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[This corrects the article DOI: 10.1016/j.lana.2022.100366.].
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Background: COVID-19 vaccines have proven safe and efficacious in reducing severe illness and death. Cuban protein subunit vaccine Abdala has shown safety, tolerability and efficacy (92·3% [95% CI: 85·7â95·8]) against SARS-CoV-2 in clinical trials. This study aimed to estimate Abdala's real-world vaccine effectiveness (VE). Methods: This retrospective cohort study in Havana analyzed Cuban Ministry of Public Health databases (May 12-August 31, 2021) to assess VE in preventing severe illness and death from COVID-19 (primary outcomes). Cox models accounting for time-varying vaccination status and adjusting by demographics were used to estimate hazard ratios. A subgroup analysis by age group and a sensitivity analysis including a subgroup of tested persons (qRT-PCR) were conducted. Daily cases and deaths were modelled accounting for different VE. Findings: The study included 1 355 638 persons (Mean age: 49·5 years [SD: 18·2]; 704 932 female [52·0%]; ethnicity data unavailable): 1 324 vaccinated (partially/fully) and 31 433 unvaccinated. Estimated VE against severe illness was 93·3% (95% CI: 92·1-94·3) in partially- vaccinated and 98·2% (95% CI: 97·9-98·5) in fully-vaccinated and against death was 94·1% (95% CI: 92·5-95·4) in partially-vaccinated and 98·7% (95% CI: 98·3-99·0) in fully-vaccinated. VE exceeded 92·0% in all age groups. Daily cases and deaths during the study period corresponded to a VE above 90%, as predicted by models. Interpretation: The Cuban Abdala protein subunit vaccine was highly effective in preventing severe illness and death from COVID-19 under real-life conditions. Funding: Cuban Ministry of Public Health. Genetic Engineering and Biotechnology Centre.
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Resumen La infección por el virus de la hepatitis C (VHC) se distribuye en todo el mundo, frecuentemente se convierte en hepatitis crónica, cirrosis y hepatocarcinoma. El genoma del VHC es una molécula de ARN monocatenario, de polaridad positiva, de aproximadamente 9.6 kb de longitud. Esta revisión resume el conocimiento actual y los avances recientes en la investigación de la biología molecular del VHC.
Abstract Infection with hepatitis C virus (HCV), which is distributed worldwide, often becomes in chronic hepatitis, cirrhosis and hepatocellular carcinoma. The HCV genome is a single-stranded RNA molecule of positive polarity approximately 9.6 kb in length. This review summarizes the current knowledge of recent advances in the investigation of the molecular biology of HCV.
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Chronic infection with HCV is a leading cause of cirrhosis, hepatocellular carcinoma and liver failure. One of the least understood steps in the HCV life cycle is the morphogenesis of new viral particles. HCV infection alters the lipid metabolism and generates a variety of microenvironments in the cell cytoplasm that protect viral proteins and RNA promoting viral replication and assembly. Lipid droplets (LDs) have been proposed to link viral RNA synthesis and virion assembly by physically associating these viral processes. HCV assembly, envelopment, and maturation have been shown to take place at specialized detergent-resistant membranes in the ER, rich in cholesterol and sphingolipids, supporting the synthesis of luminal LDs-containing ApoE. HCV assembly involves a regulated allocation of viral and host factors to viral assembly sites. Then, virus budding takes place through encapsidation of the HCV genome and viral envelopment in the ER. Interaction of ApoE with envelope proteins supports the viral particle acquisition of lipids and maturation. HCV secretion has been suggested to entail the ion channel activity of viral p7, several components of the classical trafficking and autophagy pathways, ESCRT, and exosome-mediated export of viral RNA. Here, we review the most recent advances in virus morphogenesis and the interplay between viral and host factors required for the formation of HCV virions.
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Hepacivirus/ultraestrutura , Hepatite C/virologia , Vírion/ultraestrutura , Montagem de Vírus/genética , Genoma Viral , Hepacivirus/genética , Hepatite C/genética , Humanos , Gotículas Lipídicas/metabolismo , RNA Viral/genética , Vírion/genética , Replicação Viral/genéticaRESUMO
Hepatitis C virus (HCV) infection is a worldwide health problem. Vaccines against this pathogen are not available and advances in this field are limited because of the high genetic variability of the virus, inaccessibility of animal models, and incomplete definition of immunological correlates of protection. In the present work, a chimeric protein, Eq1, encompassing HCV amino acid regions from structural antigens, was generated. Eq1 was expressed in GC-366 bacterial cells. After cell disruption, Eq1 was purified from the insoluble fraction by sequential steps of differential solubilization and metal chelating affinity chromatography. Eq1 was specifically recognized by anti-HCV positive human sera. Moreover, immunization of BALB/c mice with different doses of Eq1 formulated either in Alum or Freund's incomplete adjuvant elicited both humoral- and cellular-specific immune responses. Doses of 20 µg of Eq1 induced the strongest cell-mediated immune responses and only the formulation of this dose in Alum elicited a neutralizing antibody response against heterologous cell culture HCV. All these data together indicate that Eq1 is immunogenic in mice and might be an interesting component of vaccine candidates against HCV infection.
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Hepacivirus/imunologia , Hepatite C/imunologia , Imunidade Celular , Imunidade Humoral , Proteínas Recombinantes de Fusão/imunologia , Animais , Epitopos/imunologia , Adjuvante de Freund , Hepatite C/prevenção & controle , Humanos , Lipídeos , Camundongos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genéticaRESUMO
AIM: To analyze hepatitis C virus (HCV)-specific immune responses in chronically infected patients under triple therapy with interferon-α (IFN-α) plus ribavirin and CIGB-230. METHODS: CIGB-230 was administered in different schedules with respect to IFN-α plus ribavirin therapy. Paired serum and peripheral blood mononuclear cells (PBMC) samples from baseline and end of treatment were analyzed. The HCV-specific humoral response was tested by enzyme-linked immunosorbent assay, neutralizing antibodies were evaluated by cell culture HCV neutralization assays, PBMC proliferation was assayed by carboxyfluorescein succinimidyl ester staining and IFN-γ secretion was assessed by enzyme-linked immunospot. Data on virological and histological response and their association with immune variables are also provided. RESULTS: From week 12 to week 48, all groups of patients showed a significant reduction in mean leukocyte counts. Statistically significant reductions in antibody titers were frequent, but only individuals immunized with CIGB-230 as early add-on treatment sustained the core-IgG response, and the neutralizing antibody response was enhanced only in patients receiving CIGB-230. Cell-mediated immune responses also tended to decline, but significant reductions in IFN-γ secretion and total absence of core-specific lymphoproliferation were exclusive of the control group. Only CIGB-230-immunized individuals showed de novo induced lymphoproliferative responses against the structural antigens. Importantly, it was demonstrated that the quality of the CIGB-230-induced immune response depended on the number of doses and timing of administration in relation to the antiviral therapy. Specifically, the administration of 6 doses of CIGB-230 as late add-on to therapy increased the neutralizing antibody activity and the de novo core-specific IFN-γ secretion, both of which were associated with the sustained virological response. CONCLUSION: CIGB-230, combined with IFN-α-based therapy, modifies the immune response in chronic patients. The study provides evidence for the design of more effective therapeutic vaccine interventions against HCV.
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Antivirais/administração & dosagem , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Ribavirina/administração & dosagem , Vacinas de DNA/administração & dosagem , Vacinas contra Hepatite Viral/administração & dosagem , Adulto , Antivirais/efeitos adversos , Biomarcadores/sangue , Células Cultivadas , Cuba , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Hepacivirus/genética , Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/sangue , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/imunologia , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Esquemas de Imunização , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Interferon gama/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Ribavirina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Vacinas de DNA/efeitos adversos , Vacinas contra Hepatite Viral/efeitos adversosRESUMO
Hepatitis C virus (HCV) infects approximately 3% of global population. This pathogen is one of the main causes of chronic viral hepatitis, cirrhosis, and liver cancer, as well as the principal reason for liver transplant in Western countries. Therapy against HCV infection is effective in only half of treated patients. There is no vaccine available against HCV. Some vaccine candidates have reached the clinical trials but several factors, including the incomplete definition of immunological correlates of protection and treatment-related clearance have slowed down vaccine development. Precisely, the present review discusses the state of the art in the establishment of parameters related with immunity against HCV. Validity and limitations of the information accumulated from chimpanzees and other animal models, analysis of studies in humans infected with HCV, and relevance of aspects like type, strength, duration, and specificity of immune response related to successful outcome are evaluated in detail. Moreover, the immune responses induced in some clinical trials with vaccine candidates resemble the theoretical immunological correlates, raising questions about the validity of those correlates. When all facts are taken together, complete definition of immunological correlates for protection or treatment-related clearance is an urgent priority. A limited or wrong criterion with respect to this relevant matter might cause incorrect vaccine design and selection of immunization strategies or erroneous clinical evaluation.
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Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/imunologia , Hepatite C/prevenção & controle , Vacinas contra Hepatite Viral/imunologia , Animais , Modelos Animais de Doenças , Hepacivirus/efeitos dos fármacos , Hepatite C/imunologia , Hepatite C/virologia , Humanos , Camundongos , Pan troglodytes , Vacinação/métodos , Vacinas contra Hepatite Viral/administração & dosagemRESUMO
Human immunodeficiency virus type-1 (HIV-1) viral load is useful for monitoring disease progression in HIV-infected individuals. We generated RNA standards of HIV-1 and internal control (IC) by in vitro transcription and evaluated its performance in a quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay. HIV-1 and IC standards were obtained at high RNA concentrations, without DNA contamination. When these transcripts were included as standards in a qRT-PCR assay, it was obtained a good accuracy (±0.5 log(10) unit of the expected results) in the quantification of the HIV-1 RNA international standard and controls. The lower limit detection achieved using these standards was 511.0 IU/mL. A high correlation (r = 0.925) was obtained between the in-house qRT-PCR assay and the NucliSens easyQ HIV-1 test (bioMerieux) for HIV-1 RNA quantitation with clinical samples (N = 14). HIV-1 and IC RNA transcripts, generated in this study, proved to be useful as standards in an in-house qRT-PCR assay for determination of HIV-1 viral load.
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Approximately 170 million people are infected with the hepatitis C virus (HCV) worldwide. Infection with this pathogen is persistent in more than 80% of cases, frequently developing severe forms of liver damage such as cirrhosis and hepatocellular carcinoma. No preventive vaccine is available against HCV, and current treatment based on the combination of pegylated interferon and ribavirin is effective in â¼55% of patients infected with genotype 1, the most prevalent genotype. This review analyzes several factors influencing the achievement of a sustained virological response, namely undetectable HCV RNA at 6 months after conclusion of therapy. Particularly, the relevant issue of age and duration of infection is discussed in detail. Indeed, the final decision for starting treatment should be a case-by-case point. However, the cost-benefit analysis seems to indicate that in patients who are motivated and without contraindications, starting the treatment as early as possible is probably the best choice for success.
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Hepacivirus/fisiologia , Hepatite C Crônica/terapia , Interferons/uso terapêutico , RNA Viral/análise , Ribavirina/uso terapêutico , Animais , Análise Custo-Benefício , Hepacivirus/patogenicidade , Hepatite C Crônica/imunologia , Humanos , Imunidade , Interferons/economia , Medicina de Precisão , Ribavirina/economiaRESUMO
HCV (hepatitis C virus) infection is among the leading causes of chronic liver disease, but currently there is no vaccine available. Data have accumulated about the importance of targeting different HCV antigens in vaccine candidate preparations. Here, a surface response study to select the optimal ratio of recombinant HCV structural antigens in a vaccine preparation, capable of generating in vivo functional cellular immune response in mice, was performed. The immunogenicity of the selected HCV structural protein mixture (Co-E1-E2) in mice and African green monkeys, after five doses of immunization, was also demonstrated. Specific T-cell proliferative response against HCV structural antigens was induced in vaccinated mice. Moreover, on challenge with recombinant HCV VV (vaccinia virus), all mice controlled the viraemia and 80% were protected. On the other hand, monkeys immunized with Co-E1-E2 developed antibodies, specifically directed to region 412-438 of E2 protein, that include an epitope implicated in HCV neutralization, in addition to a specific proliferative response against HCV Core and E2 proteins. These results indicated that the optimal amount and ratio of HCV recombinant proteins should be taken into account to elicit a successful immune response against HCV and therefore have important implications for vaccine design.
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Hepatite C Crônica/imunologia , Imunidade Celular , Proteínas do Core Viral/imunologia , Proteínas do Envelope Viral/imunologia , Vacinas contra Hepatite Viral/imunologia , Animais , Chlorocebus aethiops , Feminino , Anticorpos Anti-Hepatite C/sangue , Antígenos da Hepatite C/imunologia , Antígenos da Hepatite C/farmacologia , Hepatite C Crônica/prevenção & controle , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Proteínas do Core Viral/farmacologia , Proteínas do Envelope Viral/farmacologiaRESUMO
BACKGROUND: In the present study, we evaluated the safety of CIGB-230, a novel vaccine candidate based on the mixture of a plasmid for DNA immunization, expressing hepatitis C virus (HCV) structural antigens, with a recombinant HCV Core protein. METHODS: Fifteen HCV chronically-infected volunteers with detectable levels of HCV RNA genotype 1b, who were nonresponders to previous treatment with interferon plus ribavirin, were intramuscularly injected with CIGB-230 on weeks 0, 4, 8, 12, 16 and 20. Individuals were also immunized at weeks 28, 32 and 36 with a recombinant vaccine against hepatitis B. Adverse events were recorded and analyzed. Blood samples were taken every 4 weeks up to month 12 for hematological, biochemical, virological and immunological analysis. RESULTS: All patients completed the treatment with CIGB-230. Adverse events were only slight (83.6%) or moderate (16.4%). No significant differences in hematological and biochemical parameters, including serum aminotransferases, were detected between the baseline and post-treatment state. Induction of a CD4+ T lymphocyte response against a particular region in HCV E1, spanning amino acids 230-312 in HCV polyprotein, was detected in 42.8% of patients during treatment with CIGB-230. The ability of T cells to proliferate in response to mitogenic stimulation was not weakened. Most individuals (78.6%) were seroprotected after anti-hepatitis B vaccination and 42.8% were hyper-responders (antibody titers > 100 UI/ml). No anti-mitochondrial, anti-nuclear and anti-extractable nuclear antigen antibodies were generated during immunization with CIGB-230. CONCLUSIONS: Vaccination with CIGB-230 in HCV chronically-infected individuals was safe, well tolerated and did not impair the ability to respond to non-HCV antigens.
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Vacinas contra Hepatite B/imunologia , Hepatite B/prevenção & controle , Hepatite C Crônica/prevenção & controle , Imunidade/imunologia , Vacinação/efeitos adversos , Vacinas de DNA/imunologia , Adulto , Anticorpos Antinucleares/imunologia , Formação de Anticorpos/efeitos dos fármacos , Formação de Anticorpos/imunologia , Proliferação de Células/efeitos dos fármacos , Epitopos/imunologia , Feminino , Hepatite B/imunologia , Anticorpos Anti-Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Hepatite C Crônica/imunologia , Humanos , Imunidade/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mitógenos/farmacologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Proteínas do Envelope Viral/imunologiaRESUMO
CIGB-230, a mixture of a DNA plasmid expressing hepatitis C virus (HCV) structural antigens and a HCV recombinant capsid protein, has demonstrated to elicit strong immune responses in animals. The present study evaluated the plasmid biodistribution after the administration of CIGB-230 in mice, as well as toxicity of this vaccine candidate in rats. In the biodistribution study, mice received single or repeated intramuscular injections of CIGB-230, 50 microg of plasmid DNA mixed with 5 microg of Co.120 protein. Plasmid presence was assessed in ovaries, kidney, liver, pancreas, mesenteric ganglion, blood, and muscle of the injection site by a qualitative polymerase chain reaction. The toxicology evaluation included treatment groups receiving doses 5, 15, or 50 times higher, according to the body weight, than the expected therapeutic clinical dose. During the first hour after repeated inoculation, a promiscuous distribution was observed. However, 3 months later, plasmid could not be detected in any tissue. There was an absence of detectable adverse effects on key toxicology parameters and no damage evidenced in inspected organs and tissues. These results indicate that CIGB-230 is nontoxic at local and systemic levels and no concerns about persistence are observed, which support clinical testing of this vaccine candidate against HCV.
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Hepacivirus/imunologia , Hepatite C/prevenção & controle , Vacinas de DNA/farmacocinética , Vacinas de DNA/toxicidade , Vacinas contra Hepatite Viral/farmacocinética , Vacinas contra Hepatite Viral/toxicidade , Animais , Feminino , Hepacivirus/genética , Antígenos de Hepatite/genética , Antígenos de Hepatite/imunologia , Hepatite C/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Testes de Toxicidade , Proteínas do Core Viral/genética , Proteínas do Core Viral/imunologiaRESUMO
Hepatitis C virus (HCV) causes chronic infection in approximately two thirds of cases, leading to chronic hepatitis, liver cirrhosis and hepatocellular carcinoma in a substantial proportion of the 170 million HCV-infected individuals worldwide. As there is neither prophylactic nor therapeutic vaccines for this virus, the research in this area is of special importance. Several vaccine candidates have been evaluated in pre-clinic, but only a few have reached the clinical evaluation. DNA immunization is one of the most evaluated approaches to obtain an effective vaccine against HCV infection. In the last few years a group of technical refinements in DNA vaccines has allowed to increase their immunogenicity. Two DNA vaccine candidates against HCV have already reached clinical evaluation, and are well tolerated and immunogenic in HCV-chronically infected individuals. The main results, opportunities and challenges of DNA immunization against HCV are discussed further in the present commentary. DNA vaccination is already a valuable tool for research HCV. Further improvements in formulation and delivery devices might be sufficient for becoming a real alternative in HCV vaccine.
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Hepacivirus/imunologia , Hepatite C Crônica/prevenção & controle , Vacinação , Vacinas de DNA/imunologia , Vacinas contra Hepatite Viral/imunologia , Ensaios Clínicos como Assunto , Humanos , Vacinas de DNA/uso terapêutico , Vacinas contra Hepatite Viral/uso terapêuticoRESUMO
In the present work, immunogenicity of recombinant in vitro assembled hepatitis C virus core particles, HCcAg.120-VLPs, either alone or in combination with different adjuvants was evaluated in BALB/c mice. HCcAg.120-VLPs induced high titers of anti-HCcAg.120 antibodies and virus-specific cellular immune responses. Particularly, HCcAg.120-VLPs induced specific delayed type hypersensitivity, and generated a predominant T helper 1 cytokine pro file in immunized mice. In addition, HCcAg.120-VLPs prime splenocytes proliferate in vitro against different HCcAg.120-specific peptides, depending on either the immunization route or the adjuvant used. Remarkably, immunization with HCcAg.120-VLPs/Montanide ISA888 formulation resulted in a significant control of vaccinia virus titer in mice after challenge with a recombinant vaccinia virus expressing HCV core protein, vvCore. Animals immunized with this formulation had a marked increase in the number of IFN-gamma producing spleen cells, after stimulation with P815 cells infected with vvCore. These results suggest the use of recombinant HCV core particles as components of therapeutic or preventive vaccine candidates against HCV.
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Hepacivirus/imunologia , Hepatite C/imunologia , Interferon gama/biossíntese , Interleucina-4/biossíntese , Fragmentos de Peptídeos/imunologia , Baço/imunologia , Proteínas do Core Viral/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Feminino , Hepatite C/prevenção & controle , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/administração & dosagem , Baço/citologia , Células Th2/imunologia , Proteínas do Core Viral/administração & dosagemRESUMO
Because the acquisition of in vitro transcription kits, for production of RNA standards, might not be affordable for some small laboratories, the current work describes some alternatives to the commercial Promega protocols. Yields of tested reactions were all higher than the ones reported for the standard Riboprobe kit (1mug RNA/mug template, 1x) and the optimized variant for high yields (5-10x). They were also as good as the ones described for the high RNA production kit RiboMAX (10-20x), exceeding them in approximately 70% of reactions. Our best results, achieved in a 500-mul format, were three to five times higher than the ones reported for the Promega kit.
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RNA Viral/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Transcrição Gênica , Hepacivirus/genética , RNA Viral/genética , Padrões de Referência , Reação em Cadeia da Polimerase Via Transcriptase Reversa/normasRESUMO
In the present work, immunogenicity of recombinant in vitro assembled hepatitis C virus core particles, HCcAg.120-VLPs, either alone or in combination with different adjuvants was evaluated in BALB/c mice. HCcAg.120-VLPs induced high titers of anti-HCcAg.120 antibodies and virus-specific cellular immune responses. Particularly, HCcAg.120-VLPs induced specific delayed type hypersensitivity, and generated a predominant T helper 1 cytokine pro file in immunized mice. In addition, HCcAg.120-VLPs prime splenocytes proliferate in vitro against different HCcAg.120-specific peptides, depending on either the immunization route or the adjuvant used. Remarkably, immunization with HCcAg.120-VLPs/Montanide ISA888 formulation resulted in a significant control of vaccinia virus titer in mice after challenge with a recombinant vaccinia virus expressing HCV core protein, vvCore. Animals immunized with this formulation had a marked increase in the number of IFN-γ producing spleen cells, after stimulation with P815 cells infected with vvCore. These results suggest the use of recombinant HCV core particles as components of therapeutic or preventive vaccine candidates against HCV.
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Animais , Feminino , Humanos , Camundongos , Hepacivirus/imunologia , Hepatite C/imunologia , Interferon gama/biossíntese , /biossíntese , Fragmentos de Peptídeos/imunologia , Baço/imunologia , Proteínas do Core Viral/imunologia , Adjuvantes Imunológicos/administração & dosagem , Hepatite C/prevenção & controle , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/administração & dosagem , Baço/citologia , /imunologia , Proteínas do Core Viral/administração & dosagemRESUMO
AIM: In the present study, antibody and peripheral blood mononuclear cells (PBMC) proliferative responses against hepatitis C virus (HCV) antigens were evaluated in HCV chronically infected patients. METHODS: Paired serum and PBMC samples were taken six months apart from 34 individuals, either treated or not, and tested by enzyme-linked immunosorbent assay (ELISA) and carboxyfluorescein succinimidyl ester staining. RESULTS: Over 70% of the patients showed specific IgG and IgM against capsid, E1 and NS3, while HVR-1 was recognized by half of the patients. An increase in the levels of the anti-capsid IgM (P = 0.027) and IgG (P = 0.0006) was observed in six-month samples, compared to baseline. Similarly, a significantly higher percent of patients had detectable IgA reactivity to capsid (P = 0.017) and NS3 (P = 0.005) after six months, compared to baseline. Particularly, IgA against structural antigens positively correlated with hepatic damage (P = 0.036). IgG subclasses evaluation against capsid and NS3 revealed a positive recognition mediated by IgG1 in more than 80% of the individuals. On the contrary, less than 30% of the patients showed a positive proliferative response either of CD4+ or CD8+ T cells, being the capsid poorly recognized. CONCLUSION: These results confirm that while the cellular immune response is narrow and weak, a broad and vigorous humoral response occurs in HCV chronic infection. The observed correlation between IgA and hepatic damage may have diagnostic significance, although it warrants further confirmation.
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Proliferação de Células , Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/sangue , Antígenos da Hepatite C/imunologia , Hepatite C Crônica/imunologia , Imunoglobulina A/sangue , Leucócitos Mononucleares/imunologia , Adulto , Formação de Anticorpos , Antivirais/uso terapêutico , Proteínas do Capsídeo/imunologia , Proliferação de Células/efeitos dos fármacos , Feminino , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Ribavirina/uso terapêutico , Linfócitos T/imunologia , Linfócitos T/virologia , Regulação para Cima , Proteínas do Envelope Viral/imunologia , Proteínas não Estruturais Virais/imunologiaRESUMO
HCV (hepatitis C virus) is a worldwide health problem nowadays. No preventive vaccine is available against this pathogen, and therapeutic treatments currently in use have important drawbacks, including limited efficacy. In the present work a recombinant fowlpox virus, FPCoE1, expressing a truncated HCV core-E1 polyprotein, was generated. FPCoE1 virus generally failed to elicit a humoral immune response against HCV antigens in BALB/c mice. By contrast, mice inoculated with FPCoE1 elicited a positive interferon-gamma secretion response against HCV core in ex-vivo ELISPOT (enzyme-linked immunospot) assays. Remarkably, mice inoculated with FPCoE1 significantly controlled viraemia in a surrogate challenge model with vvRE, a recombinant vaccinia virus expressing HCV structural antigens. In fact, 40% of the mice had no detectable levels of vvRE in their ovaries. Administration of FPCoE1 in vervet monkeys [Chlorocebus (formerly Cercophitecus) aethiops sabaeus] induced lymphoproliferative response against HCV core and E1 proteins in 50% of immunized animals. Monkeys immunized with FPCoE1 had no detectable levels of vvRE in their blood, whereas monkeys inoculated with FP9, the negative control virus, had detectable levels of vvRE in blood up to 7 days after challenge. In conclusion, recombinant fowlpox virus FPCoE1 is able to induce an anti-HCV immune response in mice and monkeys. This ability could be rationally employed to develop effective strategies against HCV infection by using FPCoE1 in combination with other vaccine candidates or antiviral treatments.