients with other infections (P = 0.02). We also found a significant difference (P = 0.005) in the prevalence of peptide IgA antibodies between serum samples collected from blood donors during summer (20%), the prevalent season of enterovirus infections, and winter (6%). A polymeric IgA activity against the peptide was detected in only three patients with an enterovirus infection. In contrast, when a heated coxsackie B5 (coxB5) virus antigen was used, the prevalence of total serum IgA antibodies was not significantly different between patients with an acute enterovirus infection and patients with other infections (71% vs. 53% respectively; P = 0.3). Also no difference was found between the two groups of blood donors (47% in summer vs. 51% in winter; P = 0.7). However, the prevalence of serum polymeric IgA antibodies against coxsackie B5 antigen was significantly greater (P = 0.02) in patients with an acute enterovirus infection (57%) than in patients with other infections (18%). These findings suggest that the presence (18%). These findings suggest that the presence of total peptide-IgA or of polymeric coxsackie B5-IgA in serum is a specific marker of acute enterovirus infection. Finally, we show that the total peptide-IgA- and polymeric coxsackie B5-ELISAs may have a diagnostic value for the serodiagnosis of enterovirus infections when they are used in combination with enteroviral IgG-ELISA.

Amino Acid Sequence↗
PubMed2005

Association between enterovirus endomyocardial infection and late severe cardiac events in some adult patients receiving heart transplants.

Enteroviruses and other cardiotropic viruses have been associated with the development of late severe adverse cardiac events in infants receiving heart transplants. However, the source and the chronology of cardiac allograft infection by an enterovirus in patients receiving heart transplants remain unknown. Using RT-PCR and immunohistochemistry assays, endomyocardial tissue samples of 30 adult patients were tested to detect the presence of specific enterovirus 5' non-coding (5'NC) sequences and of VP1 capsid protein, and this at the time of cardiac transplantation and at the 12-month biopsy for graft rejection control. Moreover, the endomyocardial detection of genomic sequences of enteroviruses, Epstein-Barr virus, herpes simplex virus, cytomegalovirus (CMV), varicella-zoster virus, adenoviruses, and parvovirus B19 was carried out by RT-PCR and polymerase chain reaction (PCR) assays at the time of late severe cardiac events. Enterovirus RNA and VP1 antigen were both detected in 4 (13%) of 30 patients at the time of the 12-month biopsy for graft rejection control, whereas no enterovirus component was detected in the explanted and implanted heart tissues taken from these 4 patients at the time of transplantation. At the time when severe cardiac events were developed, within 3 months after the positive enterovirus cardiac detection, these four patients demonstrated the presence of endomyocardial enterovirus RNA sequences whereas they were tested negative for the endomyocardial detection of genomic sequences from DNA viruses (except for CMV in two cases), and for a significant level of pp65 CMV antigenemia. Taken together, these findings indicate that enteroviruses could be acquired as a new endomyocardial infection within 12 months after transplantation in adults receiving heart transplants, and suggest that this infection might be an etiological cause for unexplained late severe adverse cardiac events in the heart-transplantated adults.

5' Untranslated Regions↗
PubMed2006

Reticulon 3 binds the 2C protein of enterovirus 71 and is required for viral replication.

Enterovirus 71 is an enterovirus of the family Picornaviridae. The 2C protein of poliovirus, a relative of enterovirus 71, is essential for viral replication. The poliovirus 2C protein is associated with host membrane vesicles, which form viral replication complexes where viral RNA synthesis takes place. We have now identified a host-encoded 2C binding protein called reticulon 3, which we found to be associated with the replication complex through direct interaction with the enterovirus 71-encoded 2C protein. We observed that the N terminus of the 2C protein, which has both RNA- and membrane-binding activity, interacted with reticulon 3. This region of interaction was mapped to its reticulon homology domain, whereas that of 2C was encoded by the 25th amino acid, isoleucine. Reticulon 3 could also interact with the 2C proteins encoded by other enteroviruses, such as poliovirus and coxsackievirus A16, implying that it is a common factor for such viral replication. Reduced production of reticulon 3 by RNA interference markedly reduced the synthesis of enterovirus 71-encoded viral proteins and replicative double-stranded RNA, reducing plaque formation and apoptosis. Furthermore, reintroduction of nondegradable reticulon 3 into these knockdown cells rescued enterovirus 71 infectivity, and viral protein and double-stranded RNA synthesis. Thus, reticulon 3 is an important component of enterovirus 71 replication, through its potential role in modulation of the sequential interactions between enterovirus 71 viral RNA and the replication complex.

Animals↗
PubMed2000

Enterovirus infection as a risk factor for beta-cell autoimmunity in a prospectively observed birth cohort: the Finnish Diabetes Prediction and Prevention Study.

Previous studies suggest that enterovirus infections may initiate and accelerate beta-cell damage years before the clinical manifestation of type 1 diabetes. We have now analyzed the role of enterovirus infections in the initiation of autoimmunity in children who have tested positive for diabetes-associated autoantibodies in a prospective study starting at birth (the Finnish Diabetes Prediction and Prevention Study). The frequency of enterovirus infections was studied using both serology and testing for the presence of enterovirus RNA in the sera of 21 children who developed and retained autoantibodies and in 104 control subjects chosen from the same study cohort and matched for the time of birth, sex, and HLA alleles determining genetic diabetes susceptibility. Sample intervals were taken as basic units of follow-up, to which the observed number of infections was adjusted. Enterovirus infections were detected in 26% of sample intervals in the case subjects and in 18% of the sample intervals in the control children (P = 0.03). A temporal relationship between enterovirus infections and the induction of autoimmunity was found; enterovirus infections were detected in 57% of the case subjects during a 6-month follow-up period preceding the first appearance of autoantibodies compared with 31% of the matched control children in the same age-group (odds ratio 3.7, 95% CI 1.2-11.4). The frequency of adenovirus infections did not differ between the patient and control groups. Our data imply that enterovirus infections are associated with the development of beta-cell autoimmunity and provide evidence for the role of enteroviruses in the initiation of beta-cell destruction.

Alleles↗
PubMed2002

Maternal first-trimester enterovirus infection and future risk of type 1 diabetes in the exposed fetus.

Previous studies have suggested that enterovirus infections during pregnancy may increase the risk of type 1 diabetes in the offspring. Our aim was to evaluate the role of first trimester enterovirus infections in a larger cohort of pregnant women. Two series of pregnant women were analyzed as follows: 948 women (series 1) and 680 women (series 2) whose child developed clinical diabetes before the ages of 15 or 7 years, respectively. An equal number of control women with a nondiabetic child was selected. Acute enterovirus infections were diagnosed by measuring IgM class antibodies against coxsackievirus B5 (series 1) and a mixture of coxsackievirus B3, coxsackievirus A16, and echovirus 11 antigens (series 2). In series 2, all sera were also analyzed for IgG class antibodies against an enterovirus peptide antigen. In addition, 152 randomly selected case-control pairs and all IgM-positive mothers' sera were tested for enterovirus RNA (series 2). In series 1, 3.1% of case women had IgM antibodies against coxsackievirus B5 antigen compared with 4.1% of control women (NS). In series 2, 7.1% of case and 5.3% of control women had IgM against the mixture of enterovirus antigens (NS). IgG class enterovirus antibodies did not differ between the groups. Enterovirus RNA was found only in one case woman (0.3%) of the subgroup of samples and in 5.7% of 70 IgM-positive women. The results suggest that enterovirus infection during the first trimester of pregnancy is not associated with increased risk for type 1 diabetes in the child.

Antibodies, Viral↗
PubMed2004

Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells.

AIMS/HYPOTHESIS: It is thought that enterovirus infections cause beta-cell damage and contribute to the development of Type 1 diabetes by replicating in the pancreatic islets. We sought evidence for this through autopsy studies and by investigating known enterovirus receptors in cultured human islets. METHODS: Autopsy pancreases from 12 newborn infants who died of fulminant coxsackievirus infections and from 65 Type 1 diabetic patients were studied for presence of enteroviral ribonucleic acid by in situ hybridisation. Forty non-diabetic control pancreases were included in the study. The expression and role of receptor candidates in cultured human islets were investigated with receptor-specific antibodies using immunocytochemistry and functional assays. RESULTS: Enterovirus-positive islet cells were found in some of both autopsy specimen collections, but not in control pancreases. No infected cells were seen in exocrine tissue. The cell surface molecules, poliovirus receptor and integrin alphavbeta3, which act as enterovirus receptors in established cell lines, were expressed in beta cells. Antibodies to poliovirus receptor, human coxsackievirus and adenovirus receptor and integrin alphavbeta3 protected islets and beta cells from adverse effects of poliovirus, coxsackie B viruses, and several of the arginine-glycine-aspartic acid motifs containing enteroviruses and human parechovirus 1 respectively. No evidence was found for expression of the decay-accelerating factor which acts as a receptor for several islet-cell-replicating echoviruses in established cell lines. CONCLUSIONS/INTERPRETATION: The results show a definite islet-cell tropism of enteroviruses in the human pancreas. Some enteroviruses seem to use previously identified cell surface molecules as receptors in beta cells, whereas the identity of receptors used by other enteroviruses remains unknown.

Adolescent↗
PubMed2006

Longitudinal observation of enterovirus and adenovirus in stool samples from Norwegian infants with the highest genetic risk of type 1 diabetes.

BACKGROUND: Enterovirus and adenovirus are common in infancy, causing mostly asymptomatic infections. However, even an asymptomatic infection may be associated with increased risk of development of certain chronic non-infectious diseases, as has been suggested for enterovirus and type 1 diabetes. Data on occurrence and course of the infections in infancy are therefore important for designing effective approaches towards study of the association. OBJECTIVES: To estimate the frequency of enterovirus and adenovirus infections in Norwegian infants, to evaluate the duration of the infections, to investigate their association with symptoms, and to establish a robust procedure that will be used to study the association between these viruses and the development of auto-immunity leading to type 1 diabetes. STUDY DESIGN: Parents of infants, recruited for a study on environmental triggers of type 1 diabetes, submitted monthly samples of infant faeces, as well as information on symptoms of infection. The samples were analysed for enterovirus and adenovirus using quantitative real-time PCR, and enterovirus-positive samples were sequenced. RESULTS: Enteroviruses were found in 142/1,255 (11.3%), and adenoviruses in 138/1,255 (11.0%) of stool samples. Approximately half of the infants were exposed to these viruses at least once during the first year of observation (period 3-14 months of age). The presence of adenovirus was associated with fever and with symptoms of cold but not with diarrhoea and vomiting. The enterovirus positivity was not associated with any symptoms. CONCLUSIONS: The prevalence of enterovirus and adenovirus in longitudinally obtained faecal samples from infants is sufficiently high to enable studies of their association with chronic diseases. The present protocol for evaluating exposure to these viruses is well suited for large-scale efforts aimed at assessing possible long-term consequences, particularly in relation to type 1 diabetes.

Adenovirus Infections, Human↗
PubMed1999

Enteroviruses and myocardial infarction.

BACKGROUND: Several lines of evidence suggest that some microbial infections are involved in the pathogenesis of atherosclerosis. The aim of the studies referred to here was to evaluate the possible role of enteroviral infections as potential risk factors for cardiac events. METHODS AND RESULTS: The association of enterovirus-specific antibodies and cardiac events was analyzed in 3 large, prospective population studies with the nested case-control design. Stored sera collected at the study baseline were tested for enterovirus group-specific immunoglobulin G antibodies. The study samples from the North Karelia Project, the Helsinki Heart Study, and the Mobile Clinic Health Service were composed of 183, 241, and 276 men with myocardial infarction, respectively, and their matched control patients. In 2 of the 3 studies, male cases without evidence of heart disease at the baseline had significantly higher levels of antibodies to enteroviruses than their matched control patients. High enterovirus antibody level was found to be a definite independent risk factor for future cardiac events. In the North Karelia study the risk was high in men aged 25 to 49 years, whereas in the Mobile Clinic Health Service study the risk was particularly strong in those with low levels of serum cholesterol. No association with high levels of enterovirus antibodies and cardiac events was seen in the Helsinki Heart Study, which consisted of hypercholesteremic men. CONCLUSIONS: If a high level of enterovirus group-specific antibodies can be considered as a sign of frequent enterovirus infections in the past, these studies suggest that enterovirus infections increase the risk of myocardial infarction at least in normocholesteremic men.

Adult↗
PubMed1984

Epidemiology of neonatal enterovirus infection.

During a typical enterovirus season in Rochester, New York, none of 666 neonates or 629 mothers were found to be excreting nonpolio enteroviruses within 1 day of delivery. No enteroviruses were isolated from weekly cultures of the 23 infants who died or remained hospitalized during the first month of life. After discharge, culture specimens were obtained in 586 infants at one to four weekly home visits until 1 month of age. The incidence of acquisition of nonpolio enterovirus infection was 12.8%, and the overall prevalence of enterovirus excretion was 5.3%. Risk of virus infection was associated only with lower socioeconomic status (P less than 0.0001) and lack of breast-feeding (P less than 0.0001). Four percent of all infants and 21% of infants in whom cultures for enterovirus were positive were readmitted to the hospital in the first month of life; 79% of infants with positive enterovirus cultures were asymptomatic. We conclude that enterovirus infection during the first month of life is very common in the late summer and early fall. Most infants are asymptomatic, but the risk of hospitalization is high. Breast-feeding may be associated with protection from infection.

Adolescent↗
PubMed1998

Enterovirus infections and insulin dependent diabetes mellitus--evidence for causality.

BACKGROUND: Insulin-dependent diabetes mellitus (IDDM) has a long subclinical period characterised by gradually progressing autoimmune damage of insulin producing beta-cells. Clinical IDDM is manifested when 90% of beta-cells have been destroyed. Several studies have indicated that enterovirus infections, coxsackievirus B (CVB) infections especially, are frequent at the manifestation of clinical IDDM suggesting that they can precipitate the symptoms of IDDM in individuals who already have an advanced beta-cell damage. Recently, the first prospective studies have been published suggesting that enterovirus infections can also initiate the process several years before clinical IDDM. This implies that enterovirus infections may have a crucial role in the pathogenesis of human IDDM. OBJECTIVE: The recent findings have brought up the question whether the time has come when a causal association between enterovirus infections and IDDM could finally be confirmed. This review focuses on this question summarising the current knowledge and the prospects of future research. STUDY DESIGN: Review of the recent progress in studies evaluating the role of enterovirus infections in human IDDM. CONCLUSIONS: The currently available information supports the assumption that the role of enterovirus infections may be more important than previously estimated. Enterovirus infections are obviously associated with increased risk of IDDM, but whether this association reflects causal relationship remains to be confirmed in future studies. Prospective birth-cohort studies will be among the most important ones giving important data on the etiologic fraction of enterovirus infections, the properties of diabetogenic virus variants and the mechanisms of beta-cell damage.

Diabetes Mellitus, Type 1↗