Acute Self-limiting Infection Research Articles

Oxysterol binding protein (OSBP) contributes to hepatitis E virus replication

Hepatitis E virus (HEV) is a positive-sense, single-stranded RNA virus and causes primarily acute self-limiting infections. The ORF1 of the HEV genome encodes a polyprotein around 190 kDa, which contains several putative domains, including helicase and RNA-dependent RNA polymerase. The HEV-encoded helicase is a member of the superfamily 1 helicase family and possesses multiple enzymatic functions, such as RNA 5′-triphosphatase, RNA unwinding, and NTPase, which are thought to contribute to viral RNA synthesis. However, the helicase interaction with cellular proteins remains less known. Oxysterol binding protein (OSBP) is a lipid regulator that shuffles between the Golgi apparatus and the endoplasmic reticulum for cholesterol and phosphatidylinositol-4-phosphate exchange and controls the efflux of cholesterol from cells. In this study, the RNAi-mediated silencing of OSBP significantly reduced HEV replication. Further studies indicate that the HEV helicase interacted with OSBP, shown by co-immunoprecipitation and co-localization in co-transfected cells. The presence of helicase blocked OSBP preferential translocation to the Golgi apparatus. These results demonstrate that OSBP contributes to HEV replication and enrich our understanding of the HEV-cell interactions.

First serological and molecular investigation of hepatitis E virus infection in dromedary camels in Algeria.

Hepatitis E is an acute self-limited or fulminant infection in humans, caused by the hepatitis E virus (HEV). This member of the Hepeviridae family has been identified in a wide range of domestic and wild animals all over the world, with a possible transmission to humans through fecal oral route, direct contact and ingestion of contaminated meat products, making it one of the global zoonotic and public health major concerns. Since there is no monitoring program and a lack of data on HEV in animals in Algeria, the current preliminary survey has been undertaken to elucidate the exposure to the virus in camels at abattoirs of six southern provinces of Algeria. Two-hundred and eight sera/plasma were collected and analyzed (by double antigen sandwich ELISA) for the presence of total anti-HEV antibodies, among which 35.1% were positive, but no HEV RNA could be isolated from them (by two pan-HEV nested RT-PCR and broad range real-time reverse transcription RT-PCR). The univariate analysis showed significant associations (p < 0.05) between HEV seroprevalence and province of origin, age, and sex of camels, whereas the multivariable logistic regression analysis revealed a negative impact of camels' age on it. The obtained results confirm that HEV infection is widespread established in the camelid population of Algeria.

Q fever and coxiellosis: implications for livestock and human health in the UK

Q fever is a disease which can cause an acute self-limiting infection or long-term chronic condition in people exposed to the bacteria Coxiella burnetii. Most human cases in the UK are associated with livestock, particularly small ruminants, which act as a source of the bacteria. This occurs especially around abortion, which is a common symptom of livestock infection where large numbers of organisms are shed into the environment. While the bacteria is endemic in UK livestock, reported clinical cases of human and, indeed, livestock disease remain relatively uncommon, with sporadic outbreaks reported. Vaccination of livestock remains an effective One Health strategy for reducing environmental contamination and therefore exposure to the infection; however, it remains essential that appropriate precautions are taken, including wearing personal protective equipment, when handling the birth products of ruminant livestock.

Mathematical modeling of plus-strand RNA virus replication to identify broad-spectrum antiviral treatment strategies.

Plus-strand RNA viruses are the largest group of viruses. Many are human pathogens that inflict a socio-economic burden. Interestingly, plus-strand RNA viruses share remarkable similarities in their replication. A hallmark of plus-strand RNA viruses is the remodeling of intracellular membranes to establish replication organelles (so-called "replication factories"), which provide a protected environment for the replicase complex, consisting of the viral genome and proteins necessary for viral RNA synthesis. In the current study, we investigate pan-viral similarities and virus-specific differences in the life cycle of this highly relevant group of viruses. We first measured the kinetics of viral RNA, viral protein, and infectious virus particle production of hepatitis C virus (HCV), dengue virus (DENV), and coxsackievirus B3 (CVB3) in the immuno-compromised Huh7 cell line and thus without perturbations by an intrinsic immune response. Based on these measurements, we developed a detailed mathematical model of the replication of HCV, DENV, and CVB3 and showed that only small virus-specific changes in the model were necessary to describe the in vitro dynamics of the different viruses. Our model correctly predicted virus-specific mechanisms such as host cell translation shut off and different kinetics of replication organelles. Further, our model suggests that the ability to suppress or shut down host cell mRNA translation may be a key factor for in vitro replication efficiency, which may determine acute self-limited or chronic infection. We further analyzed potential broad-spectrum antiviral treatment options in silico and found that targeting viral RNA translation, such as polyprotein cleavage and viral RNA synthesis, may be the most promising drug targets for all plus-strand RNA viruses. Moreover, we found that targeting only the formation of replicase complexes did not stop the in vitro viral replication early in infection, while inhibiting intracellular trafficking processes may even lead to amplified viral growth.

Hepatitis B virus-specific CD4 T cell responses differentiate functional cure from chronic surface antigen+ infection

With or without antiviral treatment, few individuals achieve sustained functional cure of chronic hepatitis B virus (HBV) infection. A better definition of what mediates functional cure is essential for improving immunotherapeutic strategies. We aimed to compare HBV-specific T cell responses in patients with different degrees of viral control. We obtained blood from 124 HBV-infected individuals, including those with acute self-limiting HBV infection, chronic infection, and chronic infection with functional cure. We screened for HBV-specific T cell specificities by ELISpot, assessed the function of HBV-specific T cells using intracellular cytokine staining, and characterized HBV-specific CD4 T cells using human leukocyte antigen (HLA) class II tetramer staining, all directly exvivo. ELISpot screening readily identified HBV-specific CD4 and CD8 T cell responses in acute resolving infection compared with more limited reactivity in chronic infection. Applying more sensitive assays revealed higher frequencies of functional HBV-specific CD4 T cells, but not CD8 T cells, in functional cure compared to chronic infection. Function independent analysis using HLA multimers also identified more HBV-specific CD4 T cell responses in functional cure compared to chronic infection, with the emergence of CD4 T cell memory both after acute and chronic infection. Functional cure is associated with higher frequencies of functional HBV-specific CD4 memory T cell responses. Thus, immunotherapeutic approaches designed to induce HBV functional cure should also aim to improve CD4 T cell responses. Immunotherapy is a form of treatment that relies on harnessing the power of an individual's immune system to target a specific disease or pathogen. Such approaches are being developed for patients with chronic HBV infection, in an attempt to mimic the immune response in patients who control HBV infection spontaneously, achieving a so-called functional cure. However, what exactly defines protective immune responses remains unclear. Herein, we show that functional cure is associated with robust responses by HBV-specific CD4 T cells (a type of immune cell).

Co-Circulation of Different Hepatitis E Virus Genotype 3 Subtypes in Pigs and Wild Boar in North-East Germany, 2019.

Hepatitis E is a major cause of acute liver disease in humans worldwide. The infection is caused by hepatitis E virus (HEV) which is transmitted in Europe to humans primarily through zoonotic foodborne transmission from domestic pigs, wild boar, rabbits, and deer. HEV belongs to the family Hepeviridae, and possesses a positive-sense, single stranded RNA genome. This agent usually causes an acute self-limited infection in humans, but in people with low immunity, e.g., immunosuppressive therapy or underlying liver diseases, the infection can evolve to chronicity and is able to induce a variety of extrahepatic manifestations. Pig and wild boar have been identified as the primary animal reservoir in Europe, and consumption of raw and undercooked pork is known to pose a potential risk of foodborne HEV infection. In this study, we analysed pig and wild boar liver, faeces, and muscle samples collected in 2019 in Mecklenburg-Western Pomerania, north-east Germany. A total of 393 animals of both species were investigated using quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR), conventional nested RT-PCR and sequence analysis of amplification products. In 33 animals, HEV RNA was detected in liver and/or faeces. In one individual, viral RNA was detected in muscle tissue. Sequence analysis of a partial open reading frame 1 region demonstrated a broad variety of genotype 3 (HEV-3) subtypes. In conclusion, the study demonstrates a high, but varying prevalence of HEV RNA in swine populations in Mecklenburg-Western Pomerania. The associated risk of foodborne HEV infection needs the establishment of sustainable surveillance and treatment strategies at the interface between humans, animals, and the environment within a One Health framework.

P146 Hepatitis E infection in rheumatic disease: no evidence of chronicity

Abstract Background/Aims Hepatitis E virus [HEV] is the most common cause of acute hepatitis in developing countries but rare in the industrialised world. In the vast majority it causes an acute self-limiting infection which is often asymptomatic. It is usually detected due to raised transaminases in liver function tests [LFTs] which are checked as part of DMARD monitoring. There is increasing literature that immunocompromised patients with human immunodeficiency virus or transplant recipients are at risk of developing chronic HEV infection, which can progress to liver failure. It is unclear that immunosuppressed patients who have a rheumatological conditions have similar issues, which we have looked into locally. Chronic infection is defined as having detectable RNA for over 3 months. Methods Retrospective review of patients attending rheumatology outpatient clinic for blood monitoring, who had positive Hepatitis E serology between 2010 and 2021. Results We identified nine patients attending the rheumatology clinic in Sheffield, confirmed as having acute infection with HEV as Hep E IgM antibody was positive. They were all on immunosuppression and hence having regular monitoring bloods and were receiving either prednisolone, DMARDS or biologics or in combination. There were five males and four females, with an age range of 38 to 71 years. Eight patients had acutely abnormal LFTs with a peak ALT [normal &amp;lt;41 IU/L] ranging from 59 to 1651 while in one the LFTs remained normal. Eight out of nine patient's LFTs recovered to baseline over a period ranging from 3 to 6 weeks (one moved out of area). Five patients had HEV RNA tested after the positive IgM. Two patients had HEV RNA detected initially, the rest had undetectable RNAs. Repeat RNA testing 2 months later was undetectable in both patients, suggesting no chronic HEV infection in all patients. No patients were given HEV antiviral treatment. Almost all patients had their immunosuppressant treatment paused, which was recommenced once their LFTs normalised. In all patients LFTs have remained normal even after 5 years with no evidence of reactivation in spite of ongoing immunosuppression. We plan to check HEV RNA if the LFTs were to become abnormal. Conclusion Our case series raises awareness that rheumatologists should consider HEV as a differential in patients with a marked unexpected rise in transaminases. We observed that all our patients cleared HEV infection and there was no evidence of chronicity even with ongoing immunosuppression, which is different from Hepatitis B &amp; C. We recommend that immunosuppressant treatment should be stopped initially following HEV infection and reintroduced once LFTs have normalised and HEV RNA is undetectable. Disclosure C.A. Zollinger-Read: None. M. Raza: None. M.F. Kazmi: None.

Hepatitis B seroconversion revisited: new insights into the natural history of acute hepatitis B virus (HBV) infection from quantitative and highly sensitive assays and novel biomarkers

BackgroundHepatitis B virus (HBV) serum markers during typical acute self-limited infection are usually depicted as a composite of traditional HBV markers. The current study updates and expands our knowledge of acute hepatitis B with quantitative molecular and serological data on longitudinal samples from five plasmapheresis donors with acute HBV.Methods137 longitudinal samples from five plasmapheresis donors with acute HBV were tested, four with self-limited infection and one who developed persistent infection. Testing included quantitative hepatitis B surface antigen (HBsAg), antibodies to HBV antigens, quantitative HBV e antigen (HBeAg), HBV DNA, quantitative HBV core-related antigen (HBcrAg), the highly sensitive ARCHITECT HBsAg NEXT (HBsAgNx) assay, and a quantitative research assay for HBV pregenomic RNA (pg RNA).ResultsPeak levels of HBV DNA and HBsAg differed by several orders of magnitude among the panels (2.2 × 105–2.7 × 109 IU/ml for HBV DNA and 7.9–1.1 × 105 IU/ml for HBsAg). HBsAg levels peaked an average of 2.8 days after the HBV DNA peak. The overall duration of observed HBsAg positivity was increased by the more sensitive HBsAgNx assay compared to the quantitative assay in four panels. Intermittently detectable low-level HBV DNA was observed after HBsAg loss in three panels. Peak HBeAg levels occurred 2–20 days after the DNA peak and ranged from 1.1 to 4.5 × 103 IU/ml. In four panels with resolution of infection, anti-HBs levels indicating immunity (≥ 10 mIU/ml) were detected 19–317 days after the HBV DNA peak. Maximum HBcrAg concentrations ranged from 1 × 105 to > 6.4 × 106 U/ml and correlated with HBeAg values (R2 = 0.9495) and with HBV DNA values (R2 = 0.8828). Peak pgRNA values ranged from 1.6 × 103 to 1.4 × 108 U/ml and correlated with HBV DNA (R2 = 0.9013).ConclusionTraditional and new/novel HBV biomarkers were used to generate molecular and serological profiles for seroconversion panels spanning the early to late phases of acute HBV. Seroconversion profiles were heterogeneous and may be instructive in appreciating the spectrum of acute profiles relative to the typical composite representation.

In Vivo Bioluminescence Imaging of HBV Replicating Hepatocytes Allows for the Monitoring of Anti-Viral Immunity.

Immunity against hepatitis B virus (HBV) infection is complex and not entirely understood so far, including the decisive factors leading to the development of chronic hepatitis B. This lack of a mechanistic understanding of HBV-specific immunity is also caused by a limited number of suitable animal models. Here, we describe the generation of a recombinant adenovirus expressing an HBV 1.3-overlength genome linked to luciferase (Ad-HBV-Luc) allowing for precise analysis of the quantity of infected hepatocytes. This enables sensitive and close-meshed monitoring of HBV-specific CD8 T cells and the onset of anti-viral immunity in mice. A high dose of Ad-HBV-Luc developed into chronic hepatitis B accompanied by dysfunctional CD8 T cells characterized by high expression of PD1 and TOX and low expression of KLRG1 and GzmB. In contrast, a low dose of Ad-HBV-Luc infection resulted in acute hepatitis with CD8 T cell-mediated elimination of HBV-replicating hepatocytes associated with elevated sALT levels and increased numbers of cytotoxic HBV-specific CD8 T cells. Thus, the infectious dose was a critical factor to induce either acute self-limited or chronic HBV infection in mice. Taken together, the new Ad-HBV-Luc vector will allow for highly sensitive and time-resolved analysis of HBV-specific immune responses during acute and chronic infection.

Evaluation of hepatitis E antigen kinetics and its diagnostic utility for prediction of the outcomes of hepatitis E virus genotype 1 infection

ABSTRACT HEV-Ag ELISA assay is a reliable diagnostic test in resource-limited areas. HEV genotype 1 (HEV-1) infections are either self-limited or progress to fulminant hepatic failure (FHF) and death if anti-HEV therapy is delayed. Limited data is available about the diagnostic utility of HEV Ag on HEV-1 infections. Herein we aimed to study the kinetics of HEV Ag during HEV-1 infections at different stages, i.e., acute HEV infection, recovery, and progression to FHF. Also, we evaluated the diagnostic utility of this marker to predict the outcomes of HEV-1 infections. Plasma of acute hepatitis E (AHE) patients were assessed for HEV RNA by RT-qPCR, HEV Ag, and anti-HEV IgM by ELISA. The kinetics of HEV Ag was monitored at different time points; acute phase of infection, recovery, FHF stage, and post-recovery. Our results showed that the level of HEV Ag was elevated in AHE patients with a significantly higher level in FHF patients than recovered patients. We identified a plasma HEV Ag threshold that can differentiate between self-limiting infection and FHF progression with 100% sensitivity and 88.89% specificity. HEV Ag and HEV RNA have similar kinetics during the acute phase and self-limiting infection. In the FHF stage, HEV Ag and anti-HEV IgM have similar patterns of kinetics which could be the cause of liver damage. In conclusion, the HEV Ag assay can be used as a biomarker for predicting the consequences of HEV-1 infections which could be diagnostically useful for taking the appropriate measures to reduce the complications, especially for high-risk groups.

Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment.

The hepatitis E virus (HEV) is the fifth known form of viral hepatitis and was first recognized as the cause of an epidemic of unexplained acute hepatitis in the early 1980s. Globally, it is one of the most frequent causes of acute viral hepatitis. The majority of HEV infections are asymptomatic and lead to the spontaneous clearance of the virus. Among the eight different genotypes identified to date, HEV genotype 1 (HEV1), HEV2, HEV3, and HEV4 are the most frequent genotypes causing infections in humans. HEV1 and HEV2 are prevalent in developing regions and able to result in large-scale outbreaks originating from contaminated water supplies. They are also responsible for severe hepatitis in pregnant patients and infants. In contrast, HEV3 and HEV4 are zoonotic, and the transmission of these genotypes to humans occurs mainly through the fecal contamination of water and consumption of contaminated meat from infected animals. Their main reservoir is the pig, and they are mostly encountered in developed countries. The major risk groups for HEV infection and its ensuing adverse consequences are pregnant women, infants, older people, immunocompromised individuals, patients with underlying chronic liver diseases, and workers that come into close contact with HEV-infected animals. In the clinical perspective, HEV infections have diverse clinical manifestations including acute and self-limiting hepatitis, acute-on-chronic liver disease, chronic hepatitis, cirrhosis, and liver failure. Although HEV mainly results in acute self-limiting infection, chronic HEV infection may occur among immunocompromised patients (e.g., solid-organ transplant recipients). Additionally, HEV-associated extrahepatic manifestations involving various organs have been reported in the last decade, although the causal link for many of them still needs to be proven. Ribavirin and interferon-alpha are the most widely used agents for the treatment of HEV infections with a certain level of success. However, ribavirin is contraindicated in pregnant patients, and interferon-alpha cannot be used in most transplant recipients. Therefore, there is an urgent need for novel antiviral compounds that are safe and effective particularly for patients having contraindications for ribavirin or interferon-alpha and infected by the ribavirin-resistant HEV. In this review article, a literature search using PubMed and MEDLINE databases was performed, up to March 2020. Only the articles published in English were reviewed.

New Challenge for Zika Virus Infection: Human Reservoirs?

Zika virus (ZIKV) is considered to cause an acute self-limited infection in adults, and microcephaly in fetus. Presence of the virus for long periods has been detected in body fluids; however, persistent viremia in serum for more than 1 year has not yet been reported. We have investigated persistence of ZIKV in serum samples of 77 subjects who were infected by the virus between 18 months and 3 years before the start of this study. The subjects included children with microcephaly and their parents. Serum samples were subjected to routine RT-qPCR assay for ZIKV, Chikungunya virus, and Dengue virus. From the 77 subjects, five showed positive for the presence of ZIKV particles by RT-qPCR, including four members of the same family. Viral isolation in Vero cells and C6/36 cells confirmed the result and showed the viral particles were active. We have detected viremia in healthy carriers up to 3 years after symptom onset. Humans acting as potential viral reservoirs have major implication for the current understanding of ZIKV infection.

Immunopathogenesis of HBV Infection.

More than 95% of adult infected with HBV show acute self-limited infection and eventually eliminate the virus. In contrast, about 90% of people exposed to HBV in early childhood develop chronic infection. The specificity of the virus and the host's antiviral immune responses together determine the outcome of HBV infection. It is generally believed that viral genome variation, viral titers, and inhibition of viral components against the host immune system are associated with persistent infection and liver damage. The dysfunction of innate immune cells (NK cells, monocyte/macrophages, NKT cells, etc.) and adaptive immune cells (antigen-presenting cells, T cells, B cells) is a key factor leading to virus clearance failure and liver inflammation. In this chapter, we summarize these viral factors and host factors in acute and chronic hepatitis B and update recent understanding of the immune-tolerant phase and pathological mechanisms associated with age and vertical transmission. This will help us to understand more fully the mechanisms of chronic HBV infection and liver injury and to develop combined treatment strategies of direct antiviral drugs for HBV life cycle and immunomodulators.

Spatially-implicit modelling of disease-behaviour interactions in the context of non-pharmaceutical interventions.

Pair approximation models have been used to study the spread of infectious diseases in spatially distributed host populations, and to explore disease control strategies such as vaccination and case isolation. Here we introduce a pair approximation model of individual uptake of non-pharmaceutical interventions (NPIs) for an acute self-limiting infection, where susceptible individuals can learn the NPIs either from other susceptible individuals who are already practicing NPIs ("social learning"), or their uptake of NPIs can be stimulated by being neighbours of an infectious person ("exposure learning"). NPIs include individual measures such as hand-washing and respiratory etiquette. Individuals can also drop the habit of using NPIs at a certain rate. We derive a spatially defined expression of the basic reproduction number R0 and we also numerically simulate the model equations. We find that exposure learning is generally more efficient than social learning, since exposure learning generates NPI uptake in the individuals at immediate risk of infection. However, if social learning is pre-emptive, beginning a sufficient amount of time before the epidemic, then it can be more effective than exposure learning. Interestingly, varying the initial number of individuals practicing NPIs does not significantly impact the epidemic final size. Also, if initial source infections are surrounded by protective individuals, there are parameter regimes where increasing the initial number of source infections actually decreases the infection peak (instead of increasing it) and makes it occur sooner. The peak prevalence increases with the rate at which individuals drop the habit of using NPIs, but the response of peak prevalence to changes in the forgetting rate are qualitatively different for the two forms of learning. The pair approximation methodology developed here illustrates how analytical approaches for studying interactions between social processes and disease dynamics in a spatially structured population should be further pursued.

PWE-064 The Utility of An Enteric Bacterial PCR Panel In Evaluating Patients with Diarrhoea and Raised Faecal Calprotectin

Introduction Faecal calprotectin (FCP) assay has an important role in identifying potential cases of inflammatory bowel disease (IBD). However, a significant proportion of patients presenting with diarrhoea and raised FCP do not prove to have IBD following investigation of whom a proportion have an acute self-limiting gut infection. Enteric pathogens are alternative causes of a raised FCP. Alleviating the need for endoscopy in the patients will save money and reduce patient anxiety. However, conventional laboratory methodologies are time consuming and insensitive in detecting gut infection. Commercial nucleic acid amplification test (NAAT) technology now makes it possible to test stool for a panel of gut pathogens quickly and relatively cheaply. In this pilot study, we evaluated this technology in detecting gut infection amongst patients with a diarrhoeal illness and raised FCP, presenting in the community. Methods Ninety patients with diarrhoea had stool samples submitted from the community to the laboratory for FCP measurement. Samples were anonymised before testing with NAAT (BD MAX™ Enteric Bacterial Panel). The targets of this assay are Salmonella spp. , Campylobacter spp. Shigella ( Shigella spp . and enteroinvasive E. coli ) and verotoxigenic E coli . Samples were stratified by FCP level into sub-groups (n = 30): 150 µg/g stool and analysed for the presence and type of gut infection found. All samples were also cultured using standard media. Results 2/30 samples tested (7%, 95% CI 8–23%) with FCP > 150 µg/g tested positive by NAAT for Campylobacter. No patients with FCP below 150 µg/g had a detectable pathogen. No samples were positive by conventional culture methods. Conclusion This pilot study supports a role for the use of multiplex NAAT in detecting enteric pathogens amongst patients with diarrhoea and raised FCP. Prospective studies are required to evaluate this approach further which offers the potential to refine the IBD referral pathways from primary care and reduce the need for endoscopic and radiological tests. Disclosure of Interest None Declared

Prescribing pattern of drugs in upper respiratory tract infections in pediatric out patients

Background: Upper respiratory tract infections are the most frequently occurring illness of childhood. The common types of upper respiratory tract infections are common cold, rhinitis, laryngitis, pharyngitis, otitis media and sinusitis. Common misuse of antimicrobial agents is seen in infections caused by viruses, which are self-limited and they do not respond to the currently available anti-infective agents. Methods: A prospective observational study was conducted at pediatric out-patient department of Basaveshwara Medical College Hospital and Research Centre, Chitradurga for a period of six months. The data was collected from outpatient record in a suitably designed individual case record form of the patients diagnosed with upper respiratory tract infection. Results: A total of 120 patients aged less than 13 years were collected from the paediatric outpatient department of a tertiary care teaching hospital. The most common diagnosis was nonspecific upper respiratory tract infections (49.1%). Only 10 drugs were prescribed from the essential drug list. Amongst all drug class, respiratory drugs were prescribed in more (29%), antihistamines (24.6%), antimicrobials (24.3%), Non-steroidal anti-inflammatory drugs (18%) and nasal drops (4.1%). In antimicrobials, amoxicillin + clavulanic acid (45.8%) was the highly prescribed combination. The main drug interactions were between chlorpheneramine and terbutaline. Conclusions: Antibiotic prescriptions were inappropriate in acute self-limiting upper respiratory tract infection. Antibiotics are over prescribed for paediatric upper respiratory tract infections. Amoxicillin with clavulanic acid combination were preferentially prescribed. Doctors should be educated on more appropriate and cost effective prescribing.

Is hepatitis E virus an emerging problem in industrialized countries?

Hepatitis E virus (HEV) is yearly responsible for approximately 20 million infections worldwide. Although most infections occur in developing countries, HEV appears to be an emerging problem in several industrialized countries, where it is mostly associated with either traveling to an HEV endemic area or contact with pigs, which represent a major reservoir of HEV. The major risk groups for HEV infection and its ensuing complications are elderly men, pregnant women, young children, immunocompromised patients, patients with preexisting liver disease, and workers that come into close contact with HEV-infected animals. Whereas HEV mainly causes acute self-limiting infections, chronic infections may occur among immunocompromised patients (e.g., transplant recipients and human immunodeficiency virus [HIV]-infected patients). Accordingly, HEV-HIV coinfection leads to accelerated liver cirrhosis and increased mortality rates compared to HEV infection alone, which is, except during pregnancy, usually associated with only low mortality. In the Western world, the most common genotype (gt) causing HEV infection is gt 3. Ribavirin (RBV) and interferon have been used successfully for treatment of HEV, but this treatment is contraindicated in certain patient groups. Therefore, novel antiviral compounds are highly needed, especially given that viral isolates with RBV resistance have been recently identified. Moreover, eradication of HEV is hampered by long-term environmental persistence of the virus, which represents a continuous source of the virus. In 2011, the first prophylactic HEV vaccine, Hecolin, was approved in China, but it is not yet globally available. In this review, we will discuss the molecular virology of HEV, mode of transmission in industrialized countries, and potential implications for different specific patient populations.

Functional limitations of plasmacytoid dendritic cells limit type I interferon, T cell responses and virus control in early life.

Infant mortality from viral infection remains a major global health concern: viruses causing acute infections in immunologically mature hosts often follow a more severe course in early life, with prolonged or persistent viral replication. Similarly, the WE strain of lymphocytic choriomeningitis virus (LCMV-WE) causes acute self-limiting infection in adult mice but follows a protracted course in infant animals, in which LCMV-specific CD8+ T cells fail to expand and control infection. By disrupting type I IFNs signaling in adult mice or providing IFN-α supplementation to infant mice, we show here that the impaired early life T cell responses and viral control result from limited early type I IFN responses. We postulated that plasmacytoid dendritic cells (pDC), which have been identified as one major source of immediate-early IFN-I, may not exert adult-like function in vivo in the early life microenvironment. We tested this hypothesis by studying pDC functions in vivo during LCMV infection and identified a coordinated downregulation of infant pDC maturation, activation and function: despite an adult-like in vitro activation capacity of infant pDCs, the expression of the E2-2 pDC master regulator (and of critical downstream antiviral genes such as MyD88, TLR7/TLR9, NF-κB, IRF7 and IRF8) is downregulated in vivo at baseline and during LCMV infection. A similar pattern was observed in response to ssRNA polyU, a model ligand of the TLR7 viral sensor. This suggests that the limited T cell-mediated defense against early life viral infections is largely attributable to / regulated by infant pDC responses and provides incentives for novel strategies to supplement or stimulate immediate-early IFN-α responses.

Prime/Boost Immunization with DNA and Adenoviral Vectors Protects from Hepatitis D Virus (HDV) Infection after Simultaneous Infection with HDV and Woodchuck Hepatitis Virus

Hepatitis D virus (HDV) superinfection of hepatitis B virus (HBV) carriers causes severe liver disease and a high rate of chronicity. Therefore, a vaccine protecting HBV carriers from HDV superinfection is needed. To protect from HDV infection an induction of virus-specific T cells is required, as antibodies to the two proteins of HDV, p24 and p27, do not neutralize the HBV-derived envelope of HDV. In mice, HDV-specific CD8(+) and CD4(+) T cell responses were induced by a DNA vaccine expressing HDV p27. In subsequent experiments, seven naive woodchucks were immunized with a DNA prime and adenoviral boost regimen prior to simultaneous woodchuck hepatitis virus (WHV) and HDV infection. Five of seven HDV-immunized woodchucks were protected against HDV infection, while acute self-limiting WHV infection occurred as expected. The two animals with the breakthrough had a shorter HDV viremia than the unvaccinated controls. The DNA prime and adenoviral vector boost vaccination protected woodchucks against HDV infection in the setting of simultaneous infection with WHV and HDV. In future experiments, the efficacy of this protocol to protect from HDV infection in the setting of HDV superinfection will need to be proven.

Management of acute hepatitis B and reactivation of hepatitis B

The natural course of hepatitis B virus infection and the resulting hepatic injury is determined by the degree of virus replication and the intensity of host immune response. Upon exposure to hepatitis B virus (HBV), individuals with a vigorous and broad immune response develop acute self-limited infection, which may result in acute hepatitis. However, with stringent testing for HBV and universal precautions, acute HBV is rather rare. Reactivation of HBV most often presents as acute hepatitis B (AVH-B) and clinically, it is difficult to differentiate AVH-B from reactivation of chronic hepatitis B (CHB) and it requires a high index of suspicion. In the presence of high HBV DNA (>2 × 10(4) IU/ml) underlying liver disease should be investigated by liver biopsy, endoscopy and/or imaging. The degree of liver failure often depends on the severity of acute insult and the stage of underlying chronic liver disease. Mutations in the HBV genome, immunosuppressive therapy and viral or drug induced injury are common causes of reactivation. As most patients with AVH-B resolve the infection spontaneously, antiviral therapy is not indicated in them. However, the use of a potent oral nucleoside(tide) analogue is necessary as soon as possible in patients with CHB reactivation. Liver transplantation should be considered in patients who develop liver failure secondary to severe acute exacerbation. If this is not feasible, supportive therapy with the addition of granulocyte colony stimulating factor (GCSF) therapy could be beneficial.