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Scientific observations indicate that an actively prevailing systemic condition could alleviate the pathology of another disease. Human pegivirus (HPgV), a highly ubiquitous flavivirus is believed to be associated with slow human immunodeficiency virus (HIV) disease progression, and has seldom been linked to hepatic pathology. In this study, we investigated whether HPgV seropositivity had any impact on surrogate markers of HIV disease progression in a cohort of HIV-infected HPgV seropositive ( n  = 28) and seronegative ( n  = 12) individuals who were prospectively evaluated for absolute CD4+ T cell counts, plasma viral load (PVL), liver enzymes, and plasma cytokine levels. The HIV PVL was relatively lower in HPgV seropositive than in HPgV seronegative HIV-infected subjects. Clinical markers of hepatic injury were significantly low among HPgV seropositive HIV-infected participants. HPgV seropositive individuals showed significantly higher levels of interleukin-7 (IL-7), and although not significant, the levels of IL-6 were lower among HPgV seropositive subjects. Spearman correlation analysis showed that the absolute CD4+T cell count was inversely correlated with HIV PVL. Exposure to HPgV appears to have a positive prognostic impact on the levels of surrogate biomarkers of HIV disease progression.

GB virus B (GBV-B) is a new world monkey-associated flavivirus used to model acute hepatitis C virus (HCV) infection. Critical for evaluation of antiviral or vaccine approaches is an understanding of the effect of HCV on the liver at different stages of infection. In the absence of longitudinal human tissue samples at defined time points, we have characterized changes in tamarins. As early as 2 weeks post-infection histological changes were noticeable, and these were established in all animals by 6 weeks. Despite high levels of liver-associated viral RNA, there was reversal of hepatic damage on clearance of peripheral virus though fibrosis was demonstrated in four tamarins. Notably, viral RNA burden in the liver dropped to near undetectable or background levels in all animals which underwent a second viral challenge, highlighting the efficacy of the immune response in removing foci of replication in the liver. These data add to the knowledge of GBV-B infection in New World primates which can offer attractive systems for the testing of prophylactic and therapeutic treatments and the evaluation of their utility in preventing or reversing liver pathology., (© 2020 Crown copyright. Journal of Medical Virology published by Wiley Periodicals LLC. This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.)

Oxidative stress is induced once the balance of generation and neutralization of reactive oxygen species (ROS) is broken in the cell, and it plays crucial roles in a variety of natural and diseased processes. Infections of Flaviviridae viruses trigger oxidative stress, which affects both the cellular metabolism and the life cycle of the viruses. Oxidative stress associated with specific viral proteins, experimental culture systems, and patient infections, as well as its correlations with the viral pathogenesis attracts much research attention. In this review, we primarily focus on hepatitis C virus (HCV), dengue virus (DENV), Zika virus (ZIKV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and tick-borne encephalitis virus (TBEV) as representatives of Flaviviridae viruses and we summarize the mechanisms involved in the relevance of oxidative stress for virus-associated pathogenesis. We discuss the current understanding of the pathogenic mechanisms of oxidative stress induced by Flaviviridae viruses and highlight the relevance of autophagy and DNA damage in the life cycle of viruses. Understanding the crosstalk between viral infection and oxidative stress-induced molecular events may offer new avenues for antiviral therapeutics., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Recent advances in the study of equine pegivirus (EPgV), Theiler's disease-associated virus (TDAV) and equine hepacivirus (EqHV) highlight their importance to veterinary and human health. To gain some insight into virus distribution, possible risk factors, presence of liver damage and genetic variability of these viruses in Brazil, we performed a cross-sectional study of EPgV and TDAV infections using a simultaneous detection assay, and assessed EqHV coinfection in different horse cohorts. Of the 500 serum samples screened, TDAV, EPgV and EPgV-EqHV were present in 1.6%, 14.2% and 18.3%, respectively. EPgV-positive horses were present in four Brazilian states: Espírito Santo, Mato Grosso do Sul, Minas Gerais and Rio de Janeiro. Serum biochemical alterations were present in 40.4% of EPgV-infected horses, two of them presenting current liver injury. Chance of infection was 2.7 times higher in horses ≤5 years old (p = 0.0008) and 4.9 times higher in horses raised under intensive production systems (p = 0.0009). EPgV-EqHV coinfection was 75% less likely in horses older than 5 years comparatively to those with ≤5 years old (p = 0.047). TDAV-positive animals were detected in different horse categories without biochemical alteration. Nucleotide sequences were highly conserved among isolates from this study and previous field and commercial product isolates (≥88% identity). Tree topology revealed the formation of two clades (pp = 1) for both EPgV and TDAV NS3 partial sequences. In conclusion, the widespread presence of EPgV-RNA suggests an enzootic infection with subclinical viremia in Brazil. Horse management can influence virus spread. This first report of TDAV-infected horses outside the USA reveals the existence of subclinical viremic horses in distant geographical regions. EPgV and TDAV have similar circulating isolates worldwide. These findings contribute to global efforts to understand the epidemiology and pathogenesis of these equine viruses., (© 2019 Blackwell Verlag GmbH.)

Despite drug advances for Hepatitis C virus (HCV), re-infections remain prevalent in high-risk populations. Unfortunately, the role of preexisting viral immunity and how it modulates re-infection is unclear. GBV-B infection of common marmosets is a useful model to study tissue immune responses in hepacivirus infections, and in this study we re-challenged 4 animals after clearance of primary viremia. Although only low-to-absent viremia was observed following re-challenge, GBV-B viral RNA was detectable in liver, confirming re-infection. Microscopic hepatic lesions indicated severe-to-mild lymphocyte infiltration and fibrosis in 3 out of 4 animals. Further, GBV-B-specific T cells were elevated in animals with moderate-to-severe hepatopathology, and up to 3-fold increases in myeloid dendritic and activated natural killer cells were observed after infection. Our data indicate that occult hepacivirus re-infections occur and that new liver pathology is possible even in the presence of anti-hepacivirus T cells and in the absence of high viremia., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Human Pegivirus-1 (HPgV-1) may have a beneficial impact on disease progression in human immunodeficiency virus-1 (HIV-1) infection. However, analysis of the genotypic diversity of HPgV-1 and its relevance to the progression of HIV-1 disease remains limited. A total of 1062 HIV-1-infected individuals were recruited in all sixteen prefectures of Yunnan province, China. The reverse transcription nested polymerase chain reaction (RT-nPCR), phylogenetic analyses, and clinical data analyses were used to detect HPgV-1 infection, determine genotype, and analyze HPgV-1 genotype impact on HIV-1 disease progression. The overall positive rate of HPgV-1 RNA was 23.4% (248/1062), and the frequency of HPgV-1 infection in injecting drug users (IDUs) (28.5%, 131/460) was significantly higher than in heterosexuals (19.4%, 117/602). Multiple genotypes were identified in 212 subjects with successful sequencing for the E2 gene, including genotype 7 (55.7%), genotype 3 (34.9%), genotype 4 (4.7%), genotype 2 (3.3%), and an unclassified group (1.4%). Moreover, genotype 7 predominated in IDUs, whereas genotype 3 was the most common in heterosexuals. Our results revealed that HPgV-1 genotype 7 groups exhibited significantly lower HIV-1 viral load and higher CD4⁺ cell counts. This finding suggests that HPgV-1 genotype 7 may be associated with a better progression of HIV-1 disease.

What do Zika, Dengue and West Nile viruses have in common? All are members of a family of viruses called the Flaviviruses. Here, Sonja Best lays out the essentials of this group of significant human pathogens., (Published by Elsevier Ltd.)

To study the effect of Tembusu virus (TMUV) infection on Cherry Valley Breeding ducks of different ages, 350 five-week-old ducks were divided into 14 groups. Ducks in seven experimental group were respectively infected with 1.265×10(5) mean embryo lethal dose (ELD50) of TMUV-AHQY strain (in 4.2mL) by intravenous route. Ducks in control groups were inoculated with Phosphate-buffered Saline (PBS) in the same way. Clinical symptoms, gross and microscopic lesions, viral loads and serum antibodies were detected and recorded for 20days after infection. Some ducks infected at 7 and 21 week s of age showed severe clinical symptoms including depression and inappetence, and no obvious clinical symptoms were seen in other week-old infected ducks. Severe gross lesions including hepatomegaly, meningeal congestion, myocardial hemorrhage, intestinal, myocardial and pulmonary edema were observed in ducks infected at 7, 18 and 21 weeks of age. No or mild gross lesions were observed in ducks infected at 14 and 16 weeks of age. The main microscopic lesions including hyperaemia, degeneration and necrosis of different cells and inflammatory cellular infiltration mainly consisting of mononuclear cells or lymphocytes were observed in ducks infected at 7 and 21 week of age. But relatively intact structures and rare lymphocytic infiltration were presented in ducks infected at 14 and 16 weeks of age. Viral antigen was more frequently observed in organ slices collected from 7 week-old infected ducks and few positive staining was found in 14 and 16 week-old infected ducks. Less viral loads in different tissues and swabs were detected by a quantitative real-time PCR assay. The level of viral loads in the tissues of ducks infected at 14 and 16 weeks of age was very lower than that of ducks infected at 7 and 21 weeks of age. Meanwhile, less viral copy numbers were detected in swab samples collected from 14 and 16 week-old infected ducks. Ducks infected at 14-week-old developed significantly higher serum neutralizing antibody titers than those infected at other week of age. These results indicated that the effect of TMUV infection on Cherry Valley ducks is partly related to weeks of age. 7-10 week-old and 18-21 week-old ducks were more susceptible to TMUV infection, but 14-16 week-old ducks were more resistant to this disease., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Unlabelled: A lack of immunocompetent-small-primate models has been an obstacle for developing hepatitis C virus (HCV) vaccines and affordable antiviral drugs. In this study, HCV/GB virus B (GBV-B) chimeric virus carrying the major nonstructural proteins NS2 to NS4A (HCV NS2 to -4A chimera) was produced and used to infect common marmosets, since HCV NS2 to NS4A proteins are critical proteases and major antigens. Seven marmosets were inoculated intrahepatically with HCV NS2 to -4A chimera RNA for primary infection or intravenously injected with chimera-containing serum for passage infection. Three animals used as controls were injected with phosphate-buffered saline (PBS) or GBV-B, respectively. Six of seven HCV NS2 to -4A chimera-infected marmosets exhibited consistent viremia and one showed transient viremia during the course of follow-up detection. All six infected animals with persistent circulating viremia presented characteristics typical of viral hepatitis, including viral RNA and proteins in hepatocytes and histopathological changes in liver tissue. Viremia was consistently detected for 5 to 54 weeks of follow-up. FK506 immunosuppression facilitated the establishment of persistent chimera infection in marmosets. An animal with chimera infection spontaneously cleared the virus in blood 7 weeks following the first inoculation, but viral-RNA persistence, low-level viral protein, and mild necroinflammation remained in liver tissue. The specific antibody and T-cell response to HCV NS3 in this viremia-resolved marmoset was boosted by rechallenging, but no viremia was detected during 57 weeks of follow-up. The chimera-infected marmosets described can be used as a suitable small-primate animal model for studying novel antiviral drugs and T-cell-based vaccines against HCV infection., Importance: HCV infection causes approximately 70% of chronic hepatitis and is frequently associated with primary liver cancer globally. Chimpanzees have been used as a reliable primate model for HCV infection, but ethical considerations have restricted their utility in biomedical research. GB virus B (GBV-B) is a flavivirus related to HCV. It can infect common marmosets, a New World small primate, and induces viral hepatitis similar to HCV infection in humans. To minimize differences between GBV-B and HCV, we generated HCV NS2 to -4A/GBV-B chimeric viruses and established a chimera-infected marmoset model. HCV NS2 to -4A chimera-infected marmosets provide a small-animal model for evaluating novel antiviral drugs targeting HCV NS3-NS4A protease and T-cell-based HCV vaccines., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Background: Viral encephalitis is a common cause of lethal infections in humans, and several different viruses are documented to be responsible. Rocio virus is a flavivirus that causes a severe lethal encephalitis syndrome in humans and also mice, providing an interesting model to study the CNS compartmentalized immune response. Interleukin 33 (IL-33), a member of the IL-1 family, is an immunomodulatory cytokine that is highly expressed in the CNS. However, the role of IL-33 on viral encephalitis remains unclear. Therefore, we aimed to explore how the IL-33/ST2 axis regulates the local immune response during Rocio virus infection., Methods: Wild-type (WT), ST2 (ST2(-/-)), and nitric oxide synthase-deficient mice (iNOS(-/-)) and Stat6 (Stat6(-/-))-deficient mice were infected with different concentrations of the Rocio virus by intraperitoneal route, the cytokine mRNA level in CNS was analyzed by qPCR, and cellular immunophenotyping was performed on infected mice by the flow cytometry of isolated CNS mononuclear cells., Results: We have shown that the mRNA expression of IL-33 and ST2 receptors is increased in the CNS of Rocio virus-infected WT mice and that ST2(-/-) mice showed increased susceptibility to infection. ST2 deficiency was correlated with increased tissue pathology, cellular infiltration, and tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ) mRNA levels and higher viral load in the CNS, compared with wild-type mice. The increased Th1 cytokine levels released in the CNS acted on infiltrating macrophages, as evidenced by flow cytometry characterization of cellular infiltrates, inducing the expression of iNOS, contributing to brain injury. Moreover, iNOS(-/-) mice were more resistant to Rocio virus encephalitis, presenting a lower clinical score and reduced mortality rate, despite the increased tissue pathology., Conclusions: We provide evidences of a specific role for IL-33 receptor signaling in nitric oxide induction through local IFN-γ modulation, suggesting that nitric oxide overproduction might have an important role in the progression of experimental viral encephalitis.

Human Pegivirus (HPgV, formally GB virus C) infects lymphocytes and NK cells in vivo, and infection is associated with reduced T cell and NK cell activation in HIV-infected individuals. The mechanism by which HPgV inhibits NK cell activation has not been assessed. Following IL-12 stimulation, IFNγ expression was lower in HIV-HPgV co-infected subjects compared to HIV mono-infected subjects (p=0.02). In addition, HPgV positive human sera, extracellular vesicles containing E2 protein, recombinant E2 protein and synthetic E2 peptides containing a predicted Tyk2 interacting motif inhibited NK cell IL-12-mediated IFNγ release. E2 protein also inhibited Tyk2 activation following IL-12 stimulation. In contrast, cytolytic NK cell function was not altered by HPgV. Inhibition of NK cell-induced proinflammatory/antiviral cytokines may contribute to both HPgV persistence and reduced immune activation during HIV-coinfection. Understanding mechanisms by which HPgV alters immune activation may contribute towards novel immunomodulatory therapies to treat HIV and inflammatory diseases., (Published by Elsevier Inc.)

GB virus C (GBV-C), a pan-lymphotropic flavivirus capable of persistent infection, is associated with prolonged survival and reduced T-cell activation in HIV-infected patients. GBV-C was associated with reduced CD56brt/CD16- natural killer cell and monocyte activation, and a trend toward reduced B-cell activation by measuring cell surface activation markers or HIV entry coreceptors. The GBV-C association was independent of HIV viral load. Thus, GBV-C may influence non-T-cell immune activation in individuals with HIV infection.

An outbreak of egg drop disease occurred in many chicken and goose farms in China in 2011. By using an NS5-specific reverse transcriptase PCR (RT-PCR), we found that 56% of chicken and 38% of goose samples were positive for Tembusu-like virus (TMUV). Isolates showed high sequence homology to duck TMUVs, and chickens and geese showed signs of egg drop disease after experimental infection with duck TMUV. Our data suggest TMUV has adapted in domestic birds.

Rocio virus (ROCV) is a flavivirus, probably transmitted by Culex mosquitoes and maintained in nature as a zoonosis of wild birds. Rocio virus caused a human epidemic of severe encephalitis that lasted from 1973 to 1980 in the Ribeira valley, in the southeastern coast of Brazil. After this outbreak, serologic evidence of ROCV circulation has been reported and public health authorities are concerned about a return of ROCV outbreaks in Brazil. We show here a study on the pathogenesis and the physiopathology of ROCV disease in the central nervous system of a Balb/C young adult mice experimental model. The animals were intraperitoneally infected by ROCV and followed from 0 to 9 days after infection, when all of them died. Nervous tissue samples were collected from infected animals for immunohistochemistry and molecular biology analysis. We observed the virus in the central nervous system, the inflammatory changes induced by Th1 and Th2 cytokines, and the final irreversible damage of nervous tissues by neuronal degeneration and apoptosis. These findings can help to better understand the pathogenesis and physiopathology of the human meningoencephalomyelitis by ROCV and other flaviviruses.

In late summer 2006 considerable mortality in wild and captive Passeriformes and Strigiformes was observed in Zurich, Switzerland. All animals were found in a range of 2 km(2). Observed clinical signs involved depression, ruffled plumage, incoordination, seizures and peracute death. Nutritional status was generally moderate to poor in wild birds, and variable in captive animals. Necropsy showed marked splenomegaly, a mild hepatomegaly, and pulmonary hyperemia in most animals. Histopathologic lesions were very discrete and consisted mainly of neuronal necrosis, leucocytolysis in and around the brain blood vessels, and miliary liver necrosis. The diagnosis Usutu virus (USUV) infection was established by USUV-specific immunohistochemistry and reverse transcription-polymerase chain reaction. Partial nucleotide sequence comparisons revealed>99% identity between the viruses that emerged in Zurich in 2006, in Vienna in 2001, and in Budapest in 2005. Since 2008 a significantly lower mortality was observed in wild Passeriformes, but USUV infection was confirmed for the first time beyond Zurich city limits. Indoor housing and regular treatment against ectoparasites are likely to have prevented acute USUV disease in captive Strigiformes. USUV is a mosquito-borne flavivirus causing fatalities in various avian species. After the initial European outbreaks in Austria in 2001 it appears that the virus has extended its range in Central Europe and has established a transmission cycle between local bird and mosquito species. Further episodes of increased avian mortality in the forthcoming years, with impact on wild and captive bird populations, predominantly Passeriformes and Strigiformes, can be anticipated. Furthermore, the possibility of broader dispersal of USUV in Europe during the next mosquito seasons must be considered and an increased mortality in Passeriformes and Strigiformes must be expected until protective "flock immunity" is established. Collections of valuable and endangered Passeriformes and Strigiformes, especially young of the year, should therefore be housed indoors or treated against ectoparasites at acceptable intervals between July and September each year., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Aplastic anemia (AA) is a serious and rare disorder characterized by a hypocellular bone marrow. Hepatitis associated aplastic anemia (HAAA) is a variant of aplastic anemia in which aplastic anemia follows an acute attack of hepatitis. Several reports have noted an association between HGV and hepatitis-associated aplastic anemia besides other hepatitis causing viruses., Case Presentation: A female girl of age 11 year with a history of loose motion for one month, vomiting for last 15 days and poor oral intake for last few days is reported here. The physical examination presents fever, pallor whereas bleeding, hepatomegaly, Splenomegaly and bruising were absent, abdominal ultrasonography confirmed the absence of hepatomegaly, Splenomegaly and lymphodenopathy. The laboratory investigation parameters were: haemoglobin 6.2 g/L, total leucocytes count 1.51, neutrophils 0.47%, absolute reticulocyte count 0.5%, Monocytes 0.16%, red cell count 3.2 mil/uL, Picked cell volume (PCV) 30.13%, Mean Corpuscular Volume (MCV) 78 fL, Mean Corpuscular Hemoglobin (MCH) 26.3 pg. The liver enzymes were alanine aminotransferease (ALT) 98 IU/L, aspartate aminotransferase (AST) 114 IU/L. Serologic and molecular tests for hepatitis A, B, C, D, E, TTV, B19 were negative, whereas HGV RNA PCR test was found positive for hepatitis G virus. The bone marrow aspirate and trephine biopsy examination revealed hypo- cellularity, erythropoiesis, myelopoiesis and megakaryopoiesis., Conclusion: HAAA is an uncommon but severe condition, which may occur following idiopathic cases of acute hepatitis. Our finding suggests the involvement of HGV in the development of aplastic anemia. In patients presenting with pancytopenia after an episode of acute hepatitis, the definitive diagnosis should be considered and confirmed by RT-PCR and if possible by bone marrow biopsy.

GB virus C (GBV-C) is a common, non-pathogenic human virus that infects lymphocytes. Persistent GBV-C infection of humans with coexistent human immunodeficiency virus (HIV) infection is associated with prolonged survival, and GBV-C replication inhibits HIV replication in vitro. A GBV-C virus variant was identified in chimpanzees in 1998 and was named GBV-C(trog) or GBV-C(cpz). The prevalence and natural history of GBV-C in chimpanzees remains uncharacterized. We examined the sera from 235 captive chimpanzees for the presence of GBV-C viraemia, viral persistence and clearance, E2 antibody kinetics and RNA sequence diversity. Sequences from six isolates shared more sequence identity with GBV-C(cpz) than with human GBV-C. The prevalence of GBV-C(cpz) viraemia and E2 antibody in chimpanzees (2.5 and 11 %, respectively) was similar to human GBV-C prevalence in healthy human blood donors (1.8 and 9 %, respectively). Persistent GBV-C(cpz) infection occurred in two of the six viraemic animals and was documented for 19 years in one animal. Host subspecies troglodyte GBV-C isolates and published verus GBV-C isolates shared a high degree of sequence identity, suggesting that GBV-C in chimpanzees should be identified with a chimpanzee designation (GBV-C(cpz)). The prevalence and natural history of chimpanzee GBV-C variant (GBV-C(cpz)) appears to be similar to human GBV-C infection. The chimpanzee could serve as an animal model to study HIV-GBV-C co-infection.

Flaviviruses such as tick-borne encephalitis virus, Japanese encephalitis virus, West Nile virus, and St. Louis encephalitis virus are important neurotropic human pathogens, typically causing a devastating and often fatal neuroinfection. Flaviviruses induce neuroinflammation with typical features of viral encephalitides, including inflammatory cell infiltration, activation of microglia, and neuronal degeneration. Development of safe and effective live-virus vaccines against neurotropic flavivirus infections demands a detailed knowledge of their neuropathogenesis in a primate host that is evolutionarily close to humans. Here, we used computerized morphometric analysis to quantitatively assess the cellular inflammatory responses in the central nervous system (CNS) of rhesus monkeys infected with three antigenically divergent attenuated flaviviruses. The kinetics, spatial pattern, and magnitude of microglial activation, trafficking of T and B cells, and changes in T cell subsets within the CNS define unique phenotypic signatures for each of the three viruses. Our results provide a benchmark for investigation of cellular inflammatory responses induced by attenuated flaviviruses in the CNS of primate hosts and provide insight into the neuropathogenesis of flavivirus encephalitis that might guide the development of safe and effective live-virus vaccines.

The aim of this study was to evaluate the effect of GB virus C on laboratory markers and histological parameters among HIV-seropositive patients coinfected with HCV. Lower degrees of hepatic lesions were observed in the triple-infected patients, in comparison with HIV-HCV coinfected patients who were negative for GBV-C RNA.

Aim: To explore the pathogenicity and infectivity of hepatitis G virus (HGV) by observing replication and expression of the virus, as well as the serological and histological changes of Macaca mulatta infected with HGV genomic RNA or HGV RNA-positive serum., Methods: Full-length HGV cDNA clone (HGVqz) was constructed and proved to be infectious, from which HGV genomic RNA was transcribed in vitro. Macaca mulatta BY1 was intra-hepatically inoculated with HGV genomic RNA, HGV RNA-positive serum from BY1 was intravenously inoculated into Macaca mulatta BM1, and then BB1 was infected with serum from BM1. Serum and liver tissue were taken regularly, and checked with RT-PCR, in situ hybridization and other immunological, serological, histological assays., Results: Serum HGV RNA was detectable in all the 3 Macaca mulattas, serological and histological examinations showed the experimental animals had slightly elevated alanine transaminase (ALT) and developed HGV viremia during the infectious period. The histology, immunohis-tochemistry, and in situ hybridization in liver tissues of the inoculated animals demonstrated a very mild hepatitis with HGV antigen expression in cytoplasm of hepatocytes. RT-PCR and quantitative PCR results showed that HGV could replicate in liver., Conclusion: The genomic RNA from full-length HGV cDNA is infectious to the Macaca mulatta and can cause mild hepatitis. HGV RNA-positive serum, from HGV RNA inoculated Macaca mulatta, is infectious to other Macaca mulattas. Macaca mulatta is susceptible to the inoculated HGV, and therefore can be used as an experimental animal model for the studies of HGV infection and pathogenesis.

Usutu virus (USUV), a mosquito-borne flavivirus of the Japanese encephalitis virus group has been responsible for avian mortality in Austria since 2001. In the present study, the neuropathogenicity and neuroinvasiveness of USUV for 1-week-old suckling mice was investigated. After intraperitoneal inoculation, clinical signs like depression, disorientation, paraplegia, paralysis and coma were observed between 6 and 11 days post infection. Histologically, there was widespread neuronal apoptosis especially in the brain stem. Inflammatory infiltrates were scarce. Apoptosis was also present in white matter of cerebellum, medulla and spinal cord, and was frequently accompanied by primary demyelination. While apoptosis of neurons was clearly associated with presence of viral signals, the cause of apoptosis of white matter cells was more ambiguous. However, focal immunostaining was found in the white matter, especially in the spinal cord. As with all flaviviruses, USUV proved to be neuropathogenic for mice. In contrast to other flaviviruses, neuroinvasion occurred only in animals that were not older than 1 week at the time of inoculation. While neuronal apoptosis is a general aspect of flavivirus pathogenicity, demyelination seems to be a unique feature of USUV infection.

In vivo imaging of structural changes in the brain of patients with encephalitis has become an important aid in diagnostic and therapeutic procedures. Diffusion-weighted magnetic resonance imaging (DWI) was employed to quantitate regional and whole-brain diffusion-weighted MRI changes in a hamster model for acute flavivirus encephalitis. The regional apparent diffusion coefficient (ADC) was determined in hyperintense regions seen on T2-weighted images (i.e., the thalamic area and the temporal lobe), but anatomical variation and structural heterogeneity of encephalitic lesions severely impeded the placement of regions of interest (ROI). Therefore, quantitative whole-brain diffusion-weighted imaging was carried out and revealed a significantly reduced ADC (P = .02) in the brain of hamsters with acute encephalitis (n = 7) as compared to that of healthy, uninfected controls (n = 3). Furthermore, the ADC histogram demonstrated a reduced peak height and center of gravity during the acute encephalitis. Our findings could further support the use of diffusion-weighted imaging for in vivo monitoring of acute flavivirus encephalitis and for the study of therapeutic approaches.

GB virus type C (GBV-C) infection was studied in a convenience sample of 75 antiretroviral (ART)-naive African mothers with human immunodeficiency virus infection and their infants. GBV-C RNA was extracted from serum and amplified by reverse-transcriptase polymerase chain reaction. Twenty-seven (36%) of these 75 HIV-infected women tested positive for GBV-C RNA. To study transmission dynamics, we chose a random subsample of 20 of these women and their infants. In this cohort, there was evidence of postnatal transmission of GBV-C; however, it was not possible to demonstrate evidence of in utero or intrapartum transmission. In this pilot observational study, transmission of HIV from mother-to-infant occurs independently of the GBV-C infection status of the mother. The immunological indices measured tend to suggest an association with protection and or delayed progression of HIV disease in GBV-C-infected mothers.

Progress in understanding the pathogenesis of hepatitis C virus (HCV) has been slowed by the absence of tractable small animal models. Whereas GB virus B (GBV-B, an unclassified flavivirus) shares a phylogenetic relationship and several biologic attributes with HCV, including hepatotropism, it is not known to cause persistent infection, a hallmark of HCV. Here, we document persistent GBV-B infection in one of two healthy tamarins (Saguinus oedipus) inoculated intrahepatically with infectious synthetic RNA. High-titer viremia (108 to 109 genome equivalents per ml) and transiently elevated serum alanine transaminase activities were present from weeks 4 to 12 postinoculation in both animals. However, whereas GBV-B was eliminated from one animal by 20 weeks, the second animal remained viremic (103 to 107 genome equivalents per ml) for >2 years, with alanine transaminase levels becoming elevated again before spontaneous resolution of the infection. A liver biopsy taken late in the course of infection demonstrated hepatitis with periportal mononuclear infiltrates, hepatocellular microvesicular changes, cytoplasmic lipid droplets, and disordered mitochondrial ultrastructure, findings remarkably similar to chronic hepatitis C. GBV-B-infected hepatocytes contained numerous small vesicular membranous structures resembling those associated with expression of HCV nonstructural proteins, and sequencing of GBV-B RNA demonstrated a rate of molecular evolution comparable to that of HCV. We conclude that GBV-B is capable of establishing persistent infections in healthy tamarins, a feature that substantially enhances its value as a model for HCV. Mitochondrial structural changes and altered lipid metabolism leading to steatosis are conserved features of the pathogenesis of chronic hepatitis caused by these genetically distinct flaviviruses.

Recent reports that co-infection with GB virus C (GBV-C) is associated with a reduced mortality in HIV-infected individuals, a slower progression to AIDS, and lower HIV viral loads, suggest a potential role of GBV-C as therapy for HIV infection. Although not known to cause any human disease, GBV-C was only recently discovered and prospective studies assessing long-term consequences of infection have not been completed. Our understanding of the host-viral interactions between humans and GBV-C is in its infancy. Further research into the intriguing relationship between GBV-C and HIV is needed before intentional inoculation of GBV-C into individuals infected with HIV should proceed. This essay explores the history of the once-popular treatment of paretic tertiary syphilis with the blood-borne pathogen Plasmodium vivax, providing a historical perspective on the current state of affairs between GBV-C and HIV. A brief review of GBV-C biology and human infection is followed by a discussion of the current challenges facing the use of this organism to treat HIV.

As little is known about liver histology in the co-infection of hepatitis C virus (HCV) and hepatitis G virus (HGV), HGV RNA was investigated in 46 blood donors with hepatitis C, 22 of them with liver biopsy: co-infection HCV / HGV (n = 6) and HCV isolated infection (n = 16). Besides staging and grading of inflammation at portal, peri-portal and lobular areas (Brazilian Consensus), the fibrosis progression index was also calculated. All patients had no symptoms or signs of liver disease and prevalence of HGV / HCV co-infection was 15.2%. Most patients had mild liver disease and fibrosis progression index, calculated only in patients with known duration of infection, was 0.110 for co-infection and 0.130 for isolated HCV infection, characterizing these patients as "slow fibrosers". No statistical differences could be found between the groups, although a lesser degree of inflammation was always present in co-infection. In conclusion co-infection HCV / HGV does not induce a more aggressive liver disease, supporting the hypothesis that HGV is not pathogenic.

Objective: To observe the long-term effect of hepatitis G virus (HGV) coinfection on hepatic pathological changes of patients with chronic hepatitis B (CHB) and explore the pathogenicity of HGV., Methods: Menghini method liver biopsy was performed on 45 patients with CHB twice with an interval of 5 years on a voluntary basis. The liver tissue of 21 cases was HGV nonstructural region 5 (HGV NS5) antigen positive by peroxidase anti-peroxidase (PAP) immunohistochemical staining assay (HGV coinfection group) in these two tests, and 24 cases were negative (HGV noncoinfection group). There was no significant difference in age, sex, course of disease, amount of serum HBV-DNA by competitive quantitative polymerase chain reaction assay and severity of hepatic pathological leisions between these two groups (P < 0.05) and they were treated with the same scheme and without sustained curative effeect. The hepatic pathological changes of the two groups after 5 years were compared and analysed retrospectively., Results: There was no significant difference in basic hepatic pathological change, severity of inflammatory activity grade and fibrosis stage in these two groups. The numbers of cases of inflammatory activity grade G1, G2, G3, and G4 were 3, 7, 7, and 4 in HGV coinfection group, and 5, 8, 7, and 4 in HGV noncoinfection group in the beginning of observation; and were 3, 5, 7, and 6 in HGV coinfection group, and 4, 6, 8, and 6 in HGV noncoinfection group after 5 years. The numbers of cases in fibrosis stages S1, S2, S3, and S4 were 4, 7, 7, and 3 in HGV coinfection group, and 6, 8, 6, and 4 HGV noncoinfection group in the beginning of observation; and were 3, 6, 5, 7 in HGV coinfection group, and 4, 7, 5, and 8 in HGV noncoinfection group after 5 years (P > 0.05)., Conclusion: HGV coinfection does not lead to the activation of hepatic pathological changes and does not speed up the progression of fibrosis in patients with CHB. HGV coinfection does not play an obvious role in long-term hepatic pathological changes of patients with CHB. HGV has at most a mild hepatic pathogenicity.

Aim: To study the pathogenicity of hepatitis G virus (HGV) and observe the genesis and pathological process of hepatitis G., Methods: HGV-RNA in serum was detected by RT-PCR assay. The immunohistochemical assays of liver tissue were performed with HGV monocoloned antibody (McAb) expressed from the region of HGV NS5 nucleic acid sequence. The clinical and pathological data of 52 patients with hepatitis G were discussed. In animal experiment, the Chinese Rhesus monkeys were infected with the serum of a patient with HGV infection. And the dynamic changes in serology and liver histology of animals were observed., Results: One hundred and fifty-four patients with HGV-RNA positive were selected from 1552 patients with various kinds of hepatitis. Of 154 patients with HGV infection, 52 were infected with HGV only, which accounted for 33.8 (52/154) and 102 with positive HGV-RNA were super-infected with other hepatitis viruses, which accounted for 66.2 (102/154). The clinical and pathological observation showed that the acute and chronic hepatitis could be induced by HGV. The slight abnormality of transaminases ALT and AST in serum of monkeys lasted nearly 12 months and histological results showed a series of pathological changes., Conclusion: HGV is a hepatotropic virus and has pathogenicty.

Objective: To elucidate the pathogenicity of GBV-C/HGV in causing viral hepatitis., Methods: The sera and bioptic liver tissues, which involved 8 cases of the second liver puncture with an interval of 2 years, from 24 cases of single GBV-C/HGV RNA positive patients were observed for more than 2 years. GBV-C/HGV RNA in the sera and liver tissues was detected by using RT-PCR and in situ hybridization, respectively. Under light and electron microscope, the pathology of the liver tissues was observed., Results: At the beginning of the observation, the mean serum alanine transaminase(ALT) level was 60.17 IU/ml(range, 42.00-87.00 IU/ml), and the positive rates of anti-E2 antibody and GBV-C/HGV RNA in the sera and NS3 and/or NS5 in the liver tissues were 4.17%, 75.00% and 54.17%, respectively. In all the examined specimens, 79.17% of them showed mild acute or chronic hepatitis, mainly presenting with degeneration of hepatocytes, mild portal inflammation. GBV-C/HGV RNA and its NS3 and/or NS5 antigens were mainly detected in hepatocytes and a few mononuclear cells. In contrast, after more than 2 years, the natural change rate (negative rate of GBV-C/HGV) of 24 cases was 66.67% (P < 0.001). 75.00% had normal ALT level (P < 0.001) and 41.67% of anti-E2 antibody in the patients was positive (P < 0.001). Through histological observation, besides 2 cases of liver tissues showing very mild hydropic degeneration, there were no abnormal findings in 8 cases of the second liver biopsy., Conclusion: GBV-C/HGV could induce mild and self-limited hepatitis, which showed that GBV-C/HGV may be a light and self-limited pathogenic agent to human liver. E2 antibody appearance may indicate a recovery and provide a protection from GBV-C/HGV infection. Whether there is any other recovery marker in serum requires further study.

Objective: Our objective is to study the pathogenicity of the single HGV infection., Methods: The ELISA was used to check the serum anti-HGV antibody of 36 cases. Immunohistochemistry staining of hepatic tissue was conducted by using HGV NS5 McAb in 20 single HGV infected patients who were further confirmed by clinical diagnosis and pathological evidence. These patients included 10 cases of acute hepatitis, 7 cases of chronic hepatitis, 1 cases of subacute severe hepatitis and 2 cases of chronic severe hepatitis., Results: (1) Clinical manifestation: Acute hepatitis occurred abruptly, accompanied with fever, inertia, nausea and sometimes with vomiting and oil disgust. Chronic hepatitis developed slowly and presented mild symptoms. Severe hepatitis presented an acute onset, extreme fatigue, serious gastrointestinal symptoms, or even hepatic coma developed. (2) Changes of ALT and AST: ALT and AST increased slightly in chronic hepatitis and moderately in acute and severe hepatitis. The disproportion between ALT and BiL sometimes occurred in severe hepatitis. (3) Pathological changes in hepatic tissue: Acute hepatitis was characterized by hepatocyte swelling and inflammatory cells infiltrated in portal duct areas. Chronic hepatitis was identified by hepatocyte swelling, piecemeal necrosis or spotty necrosis, slight infiltration of inflammatory cell in portal duct areas and fibrosis. Severe hepatitis appeared as hepatic cell necrosis, inflammatory cell infiltration and slight fibrosis., Conclusions: Infection of HGV can give rise to acute hepatitis, chronic hepatitis and severe hepatitis.

Objective: To study the clinical, enzymatic and liver pathological changes in patients with hepatitis G virus (HGV) infection., Methods: RT- nested PCR was applied to detect HGV RNA in 368 patients with hepatic diseases. The liver biopsy tissue from one liver cirrhosis patient with simple HGV infection was examined., Results: Simple HGV RNA positive were found in 7 cases of 71 acute hepatitis jaundice, in 22 cases of 155 chronic hepatitis and in 3 cases of 51 liver cirrhosis. The immunohistochemistry of the liver biopsy tissue from a liver cirrhosis patient showed HGV NS5 antigen positive. However, HGV infection might occur simply or in combination with hepatitis B or C virus or super infected., Conclusions: HGV RNA could be detected in acute hepatitis jaundice, chronic hepatitis, hepatitis B or C carriers, liver cirrhosis and hepatocellular carcinoma. HGV is proved to be a hepatotropic virus by pathological examination and immunohistochemistry, the virus located in the cytoplasm of the liver cells. It may cause chronic hepatitis and even liver cirrhosis, so HGV is pathogenic to liver tissue.

Objective: To study the infection due to hepatitis G virus (HGV) in liver tissues of patients with acute hepatitis and to investigate its pathogenicity., Methods: HGV NS5 antigen was detected by using immunohistochemical method in the liver biopsy tissues of patients with acute hepatitis but serologically negative to hepatitis virus antigens from A to E. The clinical and pathological data were also analysed., Results: 37 samples were tested, HGV NS5 antigen was detected in 14 (37.8%). 4 of the 14 were positive for HGV NS5 antigen alone (acute hepatitis G group) and 10 other cases were also positive for HBsAg, hepatitis C virus (HCV) NS3 antigen or EB virus antigen (superinfection group). 7 cases were HBsAg positive alone (acute hepatitis B group) and the remaining 16 cases were negative for all the antigens mentioned above (non-A - G hepatitis group). There was no difference among the 4 groups in the detecting rate of Fas antigen, histological activity index (HAI), serum alanine transferase (ALT) and total bilirubin (TBil)., Conclusion: It is suggested that HGV appears to play some role in the pathogenesis of acute viral hepatitis and the degree of liver injury in acute hepatitis G may be as severe as that of hepatitis caused by other types of viruses.

Objective: To study the genesis, development and pathogenesis of hepatitis G., Methods: The Chinese Rhesus monkeys were intravenously injected with the serum from a hepatitis G patient only with HGV RNA positive. The dynamic changes of serum and liver tissues of the animals were observed before and after infection. Also the immunohistochemical study were done with monocolonal antibody against NS5 gene antigen of HGV. One male monkey was dissected and the internal organs were taken for histological examination 18 months after infection., Results: Serum ALT and AST became increasing 30 days after infection and showed abnormal continuously for 9 months. Spotty and focal necrosis and piecemeal necrosis were found in liver tissue from 2 to 18 months after infection. Positive staining of HGV antigen was present in cytoplasm of liver cells by immunohistochemistry. Histological observation showed that the internal organs were normal except the liver tissue in which the damages were similar with that in hepatitis., Conclusion: The successful infection of Chinese Rhesus monkey by serum from hepatitis G patient can used as a good animal model for the study of hepatitis G.