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Understanding the pathophysiology of long COVID is one of the most intriguing challenges confronting contemporary medicine. Despite observations recently made in the relevant molecular, cellular, and physiological domains, it is still difficult to say whether the post‐acute sequelae of COVID‐19 directly correspond to the consequences of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. This work hypothesizes that neutrophils and neutrophil extracellular traps (NETs) production are at the interconnection of three positive feedback loops which are initiated in the acute phase of SARS‐CoV‐2 infection, and which involve inflammation, immunothrombosis, and autoimmunity. This phenomenon could be favored by the fact that SARS‐CoV‐2 may directly bind and penetrate neutrophils. The ensuing strong neutrophil stimulation leads to a progressive amplification of an exacerbated and uncontrolled NETs production, potentially persisting for months beyond the acute phase of infection. This continuous self‐stimulation of neutrophils leads, in turn, to systemic inflammation, micro‐thromboses, and the production of autoantibodies, whose significant consequences include the persistence of endothelial and multiorgan damage, and vascular complications. [ABSTRACT FROM AUTHOR]

The SARS‐CoV‐2 VIrus PERsistence (VIPER) study investigated the presence of long‐lasting SARS‐CoV‐2 RNA in plasma, stool, urine, and nasopharyngeal samples in COVID‐19 survivors. The presence of SARS‐CoV‐2 RNA reverse transcription polymerase chain reactions (RT‐PCR) were analyzed within plasma, stool, urine, and nasopharyngeal swab samples in COVID‐19 survivors with post‐COVID symptoms and a comparison group of COVID‐19 survivors without post‐COVID symptoms matched by age, sex, body mass index and vaccination status. Participants self‐reported the presence of any post‐COVID symptom (defined as a symptom that started no later than 3 months after the initial infection). Fifty‐seven (57.9% women, age: 51.1, standard deviation [SD]: 10.4 years) previously hospitalized COVID‐19 survivors with post‐COVID symptoms and 55 (56.4% women, age: 50.0, SD: 12.8 years) matched individuals who had a past SARS‐CoV‐2 infection without post‐COVID symptoms were evaluated 27 (SD 7.5) and 26 (SD 8.7) months after hospital discharge, respectively. The presence of SARS‐CoV‐2 RNA was identified in three nasopharyngeal samples of patients with post‐COVID symptoms (5.2%) but not in plasma, stool, or urine samples. Thus, SARS‐CoV‐2 RNA was not identified in any sample of survivors without post‐COVID symptoms. The most prevalent post‐COVID symptoms consisted of fatigue (93%), dyspnea, and pain (both, 87.7%). This study did not find SARS‐CoV‐2 RNA in plasma, stool, or urine samples, 2 years after the infection. A prevalence of 5.2% of SARS‐CoV‐2 RNA in nasopharyngeal samples, suggesting a potential active or recent reinfection, was found in patients with post‐COVID symptoms. These results do not support the association between SARS‐CoV‐2 RNA in plasma, stool, urine, or nasopharyngeal swab samples and post‐COVID symptomatology in the recruited population. [ABSTRACT FROM AUTHOR]

Purpose: To study the clinical signs and mechanisms (viral and autoimmune) of myoendocarditis in the long‐term period after COronaVIrus Disease 2019 (COVID‐19). Methods: Fourteen patients (nine male, 50.1 ± 10.2 y.o.) with biopsy proven post‐COVID myocarditis were observed. The diagnosis of COVID‐19 was confirmed by IgG seroconversion. The average time of admission after COVID‐19 was 5.5 [2; 10] months. An endomyocardial biopsy (EMB) of the right ventricle was obtained. The biopsy analysis included polymerase chain reaction diagnosis of viral infection, morphological, immunohistochemical (IHC) examination with antibodies to CD3, CD45, CD68, CD20, SARS‐Cov‐2 spike, and nucleocapsid antigens. Coronary atherosclerosis was ruled out in all patients over 40 years. Results: The new cardiac symptoms (congestive heart failure 3–4 New York Heart Association class with severe right ventricular involvement, various rhythm, and conduction disturbances) appeared 1–5 months following COVID‐19. Magnetic resonance imaging showed disseminated or focal subepicardial and intramyocardial late gadolinium enhancement, hyperemia, edema, and increased myocardial native T1 relaxation time. Antiheart antibodies levels were increased 3–4 times in 92.9% of patients. The mean left ventricular (LV) ejection fraction (EF) was 28% (24.5; 37.8). Active lymphocytic myocarditis was diagnosed in 12 patients, eosinophilic myocarditis in two patients. SARS‐Cov‐2 RNA was detected in 12 cases (85.7%), in association with parvovirus B19 DNA—in one. Three patients had also endocarditis (infective and nonbacterial, with parietal thrombosis). As a result of steroid and chronic heart failure therapy, the EF increased to 47% (37.5; 52.5). Conclusions: COVID‐19 can lead to long‐term severe post‐COVID myoendocarditis, that is characterized by prolonged persistence of coronavirus in cardiomyocytes, endothelium, and macrophages (up to 18 months) in combination with high immune activity. Corticosteroids and anticoagulants should be considered as a treatment option of post‐COVID myoendocarditis. [ABSTRACT FROM AUTHOR]

More systematic analysis of hepatitis B virus (HBV) genome diversity, linked with tenofovir disoproxil fumarate (TDF) treatment and HBeAg seroconversion, are needed. GS‐US‐174–0115 was a double‐blind, placebo‐controlled, Phase 3, 192‐week clinical trial that evaluated TDF in adolescents with chronic hepatitis B (CHB). HBV full‐genome deep sequencing was performed using Illumina MiSeq at baseline (BL; n = 85), Week 8 (W8; n = 80), Week 72 (W72; PBO only, n = 42), and treatment‐free follow‐up (TDF only, n = 25). The viral diversity was calculated using Shannon entropy and population nucleotide diversity with a 2% variant cutoff. Our data showed (i) a higher viral diversity in the X region at baseline than the core/polymerase/surface regions, (ii) higher core/surface viral diversity at baseline for patients with seroconversion, (iii) an expected reduction in viral diversity after 8 weeks of TDF treatment, and (iv) a drop in viral diversity at W72 for patients receiving placebo with a seroconversion (n = 7). The higher viral diversity in X was associated with higher baseline alanine aminotransferase (ALT) levels (p <.001). Patients with greater reduction of diversity at W8 of TDF treatment had higher baseline ALT levels. For placebo patients who seroconverted, the drop in viral diversity at W72 (p =.04) coincided with reduction of serum HBV DNA (average change from baseline = −4.10 log10 copies/ml) and unique combinations of variants were enriched in a patient's viral population post seroconversion. The basal core promoter (BCP) variants, A1762T and G1764A, and the pC variant, G1896A, were most often enriched at or after seroconversion. [ABSTRACT FROM AUTHOR]

Kidney transplantation is the treatment of choice for patients with end‐stage renal disease. In the posttransplant period, the induced immunosuppression leads to an increased risk of developing infectious diseases, a leading cause of death after kidney transplantation. Human pegivirus‐1 (HPgV‐1) is considered a nonpathogenic human virus and is highly frequent in individuals parenterally exposed, however, its impact on kidney transplantation outcome is poorly understood. Given the scarcity of epidemiological data for this infection on organ recipients in Brazil, we conducted a study in a single center for kidney transplantation in Rio de Janeiro, aiming to determine HPgV‐1 prevalence and genotypic distribution. Serum samples from 61 renal recipients, followed up for the first year after transplantation, were evaluated for viral RNA and genotypes were determined by sequencing of the 5′‐untranslated region. HPgV‐1 RNA was detected in 36.1% (22/61) of patients. Genotype 2 was the most commonly found (80.9%), followed by genotypes 3 (9.5%), 1, and 5, in 4.8% each. Statistical comparisons did not reveal any significant impact of HPgV‐1 in patient outcome. Further epidemiologic studies are needed to understand if immunosuppression may interfere in HPgV‐1 persistence rates and if viremia might impact graft dysfunction rates in kidney recipients. Highlights: High prevalence of HPgV‐1‐RNA (36.1%) was found in kidney transplant recipients.No significant impact of HPgV‐1 infection in patient outcome was observed.High HPgV‐1 persistence rates were observed among kidney recipients patients.Genotype 2 was predominantly found, followed by genotypes 3, 1 and 5. [ABSTRACT FROM AUTHOR]

Control of bovine viral diarrhea virus (BVDV) in cattle populations across most of the world has remained elusive in spite of advances in knowledge about this viral pathogen. A central feature of virus perseverance in cattle herds is the unique mechanism of persistent infection. Managing BVDV infection in herds involves controlling persistently infected carrier animals using a multidimensional approach of vaccination, biosecurity, and identification of BVDV reservoirs. A decade has passed since the original American College of Veterinary Internal Medicine consensus statement on BVDV. While much has remained the same with respect to clinical signs of disease, pathogenesis of infection including persistent infection, and diagnosis, scientific articles published since 2010 have led to a greater understanding of difficulties associated with control of BVDV. This consensus statement update on BVDV presents greater focus on topics currently relevant to the biology and control of this viral pathogen of cattle, including changes in virus subpopulations, infection in heterologous hosts, immunosuppression, and vaccination. [ABSTRACT FROM AUTHOR]

The consequences of foot‐and‐mouth disease impact regional economies and food security through animal mortality and morbidity, trade restrictions and burdens to veterinary infrastructure. Despite efforts to control the disease, some regions, mostly in warmer climates, persistently report disease outbreaks. Consequently, it is necessary to understand how environmental factors influence transmission, of this economically devastating disease. Extensive research covers basic aetiology and transmission potential of livestock and livestock products for foot‐and‐mouth disease virus (FMDV), with a subset evaluating environmental survival. However, this subset, completed in the early to mid‐20th century in Northern Europe and the United States, is not easily generalized to today's endemic locations. This review uncovered 20 studies, to assess current knowledge and analyse the effects of environmental variables on FMDV survival, using a Cox proportional hazards (Coxph) model. However, the dataset is limited, for example pH was included in three studies and only five studies reported both relative humidity (RH) and temperature. After dropping pH from the analysis, our results suggest that temperature alone does not describe FMDV survival; instead, interactions between RH and temperature have broader impacts across various conditions. For instance, FMDV is expected to survive longer during the wet season (survival at day 50 is ~90% at 16°C and 86% RH) versus the dry season (survival at day 50 approaches 0% at 16°C and 37.5% RH) or comparatively in the UK versus the Southwestern United States. Additionally, survival on vegetation topped 70% on day 75 when conditions exceeded 20°C with high RH (86%), drastically higher than the survival on inanimate surfaces at the same temperature and RH (~0%). This is important in tropical regions, where high temperatures can persist throughout the year, but RH varies. Therefore, parameter estimates, for disease modelling and control in endemic areas, require environmental survival data from a wider range of conditions. [ABSTRACT FROM AUTHOR]

Classical swine fever virus (CSFV) is one of the most important pathogens affecting swine. After infection with a moderate virulence strain at 8 hours after birth, CSFV is able to induce viral persistence. These animals may appear clinically healthy or showed unspecific clinical signs despite the permanent viremia and high viral shedding, in absence of immune response to the virus. Given the role played by this infection in disease control, we aimed to evaluate the capacity of CSFV to induce postnatal persistent infection at 3 weeks after birth. Nine pigs were CSFV infected and sampled weekly during 6 weeks and viral, clinical, pathological and immunological tests were carried out. Also, the CD4/CD8 ratio was calculated with the purpose to relate this marker with the CSFV persistent infection. The IFN‐α response was detected mainly 1 week after infection, being similar in all the infected animals. However, 44.4% of animals were CSFV persistently infected, 33.3% died and 22.2% developed specific antibody response. Interestingly, in persistently infected pigs, the T‐CD8 population was increased, the T‐CD4 subset was decreased and lower CD4/CD8 ratios were detected. This is the first report of CSFV capacity to confer postnatal persistent infection in pigs infected at 3 weeks after birth, an age in which the weaning could be carried out in some swine production systems. This type of infected animals shed high amounts of virus and are difficult to evaluate from the clinical and anatomopathological point of view. Therefore, the detection of this type of infection and its elimination in endemic areas will be relevant for global CSF eradication. Finally, the low CD4/CD8 ratios found in persistently infected animals may be implicated in maintaining high CSFV replication during persistence and further studies will be performed to decipher the role of these cells in CSFV immunopathogenesis. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that microRNA-mediated gene silencing, detected during exosome intercellular communication between cells, may be exploited by persistent human viruses. Recently, it has been reported that human polyomaviruses encode microRNAs that downregulate large T expression and target host factors, helping the virus to escape immune elimination. Consequently, viral microRNAs and their genetic variability may have roles in the induction of polyomavirus reactivation, the success of persistence or replication and the development of diseases. In vitro experiments have detected polyomavirus JC (JCPyV) microRNAs in exosomes obtained from cell supernatants after viral infection and showed that they can be carried into uninfected cells. JCPyV and BKPyV microRNAs have been sought in clinical samples obtained from patients with or at risk of severe polyomavirus-associated diseases and from healthy subjects. Variable expressions of JCPyV and BKPyV microRNAs circulating in blood, urine, and cerebrospinal fluid samples were found in patients who were polyomavirus DNA positive and were also observed in negative subjects. Differences in the relationship between the JCPyV and BKPyV microRNA expressions and viral DNA load have been observed. All the data point towards a potential role of polyomavirus exosome microRNAs in viral persistence and suggest that further work is warranted to define their role in viral reactivation and to identify potential new antiviral strategies targeting these viruses. [ABSTRACT FROM AUTHOR]

The pandemic spread of Zika virus ( ZIKV), a member of the flavivirus genus of the Flaviviridae family, has become a major public health concern. Reproductive specialists are particularly concerned over the spread of ZIKV as it is now known to have both sexual and transplacental routes of transmission resulting in fetal congenital abnormalities. Other members of the Flaviviridae family, hepatitis C virus ( HCV) and bovine viral diarrhea virus ( BVDV) (which primarily affects cattle), are well known to reproductive specialists as both sexually transmitted illnesses that are capable of vertical transmission. Congenital infection with BVDV also has a predilection for neuro-teratogenicity as has been seen with ZIKV. HCV and BVDV are also known to be capable of persistent infection in offspring. Could this be the case with ZIKV? Examining what we know about HCV and BVDV, in addition to what we have already learned about ZIKV, may answer some of the questions that remain about ZIKV. Herein, we review the current literature as it pertains to ZIKV vertical transmission and neuro-teratogenicity and compare it to what is known about HCV and BVDV. [ABSTRACT FROM AUTHOR]

Hepatitis B virus ( HBV) remains a public health concern with 240 million people affected worldwide. HBV is an hepadnavirus that replicates its genome in hepatocytes. One of the key steps of the viral life cycle is the formation of ccc DNA - covalently closed circular DNA - in the nucleus, the equivalent of a viral mini-chromosome that acts as a template for subsequent virus replication. Current antiviral medications are not effective in eradicating ccc DNA, which can persist in the infected liver even in the absence of detectable HBV DNA or HBsAg in the blood. ccc DNA cannot be measured in serum, and few surrogate markers have been proposed. Persistent ccc DNA has been associated with various clinical events, including viral reactivation induced by immunosuppressive therapies, HBV recurrence after liver transplantation and hepatocellular carcinoma ( HCC). ccc DNA remains the main target to achieve a cure of HBV infection, thus extensive efforts are being made to develop new antiviral concepts to degrade or silence ccc DNA. [ABSTRACT FROM AUTHOR]

Immune homeostasis is a host characteristic that maintains biological balance within a host. Humans have evolved many host defence mechanisms that ensure the survival of individuals upon encountering a pathogenic infection, with recovery or persistence from a viral infection being determined by both viral factors and host immunity. Chronic viral infections, such as hepatitis B virus, hepatitis C virus and HIV, often result in chronic fluctuating viraemia in the face of host cellular and humoral immune responses, which are dysregulated by multi-faceted mechanisms that are incompletely understood. This review attempts to illuminate the mechanisms involved in this process, focusing on immune homeostasis in the setting of persistent viral infection from the aspects of host defence mechanism, including interferon-stimulated genes, apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3), autophagy and interactions of various immune cells, cytokines and regulatory molecules. [ABSTRACT FROM AUTHOR]

Disseminated adenovirus infections cause significant mortality in stem cell transplanted patients and are suspected to originate from asymptomatic adenovirus persistence ('latency') in lymphocytes. The infection of three human T-lymphocyte lines (Jurkat, PM1, and CEM) with human adenovirus types of species A (HAdV-A31), B (HAdV-B3, -B11), and C (HAdV-C2, -C5) was investigated for 150 days in order to establish in vitro models for adenovirus persistence. HAdV-C5 persisted with continuous production of infectious virus progeny (about 107 TCID50/ml) in PM1 cells. More than 100 copies of HAdV-C5-DNA per cell were detected by real-time PCR but hexon immunostaining showed that only 7.5% of the cells were infected ('carrier state infection'). Coxsackie and adenovirus receptor (CAR) expression was decreased in comparison to mock infected cultures suggesting selection of a semi-permissive subpopulation of PM-1 cells. By contrast, latency of HAdV-DNA (10−3-10−4 copies/cell) without production of infectious virus progeny was observed in HAdV-C2 infection of PM1 and Jurkat, HAdV-A31 infection of PM1, and HAdV-B3 infection of Jurkat cells. In addition, transcription of E1A, DNA polymerase and hexon mRNA was not detected by RT-PCR suggesting an equivalent of clinical 'HAdV latency.' Persistence of HAdV-DNA was not observed in abortive infections of PM1 cells with HAdV-B3 and -B11 and in productive, lytical infections of Jurkat cells with HAdV-C5, HAdV-B11, and HAdV-A31. In conclusion, lytic and persistent infections with and without production of infectious virus were observed depending on the type of adenovirus. Genetic determinants for viral persistence may be investigated using these newly established infection models. J. Med. Virol. 86:785-794, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

DNA-based vaccination appears of promise for chronic hepatitis B immunotherapy, although there is an urgent need to increase its efficacy. In this preclinical study, we evaluated the therapeutic benefit of cytokine ( IL-2, IFN-γ) genes co-delivery with DNA vaccine targeting hepadnaviral proteins in the chronic duck hepatitis B virus ( DHBV) infection model. Then, we investigated the persistence of replication-competent virus in the livers of apparently resolved animals. DHBV carriers received four injections of plasmids encoding DHBV envelope and core alone or co-delivered with duck IL-2 ( Du IL-2) or duck IFN-γ ( Du IFN-γ) plasmids. After long-term (8 months) follow-up, viral covalently closed circular (ccc) DNA was analysed in duck necropsy liver samples. Liver homogenates were also tested for in vivo infectivity in neonatal ducklings. Co-delivery of Du IFN-γ resulted in significantly lower mean viremia starting from week 21. Viral ccc DNA was undetectable by conventional methods in the livers of 25% and 57% of animals co-immunized with Du IL-2 and Du IFN-γ, respectively. Interestingly, inoculation of liver homogenates from 7 such apparently resolved animals, exhibiting ccc DNA undetectable in Southern blotting and DHBV expression undetectable or restricted to few hepatocytes, revealed that three liver homogenates transmitted high-titre viremia (3-5×1010 vge/mL) to naïve animals. In conclusion, our results indicate that IFN-γ gene co-delivery considerably enhances immunotherapeutic efficacy of DNA vaccine targeting hepadnaviral proteins. Importantly, we also showed that livers exhibiting only minute amounts of hepadnaviral ccc DNA could induce extremely high-titre infection, highlighting the caution that should be taken in occult hepatitis B patients to prevent HBV transmission in liver transplantation context. [ABSTRACT FROM AUTHOR]

Viral nucleic acid may be detected for up to 6 months after an acute asthma deterioration, but the pattern and consequences of viral persistence after acute asthma are incompletely understood. This study investigates the frequency of viral persistence after acute asthma, assesses viral infectivity and determines the host inflammatory responses to viral persistence. Adults and children presenting to hospital with acute asthma and a confirmed respiratory virus infection were studied acutely and at recovery 4-6 weeks later by clinical evaluation and induced sputum for viral and inflammatory mediator detection. Viral RNA was detected during both acute asthma and recovery visits in 17 subjects (viral persistence), whereas in 22 subjects viral RNA had cleared by recovery (viral clearance). The following viruses were detected at recovery: human rhinovirus: 16; respiratory syncytial virus: 2; influenza: 2. In subjects with viral persistence, eight isolates were different to the virus detected at Visit 1. Forty-four per cent of the human rhinovirus isolates were infective at recovery. Asthma and infection severity were similar in the viral clearance and viral persistence groups. Viral persistence was associated with elevated IL-10 mRNA and inducible protein-10 gene expression. Respiratory viral detection after acute asthma is common, and most often persistence is with non-infective human rhinovirus. There is a host inflammatory response with an altered cytokine environment, and the viral RNA can be source of persistent infection. These effects may have longer-term consequences in asthma. Viral persistence is a recently recognized phenomenon. It is poorly characterized in asthma. This work defines the problem of viral persistence in asthma and examines the inflammatory consequences of this phenomenon. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) is a highly mutable RNA virus with a high propensity for chronic infection, affecting over 3% of the world's population. Persistent infection is associated with chronic hepatitis that may progress to cirrhosis and hepatocellular carcinoma over many years of infection. While cellular immune response plays a key role in viral infection, HCV persistence is associated with antiviral effector T-cell dysfunction with increased CD4+ CD25+ Tregs and interleukin-10+ Tr1cells, raising the possibility that the balance between antiviral effector and regulatory T-cell subsets contributes to the outcome of HCV infection. [ABSTRACT FROM AUTHOR]

Viruses have evolved various strategies in order to persist within the host. To date, most information on mechanisms of HIV-1 persistence has been derived from studies with lymphocytes, but there is little information regarding mechanisms that govern HIV-1 persistence in macrophages. It has previously been demonstrated that virus assembly in macrophages occurs in cytoplasmic vesicles, which exhibit the characteristics of multivesicular bodies or late endosomes. The infectious stability of virions that assemble intracellularly in macrophages has not been evaluated. We demonstrate that virions assembling intracellularly in primary macrophages retain infectivity for extended intervals. Infectious virus was recovered directly from cytoplasmic lysates of macrophages and could be transmitted from macrophages to peripheral blood lymphocytes in trans 6 weeks after ongoing viral replication was blocked. Cell-associated virus decayed significantly from 1 to 2 weeks post infection, but decreased minimally thereafter. The persistence of intracellular virions did not require the viral accessory proteins Vpu or Nef. The stable sequestration of infectious virions within cytoplasmic compartments of macrophages may represent an additional mechanism for viral persistence in HIV-1-infected individuals. [ABSTRACT FROM AUTHOR]

SummaryHepatitis C virus, a recently identified member of the family Flaviviridae, is an important cause of chronic viral hepatitis and cirrhosis. There are similarities in the nature of the immune response to this pathogen with immunity in other flavivirus and hepatotropic virus infections, such as hepatitis B. However, the high rate of viral persistence after primary hepatitis C infection, and the observation that neutralizing antibodies are not protective, would suggest that there are a number of important differences between hepatitis C, other flaviviruses, and hepatitis B. The phenomenon of quasispecies evolution and other viral factors have been proposed to contribute to immune evasion by hepatitis C virus. In the face of established persistent infection, virus-specific cytotoxic T lymphocytes may exert some control over viral replication. However, these same effectors may also be responsible for the progressive liver damage characteristic of chronic hepatitis C infection. The nature of protective immunity, including the role of innate immune responses early after hepatitis C exposure, remains to be defined. [ABSTRACT FROM AUTHOR]

Bone marrow (BM) from patients affected by multiple myeloma (MM), exhibiting monoclonal gammopathy of undetermined significance (MGUS) or with non-Hodgkin lymphoma (NHL) as well as from healthy donors were investigated for the presence of human herpesvirus-8 (HHV-8) DNA sequences. ORF 26 sequences were detected in 36–56% of the patients and in 29% of the controls. In a few cases, two other HHV-8 DNA sequences were also detected. These observations indicate that the presence of the HHV-8 genome in BM is relatively common in different groups of patients as well as in healthy individuals and do not support an alleged role for HHV-8 in MM. [ABSTRACT FROM AUTHOR]