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Type 1 diabetes (T1D) is an autoimmune disease that is caused by the destruction of insulin-producing [beta] cells. Viral infections induce immune responses that can damage [beta] cells and promote T1D or on the other hand prevent the development of the disease. However, the opposing roles of viral infections in T1D are not understood mechanistically. We report here that viruses that do not inflict damage on [beta] cells provided protection from T1D by triggering immunoregulatory mechanisms. Infection of prediabetic NOD mice with Coxsackie virus B3 or lymphocytic choriomeningitis virus (LCMV) delayed diabetes onset and reduced disease incidence. Delayed T1D onset was due to transient upregulation of programmed cell death-1 ligand 1 (PD-L1) on lymphoid cells, which prevented the expansion of diabetogenic [CD8.sup.+] T cells expressing programmed cell death-1 (PD-1). Reduced T1D incidence was caused by increased numbers of invigorated [CD4.sup.+][CD25.sup.+] Tregs, which produced TGF-[beta] and maintained long-term tolerance. Full protection from T1D resulted from synergy between PD-L1 and [CD4.sup.+][CD25.sup.+] Tregs. Our results provide what we believe to be novel mechanistic insight into the role of viruses in T1D and should be valuable for prospective studies in humans., Introduction Type 1 diabetes (T1D) is an autoimmune disease that results from immune-mediated destruction of insulin-producing [beta] cells in the pancreatic islets of Langerhans and leads to severely deficient glucose [...]

Approximately 3,000 Pyrenean chamois (Rupicapra pyrenaica pyrenaica) died in northeastern Spain during 2005-2007. Border disease virus infection was identified by reverse transcription-PCR and sequencing analysis. These results implicate this virus [...]

Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants. A formal in-inactivated RSV vaccine was used to immunize children and elicited nonprotective, pathogenic antibody. Immunized infants experienced increased morbidity after subsequent RSV exposure. No vaccine has been licensed since that time. A widely accepted hypothesis attributed the vaccine failure to formalin disruption of protective antigens. Here we show that the lack of protection was not due to alterations caused by formalin but instead to low antibody avidity for protective epitopes. Lack of antibody affinity maturation followed poor Toll-like receptor (TLR) stimulation. This study explains why the inactivated RSV vaccine did not protect the children and consequently led to severe disease, hampering vaccine development for 42 years. It also suggests that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR agonists in their formulation, and it identifies affinity maturation as a key factor for the safe immunization of infants., Approximately 50% of infants are infected with RSV during their first year of life (1,2). Hospitalization rates for RSV in the United States have risen by 239% in recent decades [...]

Varicella-zoster virus (VZV) causes chickenpox and shingles but it is found that insulin-degrading enzyme (IDE) binds to the extracellular domain of VZV glycoprotein E which is required for virus infectivity. IDE is shown to be a receptor for cell-free and cell-associated VZV, at the same time transfection of cells impaired for VZV infection with an IDE-expressing plasmid increases the infection.

Chikungunya virus (CHIKV) emerged in Indian Ocean islands in 2005 and is causing an ongoing outbreak that involves >260,000 patients, including travelers returning home from these islands. We investigated cases [...]

Epstein-Barr virus (EBV), an orally transmitted herpesvirus, efficiently targets B lymphocytes through binding of the viral envelope glycoprotein gp350 to the complement receptor CD21. How the virus accesses epithelial cells is less well understood, because such cells are largely resistant to infection with cell-free virus in vitro. Here, we show that, after binding to primary B cells, most Epstein-Barr virions are not internalized but remain on the B cell surface and from there can transfer efficiently to CD21-negative epithelial cells, increasing epithelial infection by [10.sup.3]- to [10.sup.4]-fold compared with cell-free virus. Transfer infection is associated with the formation of B cell-epithelial conjugates with gp350/CD21 complexes focused at the intercellular synapse; transfer involves the gp85 and gp110 viral glycoproteins but is independent of gp42, the HLA class II ligand that is essential for B cell entry. Therefore, through efficient binding to the B cell surface, EBV has developed a means of simultaneously accessing both lymphoid and epithelial compartments; in particular, infection of pharyngeal epithelium by orally transmitted virus becomes independent of initial virus replication in the B cell system.

An Oropouche virus strain was isolated from a novel host (Callithrix sp.) in Arinos, Minas Gerais State, southeastern Brazil. The virus was identified by complement fixation test and confirmed by [...]

Flaviviral encephalitus is caused by a combination of climatic, entomologic, human behavioral, viral and host factors by a virus that is naturally transmitted among bird biting mosquitoes. The similarities and differences between the West Nile virus and other flaviviruses of the JE serogroup are reviewed.

Pogosta disease is a mosquito-borne viral disease in Finland, which is clinically manifested by rash and arthritis; larger outbreaks occur in 7-year intervals. The causative agent of the disease has [...]

Pneumococcal infections increase each winter, a phenomenon that has not been well explained. We conducted population-based active surveillance for all cases of invasive pneumococcal disease in seven states; plotted annualized [...]

Traveler's diarrhea is the most common health problem of international travelers. We determined the prevalence of Aeromonas spp. associated with traveler's diarrhea and analyzed the geographic distribution, clinical features, and [...]

RNA interference represents an exciting new technology that could have therapeutic applications for the treatment of viral infections. Hepatitis C virus (HCV) is a major cause of chronic liver disease and affects >270 million individuals worldwide. The HCV genome is a single-stranded RNA that functions as both a messenger RNA and replication template, making it an attractive target for the study of RNA interference. Double-stranded small interfering RNA (siRNA) molecules designed to target the HCV genome were introduced through electroporation into a human hepatoma cell line (Huh-7) that contained an HCV subgenomic replicon. Two siRNAs dramatically reduced virus-specific protein expression and RNA synthesis to levels that were 90% less than those seen in cells treated with negative control siRNAs. These same siRNAs protected naive Huh-7 cells from challenge with HCV replicon RNA. Treatment of cells with synthetic siRNA was effective >72 h, but the duration of RNA interference could be extended beyond 3 weeks through stable expression of complementary strands of the interfering RNA by using a bicistronic expression vector. These results suggest that a gene-therapeutic approach with siRNA could ultimately be used to treat HCV.

Granzyme B (GzmB) is a serine protease involved in many pathologies, including viral infections, autoimmunity, transplant rejection, and antitumor immunity. To measure the extent of genetic variation in GzmB, we screened the GzmB gene for polymorphisms and defined a frequently represented triple-mutated GzmB allele. In this variant, three amino acids of the mature protein [Q.sup.48][P.sup.88][Y.sup.245] are mutated to [R.sup.48][A.sup.88][H.sup.245]. In CD[8.sup.+] cytotoxic T lymphocytes, GzmB was expressed at similar levels in QPY homozygous, QPY/RAH heterozygous, and RAH homozygous individuals, demonstrating that RAH GzmB is a stable protein. Active RAH GzmB expressed in glioblastoma cell lines displayed proteolytic activity, but in contrast to QPY GzmB, it did not accumulate in the nucleus and was unable to induce Bid cleavage, cytochrome c release, or apoptosis. Molecular modeling showed that the three amino acid substitutions clustered near the C-terminal [alpha]-helix of the protein, indicating that this region of the protein may be involved in the intracellular targeting of GzmB. The triple-mutated GzmB allele that we describe appears to be incapable of inducing apoptosis in tumor cell lines, and its presence could, therefore, influence both the prognosis of cancer patients and the success rates of antitumor cellular immunotherapy.

The Aravan virus was isolated from a Lesser Mouse-eared Bat (Myotis blythi) in the Osh region of Kyrghyzstan, central Asia, in 1991. We determined the complete sequence of the nucleoprotein [...]

The authors review the publications on cellular BCL-2-related proteins. The topics of interest include identification of cellular antiapoptotic BCL-2 proteins, the role of these proteins in viral infection and the mechanisms by which they function.

Retroviruses are able to cross species barriers and have done so many times throughout evolution. Perhaps as a consequence, dominant mechanisms have arisen to block infection by murine retroviruses in mice (restriction factor Fv1) and humans (restriction factor Ref1), as well as in other mammals. Here we describe a block to HIV and simian immunodeficiency virus in monkeys. Like previously described restrictions the block is saturable and gives rise to multiple-hit infection kinetics. Furthermore, like restriction of murine leukemia virus in humans, the block is before reverse transcription. Intriguingly, African green monkey cells are able to block both HIV and simian immunodeficiency virus, and each virus is able to saturate and abrogate the restriction of the other, suggesting that a common factor is responsible.

Research has been conducted on the nucleosome obstructing transcription from the IFN-beta promoter. The mechanisms and the nature of the chromatin that remodels during IFN-beta gene activation in response to the virus infection have been investigated and the results indicate that this nucleosome slides in vivo exposing the initiation site.

The case of a 28-year-old pregnant woman who developed an infection after contact with a rabies vaccine in bait is presented. Rabies vaccine in bait is used to prevent rabies in wild animals, particularly in areas where rabies in wild animals is common.

Research has been conducted on the protein p6, the product of bacteriophage phi29. The role of this protein has been investigated in vivo via infection of the suppressor and nonsuppressor Bacillus subtilis strains with the nonsense mutation phage.

The case of a 43-year-old HIV patient illustrates that human herpesvirus 8 can cause an acute illness that may resolve completely without causing Kaposi's sarcoma. This virus has consistently been isolated from Kaposi's sarcoma tumor samples in HIV patients. This patient became ill with fever, joint pain and enlarged lymph nodes. Within 8 weeks, the lymph nodes returned to normal and he had no more symptoms. Analysis of blood samples taken before and after the illness revealed that he had seroconverted to HHV-8 during that time and the virus was detected in lymph node biopsy samples.

An outbreak of viral gastrointestinal disease in Alaska illustrates the necessity for cooperation between national health departments. A hotel operator in Fairbanks, Alaska notified the state health department after noticing that several hotel residents who arrived by bus were ill. Ill bus passengers were also found in hotels in Skagway and Valdez. They had all stopped at a restaurant in the Yukon Territory of Canada. The illness was traced to the restaurant's water supply, which came from a well. One employee lived in a building with a septic pit, which was the source of the contamination., Context. -- Small round-structured viruses (SRSVs) are known to cause viral gastroenteritis, but until now have not been confirmed in the implicated vehicle in outbreaks. Objective. -- Investigation of a gastroenteritis outbreak. Design. -- After applying epidemiologic methods to locate the outbreak source, we conducted environmental and laboratory investigations to elucidate the cause. Setting. -- Tourists traveling by bus through Alaska and the Yukon Territory of Canada. Participants. -- Staff of a restaurant at a business complex implicated as the outbreak source, convenience sample of persons on buses that had stopped there, and bus employees. Main Outcome Measures. -- Odds ratios (ORs) for illness associated with exposures. Water samples from the restaurant and stool specimens from tourists and restaurant staff were examined by nucleic acid amplification using reverse transcription polymerase chain reaction and sequencing of viral amplification products. Results. -- The itineraries of groups of tourists manifesting vomiting or diarrhea were traced back to a restaurant where buses had stopped 33 to 36 hours-previously. Water consumption was associated with illness (OR, 5.3; 95% confidence interval [CI], 2.3-12.6). Eighteen of 26 employees of the business complex were ill; although not the index case, an employee ill shortly before the outbreak lived in a building connected to a septic pit, which was found to contaminate the well supplying the restaurant's water. Genotype 2/P2B SRSV was identified in stool specimens of 2 tourists and 1 restaurant employee. Stools and water samples yielded identical amplification product sequences. Conclusions. -- The investigation documented SRSVS in a vehicle epidamiologically linked to a gastroenteritis outbreak. The findings demonstrate the power of molecular detection and identification and underscore the importance of fundamental public health practices such as restaurant inspection, assurance of a safe water supply, and disease surveillance. JAMA. 1997;278:563-568

Highly treated waters often contain viruses at concentration levels too low to detect. This paper describes a method for drawing inferences about the concentration of viruses in treated water when very few or none are detected in collected samples. The approach uses a volume-varying version of the negative binomial distribution to construct one-sided confidence intervals about the mean virus concentration. Information on the presence of viruses prior to treatment (i.e., when densities are high enough to measure) is used to estimate parameters for the model. Samples are provided based on measurements from three southern California waste-water-treatment plants. Based on 93,679 L of tertiary treated sewage effluent, confidence intervals for virus concentrations for Pomona, Calif., ranged from 0 to 2.68 [multiplied by] [10.sup.-5] plaque forming units (PFU) per liter at the 50% confidence level to 0 to 5.83 [multiplied by] [10.sup.-4] PFU/L at the 95% confidence level. These values are considerably above the risk-based public health goal that is being used to regulate viruses in drinking water (2.22 [multiplied by] [10.sup.-7] PFU/L). Direct measurements to demonstrate treatment to drinking water quality are therefore impracticable.

To the Editor: Hendra virus (HeV) and Nipah virus (NiV), the only known members of the genus Henipavirus, are 2 emerging paramyxoviruses that are highly pathogenic in a variety of [...]

Chikungunya virus infection recently reemerged in Malaysia after 7 years of nondetection. Genomic sequences of recovered isolates were highly similar to those of Malaysian isolates from the 1998 outbreak. The [...]

The largest described outbreak of chikungunya virus has been occurring on the islands of the southwest Indian Ocean since March 2005. We describe the manifestations of chikungunya virus infection in [...]

Two suspected hantavirus pulmonary syndrome (HPS) cases from Bolivia occurred in May and July 2000 and were confirmed by enzyme-linked immunosorbent assay (ELISA)-ANDES using N-Andes recombinant antigen serology. Clot RNAs [...]

A study is conducted to evaluate the rates of bioaccumulation, retention, and depuration of viruses by Crassostrea virginica and C. ariakensis when the two oyster species are maintained in separate tanks containing synthetic seawater of various salinities at 8, 12, or 20 ppt. The findings have provided guidelines to assess the threat of C. ariakensis as a vehicle for viral pathogens due to the consumption of raw oysters and has validated the role for murine norovirus 1 (MNV-1) as a surrogate for human norovirus (NoV).

Selenium (Se) is an important micronutrient that plays a vital role in the maintenance of optimal health. The different sources of Se in diets and mechanisms by which Se regulates and balances the immune system to increase resistance to viral infections are discussed.

Although the advent of antimicrobial therapy was thought to spell doom for communicable disease, viruses, both old and new, are emerging as potent infectious agents. A review is provided of some newly problematic viral diseases. Since viruses mutate rapidly, they can acquire a strong selective advantage, even though most mutants do not survive. Familiar diseases, such as influenza, are caused by continually evolving 'new' influenza viruses. Influenza varies but little from epidemic to epidemic, and it is host factors (such as age and immunological status) that primarily determine the severity of infections. Poliomyelitis is an old virus that moved into a new role when improved sanitation resulted in fewer infections in infants, where its effects were milder, to more infections in older children and adults, where it induced paralysis. Viral infections that appear to be new, usually result from transmission from animals to man. Hemorrhagic fevers, for instance, are caused by viruses carried by arthropods and rodents that can infect the liver, kidney, or brain of human beings. Often, these infections occur when an environmental change results in new contact between humans and viral vectors. Truly new viruses are relatively infrequent, and are usually a result of genetic mechanisms. Point mutations affect critical sites on critical viral proteins; when these allow the virus to avoid recognition or attack by the host immune system, a newly virulent agent can be created. Genetic reassortment refers to the rearrangement of gene segments between different viral strains when several are present at one time in the host. If the strains are similar, they can reassort to produce novel viruses, making it possible to 'skip' slow evolutionary steps. Examples of diseases caused by genetic reassortment and point mutations are provided. Human immunodeficiency virus (HIV), the virus associated with AIDS, is able to quickly produce divergent forms. Investigators are not sure if AIDS is caused by a new virus, and the HIV mutation potential is unknown. Virology is a relatively new field, but much remains to be determined about viruses, old and new. (Consumer Summary produced by Reliance Medical Information, Inc.)

Research has been conducted on Heterocapsa circularisquama virus. The authors have examined the growth characteristics and intraspecies host specificity of this virus via the study of interactions between the virus and H. circularisquama, and have described the results.

This article addresses the viral contamination of imported oysters with respect to pathogenic Norwalk-like viruses, hepatitis A virus, and enteroviruses. Data reveal that the source of Norwalk-like virus infection in Switzerland may be the imported oysters.

Pathological conditions, such as cancers, viral infections, and autoimmune diseases, are associated with abnormal cytokine production, and the morbidity associated with many medical disorders is often directly a result of cytokine production. Because of the absence of negative feedback control occurring in some pathophysiologic situations, a given cytokine may flood and accumulate in the extracellular compartment of tissues or tumors thereby impairing the cytokine network homeostasis and contributing to local pathogenesis. To evaluate whether the rise of anti-cytokine Abs by vaccination is an effective way to treat these pathological conditions without being harmful to the organism, we have analyzed each step of the cytokine process (involving cytokine production, target response, and feedback regulation) and have considered them in the local context of effector-target cell microenvironment and in the overall context of the macroenvironment of the immune system of the organism. In pathologic tissues, Abs of high affinity, as raised by anti-cytokine vaccination, should neutralize the pool of cytokines ectopically accumulated in the extracellular compartment, thus counteracting their pathogenic effects. In contrast, the same Abs should not interfere with cytokine processes occurring in normal tissues, because under physiologic conditions cytokine production by effector cells (induced by activation but controlled by negative feedback regulation) does not accumulate in the extracellular compartment. These concepts are consistent with results showing that following animal and human anti-cytokine vaccination, induction of high-affinity Abs has proven to be safe and effective and encourages this approach as a pioneering avenue of therapy.

Two human deaths caused by Australian bat lyssavirus (ABL) infection have been reported since 1996. Information was obtained from 205 persons (mostly adults from south Brisbane and the South Coast [...]

To the Editor: Cantagalo virus (CTGV) is a strain of vaccinia virus (VACV; Poxviridae) that was isolated from pustular lesions on dairy cattle and dairy workers in Rio de Janeiro [...]

To the Editor: Recently, Longtin et al. (1) reported a high rate (43%) of human bocavirus (HBoV) infection in a group of children chosen to serve as controls in a [...]

To the Editor: Kurth et al (1) recently described a cowpoxvirus chain of transmission from rat to human through an elephant in Germany. Zoonotic cowpoxvirus infections are well known in [...]

To the Editor: Stockton et al. have reported the detection of human metapneumovirus (HMPV) by using reverse transcriptase-polymerase chain reaction (PCR) in patients with influenzalike illness (1). These authors examined [...]