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1.
Emerg Microbes Infect ; 9(1): 651-663, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32192415

RESUMO

Equine parvovirus-hepatitis (EqPV-H) has recently been associated with cases of Theiler's disease, a form of fulminant hepatic necrosis in horses. To assess whether EqPV-H is the cause of Theiler's disease, we first demonstrated hepatotropism by PCR on tissues from acutely infected horses. We then experimentally inoculated horses with EqPV-H and 8 of 10 horses developed hepatitis. One horse showed clinical signs of liver failure. The onset of hepatitis was temporally associated with seroconversion and a decline in viremia. Liver histology and in situ hybridization showed lymphocytic infiltrates and necrotic EqPV-H-infected hepatocytes. We next investigated potential modes of transmission. Iatrogenic transmission via allogeneic stem cell therapy for orthopedic injuries was previously suggested in a case series of Theiler's disease, and was demonstrated here for the first time. Vertical transmission and mechanical vectoring by horse fly bites could not be demonstrated in this study, potentially due to limited sample size. We found EqPV-H shedding in oral and nasal secretions, and in feces. Importantly, we could demonstrate EqPV-H transmission via oral inoculation with viremic serum. Together, our findings provide additional information that EqPV-H is the likely cause of Theiler's disease and that transmission of EqPV-H occurs via both iatrogenic and natural routes.


Assuntos
Hepatite Viral Animal/virologia , Doenças dos Cavalos/virologia , Fígado/virologia , Infecções por Parvoviridae/veterinária , Parvovirus/fisiologia , Animais , Dípteros/virologia , Fezes/virologia , Feminino , Hepatite Viral Animal/patologia , Hepatite Viral Animal/transmissão , Hepatócitos/patologia , Hepatócitos/virologia , Doenças dos Cavalos/patologia , Doenças dos Cavalos/transmissão , Cavalos , Transmissão Vertical de Doença Infecciosa , Insetos Vetores/virologia , Fígado/patologia , Linfócitos , Masculino , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/virologia , Boca/virologia , Necrose , Infecções por Parvoviridae/patologia , Infecções por Parvoviridae/transmissão , Infecções por Parvoviridae/virologia , Parvovirus/isolamento & purificação , Parvovirus/patogenicidade , Tropismo Viral , Viremia , Eliminação de Partículas Virais
2.
Mikrobiyol Bul ; 54(1): 110-119, 2020 Jan.
Artigo em Turco | MEDLINE | ID: mdl-32050882

RESUMO

Anti-HCV and HCV RNA tests are used in laboratory diagnosis of hepatitis C virus (HCV) infections. False positive results are frequently observed in anti-HCV tests used as screening tests in societies with low prevalence of HCV. The HCV RNA test, which is a confirmatory test, is not performed in every laboratory because it is a high-cost and high-tech test, which can lead to delay in the diagnosis and treatment of patients. In this study, it was aimed to obtain an optimal anti-HCV S/CO value in our laboratory for demonstrating true antibody positivity and viremia in patients by analyzing the relationship between anti-HCV, alanine aminotransferase (ALT) and HCV RNA using retrospective data. Between July 2014 and July 2017, 754.190 anti-HCV tests were performed. Patients aged 18 years or older who were reactive with anti-HCV and those with simultaneous HCV RNA and ALT prompts were included in the study. The second generation CMIA (Abbott, USA) method was used for anti-HCV detection. For quantitative HCV RNA analysis, viral nucleic acid extraction was performed with the QIAsymphony SP/AS (Qiagen, Germany) using the QIAsymphony DSP Virus/Pathogen Midi Kit; and PCR was performed by Rotor-Gene Q (Qiagen, Germany) using Artus HCV QS-RGQ kit. ARCHITECT c and AEROSET systems (Abbott, USA) were used for ALT measurement. HCV genotype determination (622 cases) was performed using GenoSen's HCV Genotyping 1/2/3/4 RG qualitative real time PCR kit (Corbett Research, Australia) and GEN-C 2.0 Reverse Hybridization Strip Assay (NLM Diagnostics, Italy) kit at different periods covered by our study. The optimal threshold value for the relationship between anti-HCV, ALT and HCV RNA was selected based on ROC analysis. Statistical significance was accepted as p<0.05. Of the anti-HCV test results, 10.679 were found to be reactive. 1754 data of 1290 cases with anti-HCV reactivity who were simultaneously tested for HCV RNA and ALT in the same serum were evaluated. Of these, 742 (42%) were found to be HCV RNA positive and 1012 (58%) were found to be HCV RNA negative. ALT and anti-HCV levels of those who were positive for HCV RNA were significantly higher than those with negative HCV RNA (p= 0.001). The threshold point for anti-HCV S/CO according to HCV RNA was found to be 7.13 (sensitivity of 97.4%, specificity of 50.3%, positive predictive value 58.9%, negative predictive value 96.4%), and the cut-off point for ALT was found to be 27.5 IU/L (sensitivity of 77.6%, specificity of 80.8%). For HCV RNA positivity, the area under the ROC curve for anti-HCV and ALT was significantly higher than 0.5 (p= 0.001). No statistically significant difference was found between HCV genotypes in terms of ALT and anti-HCV levels. By using our new threshold in the laboratory workflow, the need to verify with HCV RNA can be reduced, especially in some patients who have been screened for antiHCV for screening purposes. Anti-HCV values below 7.13 S/CO, considering the high negative predictive value of this threshold; a false positive result in a patient presenting for screening can be predicted without waiting for the HCV RNA result. In anti-HCV reactivities determined above 7.13, the possibility of absence of viremia should be considered due to the low positive predictive value.


Assuntos
Hepacivirus , Hepatite C , Viremia , Adolescente , Adulto , Técnicas e Procedimentos Diagnósticos/normas , Alemanha , Hepacivirus/genética , Hepatite C/diagnóstico , Anticorpos Anti-Hepatite C/metabolismo , Humanos , RNA Viral/genética , Estudos Retrospectivos , Viremia/diagnóstico
3.
Emerg Microbes Infect ; 9(1): 485-495, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32100631

RESUMO

The second human pegivirus HPgV-2 is a novel blood-borne virus that is strongly associated with the hepatitis C virus (HCV) infection. However, the molecular evidence for their association as well as the natural history and tissue tropism of HPgV-2 remain to be elucidated. In this longitudinal study, a total of 753 patients including 512 HIV-1 and HCV co-infected patients were enrolled to characterize the natural history of HPgV-2 infection. Peripheral blood mononuclear cells (PBMCs) and liver biopsies were collected to determine the tissue tropism of HPgV-2 using immunohistochemical staining of the HPgV-2 antigen and in situ hybridization of HPgV-2 RNA. We documented both persistent HPgV-2 infection with the presence of HPgV-2 viral RNA and antibodies up to 4.6 years and resolved HPgV-2 infection, accompanied by a simultaneous decline of anti-HPgV-2 antibodies and clearance of HPgV-2 viremia. Furthermore, we observed the clearance of HCV, but not HPgV-2, by treatment with direct-acting antivirals (DAAs). Biochemical tests and pathological analyses did not reveal any indication of hepatic impairment caused by HPgV-2. HPgV-2 RNA and nonstructural antigen were detected in the lymphocytes, but not in the hepatocytes present in the liver biopsy samples. In addition, both positive- and negative-strand HPgV-2 RNAs were detected in PBMCs, especially in B cells. The present study is the first to provide evidence that HPgV-2 is a lymphotropic, but not a hepatotropic virus and that HPgV-2 replication is independent of HCV viremia. These new findings let us gain insights into the evolution and persistent infection of RNA viruses in humans.


Assuntos
Coinfecção , Flaviviridae/fisiologia , Hepacivirus/fisiologia , Replicação Viral , Infecções por Flaviviridae , HIV-1 , Hepatite C , Humanos , Leucócitos Mononucleares , Estudos Longitudinais , RNA Viral/genética , Viremia
4.
Viruses ; 12(2)2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31991674

RESUMO

Zika virus (ZIKV) is a mosquito-borne flavivirus associated with a febrile illness as well as severe complications, including microcephaly and Guillain-Barré Syndrome. Antibody cross-reactivity between flaviviruses has been documented, and in regions where ZIKV is circulating, dengue virus (DENV) is also endemic, leaving the potential that previous exposure to DENV could alter clinical features of ZIKV infection. To investigate this, we performed a retrospective case-control study in which we compared Canadian travellers who had been infected with ZIKV and had serological findings indicating previous DENV or other flavivirus exposure (n = 16) to those without any previous exposure (n = 44). Patient samples were collected between February 2016 and September 2017 and submitted to Public Health Ontario for testing. ZIKV infection was determined using real-time RT-PCR and antibodies against DENV were identified by the plaque-reduction neutralization test. The mean time from symptom onset to sample collection was 5 days for both groups; the magnitude of viremia was not statistically different (Ct values: 35.6 vs. 34.9, p-value = 0.2). Clinical scores were also similar. Our findings indicate that previous DENV or other flavivirus exposure did not result in greater viremia or a higher illness score.


Assuntos
Anticorpos Antivirais/sangue , Vírus da Dengue/imunologia , Viremia , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia , Zika virus/isolamento & purificação , Adulto , Canadá , Estudos de Casos e Controles , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Índice de Gravidade de Doença , Doença Relacionada a Viagens
5.
Arch Virol ; 165(3): 619-626, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31965315

RESUMO

Human pegivirus 2 (HPgV-2) is a recently recognized pegivirus of the family Flaviviridae. To investigate the epidemic features of HPgV-2 circulating in the human immunodeficiency virus (HIV)-infected population, we tested for antibodies and viral RNA of HPgV-2 and hepatitis C virus (HCV) with retrospective plasma samples collected from 771 HIV infections with multiple risk behaviors in Honghe Prefecture of Yunnan Province. A total of 195 subjects (25.29%) were seroreactive to HPgV-2, and 41 (5.32%) were RNA positive. Although the positive rate of HPgV-2 antibodies in HIV/HCV-coinfected individuals (27.69%) was significantly higher than that of HIV monoinfections (20.82%) (p = 0.036), this is the first report of HPgV-2 viremia in HIV-infected individuals without HCV infection and the presence of two HPgV-2 lineages in China. Our data indicate that HPgV-2 can also be transmitted sexually, which might be facilitated when combined with HCV infection, injecting drug use, and risky sexual behavior, which appear to have a synergistic effect on HPgV-2 infection. Phylogenetic analysis of 26 near-full-length genome sequences showed that the HPgV-2 strains in China are divided into two clusters.


Assuntos
Infecções por Flaviviridae/complicações , Infecções por Flaviviridae/epidemiologia , Flaviviridae/classificação , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Viremia , Anticorpos Antivirais/sangue , China/epidemiologia , Humanos , Incidência , Filogenia , Prevalência , RNA Viral/genética , RNA Viral/isolamento & purificação
6.
PLoS Comput Biol ; 15(11): e1006668, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31710599

RESUMO

The titre of virus in a dengue patient and the duration of this viraemia has a profound effect on whether or not a mosquito will become infected when it feeds on the patient and this, in turn, is a key driver of the magnitude of a dengue outbreak. The assessment of the heterogeneity of viral dynamics in dengue-infected patients and its precise treatment are still uncertain. Infection onset, patient physiology and immune response are thought to play major roles in the development of the viral load. Research has explored the interference and spontaneous generation of defective virus particles, but have not examined both the antibody and defective particles during natural infection. We explore the intrinsic variability in the within-host dynamics of viraemias for a population of patients using the method of population of models (POMs). A dataset from 208 patients is used to initially calibrate 20,000 models for the infection kinetics for each of the four dengue virus serotypes. The calibrated POMs suggests that naturally generated defective particles may interfere with the viraemia, but the generated defective virus particles are not adequate to reduce high fever and viraemia duration. The effect of adding excess defective dengue virus interfering particles to patients as a therapeutic is evaluated using the calibrated POMs in a bang-bang (on-off or two-step) optimal control setting. Bang-bang control is a class of binary feedback control that turns either 'ON' or 'OFF' at different time points, determined by the system feedback. Here, the bang-bang control estimates the mathematically optimal dose and duration of the intervention for each model in the POM set.


Assuntos
Vírus da Dengue/fisiologia , Dengue/virologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Animais , Culicidae , Vírus Defeituosos , Humanos , Modelos Teóricos , Carga Viral/fisiologia , Viremia , Vírion , Replicação Viral
7.
Transplant Proc ; 51(9): 2936-2938, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31711578

RESUMO

BACKGROUND: BK virus (BKV) infection represents a potentially dreadful complication after kidney transplantation (KT). When BK viremia is detected, the best therapeutic approach remains not entirely clarified. Critical elements of BK viremia treatment are immunosuppression minimization and introduction of drugs like leflunomide, everolimus, and fluoroquinolones. The study aimed to analyze the results of the BK viremia management in 2 collaborative Italian centers. METHODS: Ten patients undergoing KT in the 2 collaborative Italian centers of Sapienza University of Rome and University of L'Aquila from January 2013 to December 2017 and showing a post-KT diagnosis of BK viremia were retrospectively investigated. RESULTS: Mean time from KT to BKV positivity was 7 months (range: 1-19 months). At diagnosis, the mean viral load was 683,842 copies/mL (range: 5800-4,052,415 copies/mL), with an average zenith of 2,428,410 copies/mL (range: 6762-18,022,500 copies/mL). In the 5 patients with BKV nephropathy, we observed a switch from antimetabolite to leflunomide (n = 5), a switch from tacrolimus to everolimus (n = 3), or an introduction of fluoroquinolones (n = 3). BKV clearance was achieved in 3 patients. CONCLUSIONS: Early BKV diagnosis and stepwise minimization of immunosuppression remain the first-line approach in patients with BK viremia. In the presence of BKV nephropathy, a combination of antiviral drugs like leflunomide and fluoroquinolones/everolimus should favor viremia clearance.


Assuntos
Transplante de Rim , Infecções por Polyomavirus/complicações , Infecções por Polyomavirus/imunologia , Infecções Tumorais por Vírus/complicações , Infecções Tumorais por Vírus/imunologia , Adulto , Antivirais/uso terapêutico , Vírus BK , Feminino , Humanos , Imunossupressão/métodos , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/tratamento farmacológico , Estudos Retrospectivos , Infecções Tumorais por Vírus/tratamento farmacológico , Viremia/complicações , Viremia/tratamento farmacológico , Viremia/imunologia
8.
PLoS Negl Trop Dis ; 13(11): e0007142, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31675360

RESUMO

BACKGROUND: Dengue is the most prevalent arboviral disease of humans. Virus neutralizing antibodies are likely to be critical for clinical immunity after vaccination or natural infection. A number of human monoclonal antibodies (mAbs) have previously been characterized as able to neutralize the infectivity of dengue virus (DENV) for mammalian cells in cell-culture systems. METHODOLOGY/PRINCIPLE FINDINGS: We tested the capacity of 12 human mAbs, each of which had previously been shown to neutralize DENV in cell-culture systems, to abrogate the infectiousness of dengue patient viremic blood for mosquitoes. Seven of the twelve mAbs (1F4, 14c10, 2D22, 1L12, 5J7, 747(4)B7, 753(3)C10), almost all of which target quaternary epitopes, inhibited DENV infection of Ae. aegypti. The mAbs 14c10, 747(4)B7 and 753(3)C10 could all inhibit transmission of DENV in low microgram per mL concentrations. An Fc-disabled variant of 14c10 was as potent as its parent mAb. CONCLUSIONS/SIGNIFICANCE: The results demonstrate that mAbs can neutralize infectious DENV derived from infected human cells, in the matrix of human blood. Coupled with previous evidence of their ability to prevent DENV infection of mammalian cells, such mAbs could be considered attractive antibody classes to elicit with dengue vaccines, or alternatively, for consideration as therapeutic candidates.


Assuntos
Aedes/virologia , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Vírus da Dengue/imunologia , Dengue/imunologia , Dengue/prevenção & controle , Viremia/imunologia , Animais , Anticorpos Monoclonais/sangue , Anticorpos Antivirais/sangue , Dengue/transmissão , Dengue/virologia , Vacinas contra Dengue , Epitopos/imunologia , Humanos , Viremia/virologia
9.
Vet Microbiol ; 239: 108497, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31767085

RESUMO

The objective of this study was to evaluate the effect of concurrent vaccination with a porcine reproductive and respiratory syndrome virus (PRRSV)-1 modified-live virus (MLV) vaccine and a PRRSV-2 MLV vaccine against a dual heterologous PRRSV-1 and PRRSV-2 challenge in late term pregnancy gilts. Gilts were concurrently administered PRRSV-1 and PRRSV-2 MLV vaccines at 21 days prior to breeding at separate anatomical sites and were inoculated intranasally with both PRRSV types at 93 days of gestation. Vaccinated gilts had a higher number of live-born and weaned pigs, and a decrease in stillbirths compared to the unvaccinated control group following a dual challenge. Concurrent vaccination resulted also in the reduction of both PRRSV-1 and PRRSV-2 viremia which correlated with an increase in the number of PRRSV-1 and PRRSV-2 specific interferon-γ secreting cells (IFN-γ-SC). We believe the T cell responses contributed to the reduction of both PRRSV-1 and PRRSV-2 viremia. The results presented here demonstrate that concurrent vaccination with PRRSV-1 and PRRSV-2 MLV vaccines improves reproductive performance, reduces viremia of PRRSV-1 and PRRSV-2, and induces protective T cell reactions against dual PRRSV-1 and PRRSV-2 challenge in late term pregnancy gilts without local and systemic adverse reactions related to concurrent vaccination.


Assuntos
Síndrome Respiratória e Reprodutiva Suína/prevenção & controle , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Vacinação/veterinária , Vacinas Atenuadas/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/sangue , Feminino , Gravidez , Resultado da Gravidez/veterinária , Suínos , Vacinação/normas , Viremia/prevenção & controle , Viremia/veterinária
11.
Afr Health Sci ; 19(2): 1988-1992, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31656481

RESUMO

Background: Previous trials have investigated the effect of hepatitis C on lung functions; however, the role of viral load levels is unclear. The aim of this study was to investigate the effect of HCV viremia status on lung functions. Methods: This study was in 60 patients with chronic hepatitis C (CHC). Patients were classified into three groups (non-viremic, low-viremic and high-viremic) based on serum HCV RNA levels. Spirometric parameters (FEV1, FVC, FEV1/FVC) and the proportion of patients with spirometric abnormalities were compared between three groups. Results: High-viremic and low-viremic patients showed a significantly higher prevalance of spirometric abnormality than observed in non-viremic patients (p=0.02). Moreover, there was a significant moderate correlation between viremia level and the percentage of spirometric abnormalities (Cramer's U value=0.452, p=0.002). High-viremic patients were 14.2 times more likely to exhibiting pulmonary dysfunction than non-viremic patients. Additionally, spirometric parameters FEV1 and FVC were significantly reduced in high-viremic and low-viremic patients compared to those in non-viremic patients (p=0.013 and p<0.001 respectively). Conclusion: These results indicate that persistent HCV infection may be associated with reduced pulmonary functions, especially in patients with high viremia levels. Therefore, these patients should be carefully monitored for lung function.


Assuntos
Hepacivirus/isolamento & purificação , Anticorpos Anti-Hepatite C/análise , Hepatite C Crônica/diagnóstico , Pulmão/fisiologia , RNA Viral/sangue , Viremia/diagnóstico , Adulto , Feminino , Hepatite C Crônica/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Testes de Função Respiratória , Espirometria , Carga Viral , Viremia/epidemiologia , Viremia/virologia
13.
Medicine (Baltimore) ; 98(39): e16997, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574798

RESUMO

This study aimed to determine the association between different lymphocyte subsets and cytomegalovirus (CMV) infection status in patients with systemic lupus erythematosus (SLE). We performed a retrospective study among SLE patients with CMV infection and collected patient socio-demographic and clinical characteristics, as well as their recorded circulating lymphocyte subsets. Univariate and multivariable logistic regression analyses examined the relationship between CMV infection status and lymphocyte subset counts. We included 125 hospitalized patients with SLE, consisting of 88 with documented CMV infection and 37 without any evidence of CMV or other infections. Among the 88 CMV-infected patients, 65 (73.8%) patients developed CMV disease and 23 (26.2%) presented as CMV viremia. Compared to uninfected patients (1520 ±â€Š101 cells/µL), lymphocytes remained stable among those with CMV viremia (1305 ±â€Š272 cells/µL, P = .995). However, compared to their uninfected counterparts, there was a marked decrease in lymphocytes among patients with CMV disease (680 ±â€Š513 cells/µL, P < .001). Analysis of lymphocyte subsets via flow cytometry showed that CD4+ T cell, CD8+ T cell, and natural killer cell counts were lower among those with CMV disease compared to those with CMV viremia and those without infection. Further, multivariable analysis showed that total lymphocyte (odds ratio [OR] 0.999, 95% confidence interval [CI] 0.998-1.000, P = .007) and CD4+ T cell counts (OR 0.99, 95% CI 0.992-0.998, P = .003) were negatively associated with CMV disease. Our findings support a potential inverse relationship between lymphopenia, specifically CD4+ T-cell lymphopenia, and CMV disease among hospitalized SLE patients.


Assuntos
Infecções por Citomegalovirus/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Subpopulações de Linfócitos , Viremia/diagnóstico , Adulto , Sedimentação Sanguínea , Estudos de Casos e Controles , Feminino , Humanos , Contagem de Linfócitos , Linfopenia/complicações , Masculino , Projetos Piloto , Estudos Retrospectivos
14.
Biochemistry (Mosc) ; 84(8): 941-953, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31522676

RESUMO

Transforming growth factor beta (TGF-ß) acts as a tumor-suppressing cytokine in healthy tissues and non-malignant tumors. Yet, in malignancy, TGF-ß can exert the opposite effects that can promote proliferation of cancer cells. C-Kit plays a prominent role in stem cell activation and liver regeneration after injury. However, little is known about the cross-talk between TGF-ß and C-Kit and its role in the progression of hepatocellular carcinoma (HCC). Here, we studied the effect of increasing doses of TGF-ß1 on CD44+CD90+ liver stem cells (LSCs) and C-Kit gene expression in malignant and adjacent non-malignant liver tissues excised from 32 HCC patients. The percentage of LSCs in malignant tumors was two times higher compared to their counterparts from the non-malignant tissues. When treated with increasing doses of TGF-ß1, proliferation of both malignant and non-malignant LSCs was progressively suppressed, but low TGF-ß1 dose failed to suppress the growth of malignant LSCs. Moreover, C-Kit exons 9 and 11 were expressed in malignant LSCs, but not in their non-malignant counterparts. Analysis of C-Kit detected mutations in exon 9 (but not in exon 11) in some malignant liver cells resulting in the changes in the amino acid sequence and dysregulation of protein structure and function. Interestingly, in malignant liver cells, mutations in exon 9 were associated with high-viremia hepatitis C virus (HCV), and expression of this exon was not suppressed by the TGF-ß1 treatment at all doses. To our knowledge, this is the first report that mutations in the C-Kit gene in HCC patients are associated with high- viremia HCV. Our study emphasizes the need for investigation of the TGF-ß1 level and C-Kit mutations in patients with chronic HCV for HCC prevention and better therapy management.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Hepacivirus , Hepatite C Crônica/genética , Hepatite C Crônica/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Fator de Crescimento Transformador beta1/farmacologia , Idoso , Carcinoma Hepatocelular/etiologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Farmacorresistência Viral Múltipla , Éxons/genética , Feminino , Expressão Gênica , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Receptores de Hialuronatos/metabolismo , Fígado/patologia , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Células-Tronco Neoplásicas/metabolismo , Antígenos Thy-1/metabolismo , Viremia
15.
BMC Res Notes ; 12(1): 632, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31554515

RESUMO

OBJECTIVE: Thrombocytopenia is an abnormal decrease in blood platelets, which can affect the prognosis of people living with HIV (PLHIV). In order to assess the burden of this haematological disorder, we evaluated the frequency of thrombocytopenia according to antiretroviral drug combinations, viremia and the immune status of PLHIV. RESULTS: A cross-sectional and analytical study was conducted from June to November 2016 among 310 PLHIV at the "Chantal BIYA" International Reference Centre, Yaoundé, Cameroon. Overall rate of thrombocytopenia was 19.0% (59/310). The rate of thrombocytopenia was 64.6% (42/65) versus 6.9% (17/245) in ART-naïve versus ART-treated patients respectively, p < 0.0001. Following viral load, rate of thrombocytopenia was 15.8% (20/130) in those with undetectable viral load, and 34.1% (27/79) with viral loads > 3 log10 RNA/ml (p = 0.03). As concerns CD4-count, rate of thrombocytopenia was 16.2% (42/259) in those with ≥ 200 CD4/mm3 versus 33.3% (17/51) with < 200 CD4/mm3 (p = 0.0003). After adjusting for sex, ART, viral load and CD4, Viral load and ART exposure were significantly associated with decreased risk of thrombocytopenia (p < 0.05). Thrombocytopenia occurs especially among ART-naïve, high viremia and severe immune-compromised patients. Interestingly, ART coverage appears as an independent factor in preventing the occurrence of thrombocytopenia.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Trombocitopenia/diagnóstico , Adolescente , Adulto , Contagem de Linfócito CD4 , Camarões , Criança , Pré-Escolar , Cidades , Estudos Transversais , Combinação de Medicamentos , Feminino , Infecções por HIV/complicações , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Trombocitopenia/sangue , Trombocitopenia/complicações , Viremia/tratamento farmacológico , Viremia/virologia , Adulto Jovem
16.
Science ; 365(6457): 1025-1029, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31488688

RESUMO

Treatment of SIV-infected rhesus macaques with short-term antiretroviral therapy (ART) and partially overlapping infusions of antibody to integrin α4ß7 was reported to induce durable posttreatment viral suppression. In an attempt to replicate those observations, we treated macaques infected with the same virus and with the same ART and monoclonal antibody (mAb) regimens (anti-α4ß7 versus control mAb). Sequencing demonstrated that the virus used was actually SIVmac239-nef-stop, not wild-type SIVmac239. A positive correlation was found at 2 weeks after infection between the frequency of repair of attenuated Nef-STOP virus to pathogenic Nef-OPEN and plasma SIV RNA levels. Levels of plasma viremia before the first antibody infusion and preinfection levels of α4ß7 hi CD4+ T cells, but not treatment with antibody to α4ß7 , correlated with levels of viral replication upon discontinuation of all treatments. Follow-up plasma viremia, peripheral blood CD4+ T cell counts, and lymph node and rectal tissue viral load were not significantly different between anti-α4ß7 and control mAb groups.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Infecções por HIV/terapia , Integrina alfa4/imunologia , Cadeias beta de Integrinas/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/terapia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/imunologia , Animais , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Códon de Terminação , Linfonodos/virologia , Macaca mulatta , RNA Viral/sangue , Reto/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/fisiologia , Carga Viral , Proteínas Virais Reguladoras e Acessórias/genética , Proteínas Virais Reguladoras e Acessórias/imunologia , Viremia/sangue , Viremia/imunologia , Viremia/terapia , Viremia/virologia , Replicação Viral
17.
N Engl J Med ; 381(12): 1136-1147, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31532960

RESUMO

BACKGROUND: Maribavir is a benzimidazole riboside with activity against cytomegalovirus (CMV). The safety and efficacy of maribavir for preemptive treatment of CMV infection in transplant recipients is not known. METHODS: In a phase 2, open-label, maribavir dose-blinded trial, recipients of hematopoietic-cell or solid-organ transplants (≥18 years of age, with CMV reactivation [1000 to 100,000 DNA copies per milliliter]) were randomly assigned to receive maribavir at a dose of 400, 800, or 1200 mg twice daily or the standard dose of valganciclovir for no more than 12 weeks. The primary efficacy end point was the percentage of patients with a response to treatment, defined as confirmed undetectable CMV DNA in plasma, within 3 weeks and 6 weeks after the start of treatment. The primary safety end point was the incidence of adverse events that occurred or worsened during treatment. RESULTS: Of the 161 patients who underwent randomization, 159 received treatment, and 156 had postbaseline data available - 117 in the maribavir group and 39 in the valganciclovir group. The percentage of patients with postbaseline data available who had a response to treatment within 3 weeks was 62% among those who received maribavir and 56% among those who received valganciclovir. Within 6 weeks, 79% and 67% of patients, respectively, had a response (risk ratio, 1.20; 95% confidence interval, 0.95 to 1.51). The percentages of patients with a response to treatment were similar among the maribavir dose groups. Two patients who had a response to treatment had a recurrence of CMV infection within 6 weeks after starting maribavir at a dose of 800 mg twice daily; T409M resistance mutations in CMV UL97 protein kinase developed in both patients. The incidence of serious adverse events that occurred or worsened during treatment was higher in the maribavir group than in the valganciclovir group (52 of 119 patients [44%] vs. 13 of 40 [32%]). A greater percentage of patients in the maribavir group discontinued the trial medication because of an adverse event (27 of 119 [23%] vs. 5 of 40 [12%]). A higher incidence of gastrointestinal adverse events was reported with maribavir, and a higher incidence of neutropenia was reported with valganciclovir. CONCLUSIONS: Maribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of hematopoietic-cell or solid-organ transplants. A higher incidence of gastrointestinal adverse events - notably dysgeusia - and a lower incidence of neutropenia were found in the maribavir group. (Funded by ViroPharma/Shire Development; EudraCT number, 2010-024247-32.).


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Citomegalovirus/fisiologia , Ribonucleosídeos/uso terapêutico , Valganciclovir/uso terapêutico , Viremia/tratamento farmacológico , Adulto , Idoso , Aloenxertos , Antivirais/efeitos adversos , Antivirais/farmacologia , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacologia , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/virologia , Disgeusia/induzido quimicamente , Feminino , Gastroenteropatias/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Transplante de Órgãos/efeitos adversos , Ribonucleosídeos/efeitos adversos , Ribonucleosídeos/farmacologia , Valganciclovir/efeitos adversos , Valganciclovir/farmacologia , Ativação Viral/efeitos dos fármacos
18.
Nat Commun ; 10(1): 4316, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541110

RESUMO

Zika virus (ZIKV) and dengue virus (DENV) are co-endemic in many parts of the world, but the impact of ZIKV infection on subsequent DENV infection is not well understood. Here we show in rhesus macaques that the time elapsed after ZIKV infection affects the immune response to DENV infection. We show that previous ZIKV exposure increases the magnitude of the antibody and T cell responses against DENV. The time interval between ZIKV and subsequent DENV infection further affects the immune response. A mid-convalescent period of 10 months after ZIKV infection results in higher and more durable antibody and T cell responses to DENV infection than a short period of 2 months. In contrast, previous ZIKV infection does not affect DENV viremia or pro-inflammatory status. Collectively, we find no evidence of a detrimental effect of ZIKV immunity in a subsequent DENV infection. This supports the implementation of ZIKV vaccines that could also boost immunity against future DENV epidemics.


Assuntos
Dengue/imunologia , Interações Hospedeiro-Patógeno/imunologia , Linfócitos T/imunologia , Infecção por Zika virus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linhagem Celular , Reações Cruzadas/imunologia , Citocinas/metabolismo , Vírus da Dengue/imunologia , Humanos , Imunidade , Imunidade Celular , Macaca mulatta/imunologia , Masculino , Fatores de Tempo , Viremia , Zika virus/imunologia
19.
Transplant Proc ; 51(6): 1801-1809, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399166

RESUMO

BK viremia (BKV) is a recognized and potentially serious problem in renal transplantation. The risk factors and the impact of BKV on renal allograft and patient survival are controversial. This study reports an 8-year, single-center experience on the prevalence, risk factors, and outcomes of BKV in kidney transplant recipients. This is a retrospective analysis of all patients who received a kidney transplant at the University of Kentucky and had BK viral titers available from 2009 to 2017. BKV was defined by a polymerase chain reaction viral load of ≥ 10,000 copies per mL. Demographic, clinical, and laboratory data generated during routine outpatient follow up and inpatients records were collected. Independent risk factors for BKV were determined using uni- and multivariate analysis. Graft and patient survival was compared using Kaplan-Meier analysis, and the severity of polyomavirus nephropathy on biopsy was scored using the Banff 2017 classification. We identified 122 BK positive (19%) and 527 BK negative (81%) patients. BKV developed after a median of 115 days (range, 80-249 days) following kidney transplantation. The 1-, 5-, and 10-year graft survival was 97%, 75%, and 33% in the BKV group and 96%, 85%, and 71% in the BK negative group, respectively. Likewise, the 1-, 5-, and 10-year patient survival was 98%, 84%, and 52% in the BKV group and 98%, 92%, and 84% in the BK negative group. Male sex, age at transplantation, maintenance steroids, and alemtuzumab induction were associated with developing BKV in the multivariate analysis. We concluded that BKV is not uncommon after renal transplantation. The determinants for BKV are male sex, older transplant recipients, and maintenance steroids. BKV adversely affected graft and patient survival. A unified approach for BKV and polyomavirus nephropathy treatment is needed.


Assuntos
Vírus BK , Nefropatias/virologia , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/virologia , Complicações Pós-Operatórias/virologia , Infecções Tumorais por Vírus/virologia , Viremia/virologia , Adulto , Biópsia , Feminino , Sobrevivência de Enxerto , Humanos , Estimativa de Kaplan-Meier , Rim/virologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prevalência , Estudos Retrospectivos , Fatores de Risco , Transplante Homólogo , Carga Viral
20.
PLoS Pathog ; 15(8): e1007992, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31381617

RESUMO

Genotype I (GI) virus has replaced genotype III (GIII) virus as the dominant Japanese encephalitis virus (JEV) in the epidemic area of Asia. The mechanism underlying the genotype replacement remains unclear. Therefore, we focused our current study on investigating the roles of mosquito vector and amplifying host(s) in JEV genotype replacement by comparing the replication ability of GI and GIII viruses. GI and GIII viruses had similar infection rates and replicated to similar viral titers after blood meal feedings in Culex tritaeniorhynchus. However, GI virus yielded a higher viral titer in amplifying host-derived cells, especially at an elevated temperature, and produced an earlier and higher viremia in experimentally inoculated pigs, ducklings, and young chickens. Subsequently we identified the amplification advantage of viral genetic determinants from GI viruses by utilizing chimeric and recombinant JEVs (rJEVs). Compared to the recombinant GIII virus (rGIII virus), we observed that both the recombinant GI virus and the chimeric rJEVs encoding GI virus-derived NS1-3 genes supported higher replication ability in amplifying hosts. The replication advantage of the chimeric rJEVs was lost after introduction of a single substitution from a GIII viral mutation (NS2B-L99V, NS3-S78A, or NS3-D177E). In addition, the gain-of-function assay further elucidated that rGIII virus encoding GI virus NS2B-V99L/NS3-A78S/E177E substitutions re-gained the enhanced replication ability. Thus, we conclude that the replication advantage of GI virus in pigs and poultry is the result of three critical NS2B/NS3 substitutions. This may lead to more efficient transmission of GI virus than GIII virus in the amplifying host-mosquito cycle.


Assuntos
Vírus da Encefalite Japonesa (Espécie)/genética , Encefalite Japonesa/virologia , Mosquitos Vetores , Mutação , Proteínas não Estruturais Virais/genética , Viremia/transmissão , Animais , Galinhas , Culex , Vírus da Encefalite Japonesa (Espécie)/patogenicidade , Encefalite Japonesa/epidemiologia , Encefalite Japonesa/genética , Feminino , Genótipo , RNA Helicases/genética , Serina Endopeptidases/genética , Suínos , Replicação Viral
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