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1.
Hum Immunol ; 77(8): 643-651, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27266815

RESUMO

Autoimmune Regulator (AIRE) is a transcriptional regulator that is crucial for establishing central tolerance as illustrated by the Mendelian Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) syndrome associated with AIRE-inactivating recessive or dominant mutations. Polymorphisms in AIRE have been proposed to be implicated in genetic susceptibility to non-Mendelian organ specific autoimmune diseases. Because there is evidence that in predisposition to Graves' disease (GD) central tolerance is crucial, we investigated whether AIRE polymorphisms could modulate risk of GD. A case-control association study using 29 variants and conducted in 150 GD patients and 200 controls did not detect any significant association. This result is not exceptional: a systematic review of the literature, including GWAS, on the association of AIRE variants with organ specific autoimmune diseases did not show clear associations; similarly heterozygous recessive mutations are not associated to non-Mendelian autoimmunity. Dominant negative mutations of AIRE are associated to autoimmunity but as mild forms of APECED rather than to non-Mendelian organ specific autoimmunity. The lack of association of common AIRE polymorphisms with polygenic autoimmune diseases is counterintuitive as many other genes less relevant for immunological tolerance have been found to be associated. These findings give rise to the intriguing possibility that evolution has excluded functionally modifying polymorphisms in AIRE.


Assuntos
Doenças Autoimunes/genética , Doença de Graves/genética , Mutação/genética , Polimorfismo Genético , Fatores de Transcrição/genética , Animais , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imunidade/genética , Masculino , Grupos Populacionais
2.
J Immunol ; 194(9): 4199-206, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25801430

RESUMO

Graves' disease (GD) is an autoimmune thyroid disease defined by the production of stimulating autoantibodies to the thyroid-stimulating hormone receptor (TSHR) (TSAbs) that induce a sustained state of hyperthyroidism in patients. We previously demonstrated that TSHR, the target of this autoimmune response, is also a key susceptibility gene for GD, probably acting through thymic-dependent central tolerance. We also showed that TSHR is, unexpectedly, expressed in thymocytes. In this report, we confirm the expression of TSHR in thymocytes by protein immunoblotting and quantitative PCR, and show that expression is confined to maturing thymocytes. Using functional assays, we show that thymic TSHR is functional and that TSAbs can stimulate thymocytes through this receptor. This new activity of TSAbs on thymocytes may: 1) explain GD-associated thymic enlargement (hyperplasia), and 2) suggest the provocative hypothesis that the continuous stimulation of thymocytes by TSAbs could lead to a vicious cycle of iterative improvement of the affinity and stimulating capability of initially low-affinity antibacterial (e.g., Yersinia) Abs cross-reactive with TSHR, eventually leading to TSAbs. This may help to fill one of the gaps in our present understanding of unusual characteristics of TSAbs.


Assuntos
Autoanticorpos/imunologia , Doença de Graves/imunologia , Ativação Linfocitária/imunologia , Receptores da Tireotropina/imunologia , Timócitos/imunologia , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Receptores da Tireotropina/genética , Timócitos/citologia
3.
J Immunol ; 193(8): 3872-9, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25217160

RESUMO

Down syndrome (DS), or trisomy of chromosome 21, is the most common genetic disorder associated with autoimmune diseases. Autoimmune regulator protein (AIRE), a transcription factor located on chromosome 21, plays a crucial role in autoimmunity by regulating promiscuous gene expression (pGE). To investigate if autoimmunity in DS is promoted by the reduction of pGE owing to dysregulation of AIRE, we assessed the expression of AIRE and of several peripheral tissue-restricted Ag genes by quantitative PCR in thymus samples from 19 DS subjects and 21 euploid controls. Strikingly, despite the 21 trisomy, AIRE expression was significantly reduced by 2-fold in DS thymuses compared with controls, which was also confirmed by fluorescent microscopy. Allele-specific quantification of intrathymic AIRE showed that despite its lower expression, the three copies are expressed. More importantly, decreased expression of AIRE was accompanied by a reduction of pGE because expression of tissue-restricted Ags, CHRNA1, GAD1, PLP1, KLK3, SAG, TG, and TSHR, was reduced. Of interest, thyroid dysfunction (10 cases of hypothyroidism and 1 of Graves disease) developed in 11 of 19 (57.9%) of the DS individuals and in none of the 21 controls. The thymuses of these DS individuals contained significantly lower levels of AIRE and thyroglobulin, to which tolerance is typically lost in autoimmune thyroiditis leading to hypothyroidism. Our findings provide strong evidence for the fundamental role of AIRE and pGE, namely, central tolerance, in the predisposition to autoimmunity of DS individuals.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Síndrome de Down/imunologia , Fatores de Transcrição/biossíntese , Adolescente , Adulto , Doenças Autoimunes/complicações , Doenças Autoimunes/genética , Autoimunidade/genética , Tolerância Central , Criança , Pré-Escolar , Síndrome de Down/complicações , Síndrome de Down/genética , Feminino , Expressão Gênica , Humanos , Hipotireoidismo/complicações , Lactente , Masculino , Timo/metabolismo , Tireoglobulina/biossíntese , Tireoglobulina/imunologia , Fatores de Transcrição/imunologia , Adulto Jovem
4.
J Virol ; 87(11): 6192-200, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23536653

RESUMO

Positive-strand RNA viruses depend on recruited host factors to control critical replication steps. Previously, it was shown that replication of evolutionarily diverse positive-strand RNA viruses, such as hepatitis C virus and brome mosaic virus, depends on host decapping activators LSm1-7, Pat1, and Dhh1 (J. Diez et al., Proc. Natl. Acad. Sci. U. S. A. 97:3913-3918, 2000; A. Mas et al., J. Virol. 80:246 -251, 2006; N. Scheller et al., Proc. Natl. Acad. Sci. U. S. A. 106:13517-13522, 2009). By using a system that allows the replication of the insect Flock House virus (FHV) in yeast, here we show that LSm1-7, Pat1, and Dhh1 control the ratio of subgenomic RNA3 to genomic RNA1 production, a key feature in the FHV life cycle mediated by a long-distance base pairing within RNA1. Depletion of LSM1, PAT1, or DHH1 dramatically increased RNA3 accumulation during replication. This was not caused by differences between RNA1 and RNA3 steady-state levels in the absence of replication. Importantly, coimmunoprecipitation assays indicated that LSm1-7, Pat1, and Dhh1 interact with the FHV RNA genome and the viral polymerase. By using a strategy that allows dissecting different stages of the replication process, we found that LSm1-7, Pat1, and Dhh1 did not affect the early replication steps of RNA1 recruitment to the replication complex or RNA1 synthesis. Furthermore, their function on RNA3/RNA1 ratios was independent of the membrane compartment, where replication occurs and requires ATPase activity of the Dhh1 helicase. Together, these results support that LSm1-7, Pat1, and Dhh1 control RNA3 synthesis. Their described function in mediating cellular mRNP rearrangements suggests a parallel role in mediating key viral RNP transitions, such as the one required to maintain the balance between the alternative FHV RNA1 conformations that control RNA3 synthesis.


Assuntos
RNA Helicases DEAD-box/metabolismo , Nodaviridae/genética , Proteínas de Ligação ao Cap de RNA/metabolismo , RNA Viral/biossíntese , Proteínas de Ligação a RNA/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/virologia , RNA Helicases DEAD-box/genética , Genoma Viral , Genômica , Interações Hospedeiro-Patógeno , Nodaviridae/química , Nodaviridae/fisiologia , Proteínas de Ligação ao Cap de RNA/genética , RNA Viral/química , RNA Viral/genética , Proteínas de Ligação a RNA/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Replicação Viral
5.
Microb Cell Fact ; 10: 73, 2011 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-21943185

RESUMO

Processing bodies (PBs) and stress granules (SGs) are two highly conserved cytoplasmic ribonucleoprotein foci that contain translationally repressed mRNAs together with proteins from the mRNA metabolism. Interestingly, they also share some common features with other granules, including the prokaryotic inclusion bodies. Although the function of PBs and SGs remains elusive, major advances have been done in unraveling their composition and assembly by using the yeast Saccharomyces cerevisae.


Assuntos
Grânulos Citoplasmáticos/metabolismo , Ribonucleoproteínas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Grânulos Citoplasmáticos/genética , Ribonucleoproteínas/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
6.
Proc Natl Acad Sci U S A ; 106(32): 13517-22, 2009 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-19628699

RESUMO

Inevitably, viruses depend on host factors for their multiplication. Here, we show that hepatitis C virus (HCV) RNA translation and replication depends on Rck/p54, LSm1, and PatL1, which regulate the fate of cellular mRNAs from translation to degradation in the 5'-3'-deadenylation-dependent mRNA decay pathway. The requirement of these proteins for efficient HCV RNA translation was linked to the 5' and 3' untranslated regions (UTRs) of the viral genome. Furthermore, LSm1-7 complexes specifically interacted with essential cis-acting HCV RNA elements located in the UTRs. These results bridge HCV life cycle requirements and highly conserved host proteins of cellular mRNA decay. The previously described role of these proteins in the replication of 2 other positive-strand RNA viruses, the plant brome mosaic virus and the bacteriophage Qss, pinpoint a weak spot that may be exploited to generate broad-spectrum antiviral drugs.


Assuntos
Genoma Viral/genética , Hepacivirus/genética , Hepacivirus/fisiologia , Biossíntese de Proteínas , Proteínas/metabolismo , RNA Viral/genética , Replicação Viral , Regiões 3' não Traduzidas/metabolismo , Regiões 5' não Traduzidas/genética , Linhagem Celular Tumoral , RNA Helicases DEAD-box/metabolismo , Proteínas de Ligação a DNA/metabolismo , Endorribonucleases/metabolismo , Exorribonucleases/metabolismo , Inativação Gênica , Hepacivirus/patogenicidade , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Conformação de Ácido Nucleico , Ligação Proteica , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/química , Proteínas de Ligação a RNA/metabolismo , Replicon/genética , Transdução de Sinais
7.
J Virol ; 81(19): 10680-6, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17652404

RESUMO

Short interfering RNAs (siRNAs) targeting viral or cellular genes can efficiently inhibit human immunodeficiency virus type 1 (HIV-1) replication. Nevertheless, optimal HIV-1 gene silencing by siRNA requires precise complementarity with most of the target sequence. The emergence of mutations in the targeted gene could lead to rapid viral escape from the siRNA. In the present study, Escherichia coli endoribonuclease III (RNase III) or mammalian Dicer was used to cleave double-stranded RNA into endoribonuclease-prepared siRNA (esiRNA). esiRNAs generate a variety of siRNAs which can efficiently and specifically target multiple sites in the cognate RNA. esiRNAs targeting the region encoding the HIV-1 reverse transcriptase (RT) reduced viral replication by 90%. The inhibition was dose dependent and sequence specific because several irrelevant esiRNAs did not inhibit HIV-1 replication. Importantly, esiRNAs obtained from the prototypic RT sequence of the HXB2 strain and from highly mutated RT sequences showed similar degrees of viral inhibition, suggesting that the heterogeneous population of esiRNAs could overcome individual mismatches in the RT sequence. Finally, esiRNAs generated by Dicer cleavage were five times more potent than those generated by bacterial RNase III digestion. These results show that esiRNAs are potent HIV-1 inhibitors. Moreover, sequence targets do not need to be highly conserved to reach a high level of viral replication inhibition.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteínas de Escherichia coli/química , HIV-1/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Ribonuclease III/química , Replicação Viral/efeitos dos fármacos , Fármacos Anti-HIV/química , DNA Viral/química , Humanos , RNA de Cadeia Dupla/química , RNA Interferente Pequeno/química
8.
J Virol ; 80(2): 571-7, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16378959

RESUMO

Short interfering RNAs (siRNAs) targeting viral or cellular genes can efficiently inhibit human immunodeficiency virus type 1 (HIV-1) replication. Nevertheless, the emergence of mutations in the gene being targeted could lead to the rapid escape from the siRNA. Here, we simulate viral escape by systematically introducing single-nucleotide substitutions in all 19 HIV-1 residues targeted by an effective siRNA. We found that all mutant viruses that were tested replicated better in the presence of the siRNA than in the presence of the wild-type virus. The antiviral activity of the siRNA was completely abolished by single substitutions in 10 (positions 4 to 11, 14, and 15) out of 16 positions tested (substitution at 3 of the 19 positions explored rendered nonviable viruses). With the exception of the substitution observed at position 12, substitutions at either the 5' end or the 3' end (positions 1 to 3, 16, and 18) were better tolerated by the RNA interference machinery and only in part affected siRNA inhibition. Our results show that optimal HIV-1 gene silencing by siRNA requires a complete homology within most of the target sequence and that substitutions at only a few positions at the 5' and 3' ends are partially tolerated.


Assuntos
Inativação Gênica , HIV-1/fisiologia , RNA Interferente Pequeno/genética , Substituição de Aminoácidos , Infecções por HIV/terapia , Transcriptase Reversa do HIV/genética , HIV-1/genética , Mutação , Replicação Viral
9.
Clin Infect Dis ; 40(9): 1342-9, 2005 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15828087

RESUMO

BACKGROUND: Plasma levels of several chemokines and cytokines were evaluated in a cohort of 161 human immunodeficiency virus (HIV)positive patients to shed light on a clinically relevant mechanism that would explain the putative beneficial effect of GB virus type C (GBV-C) coinfection. METHODS: Markers for GBV-C infection were assessed in plasma samples. The syncitium-inducing (SI) capacity of isolated virus from each patient was determined in MT-2 cells. Plasma cytokine and chemokine levels were quantified with use of a commercial enzyme-linked immunosorbent assay. RESULTS: GBV-C viremia was found in 44 (27%) of 161 patients, and anti-E2 antibodies were found in 18 (21%) of 87. In contrast to the findings of ex vivo analysis, no statistically significant differences were observed in levels of CCL5, stromal cell-derived factor 1, interleukin-7, and tumor necrosis factor-alpha in plasma of patients with or without GBV-C viremia. Seventy-two (45%) and 89 (55%) of our patients harbored SI and non-SI (NSI) strains, respectively. GBV-C viremia was less prevalent among patients with SI strains (13 [18%] of 72) than among patients with NSI strains (30 [34%] of 89; P = .6). Of interest, coinfected patients with SI strains had significantly higher CD4+ T cell values than did patients who were not coinfected. CONCLUSIONS: Our results suggest that GBV-C infection does not appear to influence the expression of the cytokines and chemokines analyzed herein in a clinically relevant context. Alternative explanations for the elevated levels of HIV-inhibitory chemokines are needed to explain the putative beneficial effect of GBV-C.


Assuntos
Citocinas/metabolismo , Infecções por Flaviviridae/virologia , Vírus GB C/isolamento & purificação , Infecções por HIV/metabolismo , Adulto , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos , Estudos Transversais , Citocinas/sangue , Citocinas/genética , Feminino , Regulação da Expressão Gênica , Hepatite Viral Humana/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Viremia
10.
J Interferon Cytokine Res ; 25(3): 152-64, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15767789

RESUMO

The NS5A protein of hepatitis C virus (HCV) confers cell growth regulation and has been implicated in viral oncogenesis. Here, we investigated whether highly divergent NS5A proteins obtained from HCV-infected patients presented an oncogenic potential when expressed in mammalian cells. In general, NS5A expression was associated with increased rates of cell growth and culture proliferation. Immortalized primary hepatocyte and immortalized fibroblast cell lines expressing a subset of these sequences exhibited a significant increase in protein synthetic rate, culture saturation density, and a transformed cellular phenotype, as shown by anchorage-independent cell growth and colony formation in soft agar assays. Oncogenic transformation correlated with inhibition of protein kinase R (PKR) activity and concomitant reduction of eukaryotic initiation factor 2alpha (elF2alpha) phosphorylation levels that caused stimulation of mRNA translation. The extent of sequence variation throughout NS5A or within the previously characterized PKR-binding domain was not a predictive indicator of this cellular phenotype, suggesting that sequences outside this region contribute to PKR regulation. Our data indicate that NS5A oncogenic potential is conditional through viral sequence variation. These results provide further evidence to define the PKR pathway as a mediator of cell growth control and suggest that viral regulation of PKR may contribute to hepatocyte growth deregulation during chronic HCV infection.


Assuntos
Hepacivirus/genética , Hepacivirus/patogenicidade , Proteínas não Estruturais Virais/genética , eIF-2 Quinase/fisiologia , Sequência de Aminoácidos , Animais , Carcinoma Hepatocelular/etiologia , Linhagem Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Viral/genética , Transformação Celular Viral/fisiologia , Variação Genética , Humanos , Neoplasias Hepáticas/etiologia , Camundongos , Dados de Sequência Molecular , Células NIH 3T3 , Homologia de Sequência de Aminoácidos , Proteínas não Estruturais Virais/fisiologia
11.
J Gen Virol ; 86(Pt 4): 1067-75, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15784900

RESUMO

The quasispecies nature of hepatitis C virus (HCV) may have important implications concerning resistance to antiviral agents. To determine whether HCV NS5A quasispecies composition and dynamics are related to responsiveness to combined interferon (IFN) and ribavirin therapy, extensive sequence analyses of cloned RT-PCR amplification products of HCV-1b NS5A quasispecies of sequential isolates from 15 treated (nine sustained responders and six non-responders) and three untreated patients were performed. Accumulation of mutations in NS5A during therapy was relatively frequent in the V3 domain, but unusual elsewhere. Amino acid changes were the result of the imposition of minor variants that were already present before treatment and always occurred within the first week of therapy. Before treatment, the complexity and diversity of quasispecies were lower in isolates from responders than in those from non-responders, particularly in the V3 domain, where differences in nucleotide entropy (0.35 vs 0.64, P=0.003), genetic distance (0.0145 vs 0.0302, P=0.05) and non-synonymous substitutions (0.0102 vs 0.0203, P=0.036) were statistically significant. These differences became more apparent during treatment, because complexity and diversity remained stable or tended to increase in non-responders, whereas they tended to decrease in responders. These observations suggest that the composition and dynamics of HCV NS5A quasispecies, particularly in the V3 domain, may play a role in the response to combined IFN/ribavirin therapy.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Mutação , Ribavirina/uso terapêutico , Proteínas não Estruturais Virais/genética , Sequência de Aminoácidos , Quimioterapia Combinada , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Dados de Sequência Molecular , Proteínas Recombinantes , Análise de Sequência de DNA , Resultado do Tratamento , Proteínas não Estruturais Virais/química
12.
J Med Virol ; 71(2): 195-204, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12938193

RESUMO

The quasispecies nature of hepatitis C virus (HCV) is thought to play a central role in modulating viral functions. Recent work has linked NS5A protein with viral replication, resistance to interferon (IFN), and control of cellular growth, probably through the interaction of its protein kinase R (double stranded RNA-activated protein kinase, PKR) binding domain (PKR-bd) with cellular PKR, but knowledge of how PKR-bd viral population evolves during disease progression is limited. Since we have previously described an association between amino acid composition of the PKR-bd and the presence of HCC, in this report we further investigated the dynamic behavior of viral population parameters by sequencing an average of 20 clones per sample in 27 samples from 19 untreated patients with different degrees of liver disease, 8 of whom were followed over time. Viral population parameters varied widely from patient to patient, but no differences were observed in the complexity, diversity, types of nucleotide changes, or evolutionary pattern of the quasispecies according to the stage of liver disease. In five samples, we detected "quasispecies-tails"; that is, clones whose minimum genetic distance to the remaining clones of their own quasispecies were higher than the maximum genetic distance found between any other two clones of the same sample. In summary, independent of the degree of liver disease, or the mutations detected within the consensus sequence of the PKR-bd, the NS5A of HCV presents a flexible and variable quasispecies structure that remains largely stable during the natural course of an HCV infection, highlighting the central role of NS5A protein in viral life cycle.


Assuntos
Carcinoma Hepatocelular/fisiopatologia , Evolução Molecular , Hepacivirus/patogenicidade , Hepatite C Crônica/fisiopatologia , Cirrose Hepática/fisiopatologia , Proteínas não Estruturais Virais/genética , Sequência de Aminoácidos , Carcinoma Hepatocelular/virologia , Progressão da Doença , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/virologia , Dados de Sequência Molecular , Mutação , Filogenia , Análise de Sequência de DNA , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , eIF-2 Quinase/química , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
13.
J Clin Microbiol ; 40(11): 4363-6, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12409433

RESUMO

In July 2000, symptomatic acute hepatitis C was diagnosed in five patients who had attended the emergency room of a municipal hospital on the same day, about 6 weeks before. Investigation of the remaining 65 patients visited at the emergency room on that day disclosed that 8 patients had a positive anti-hepatitis C virus (anti-HCV) test and 4 of them had biochemical evidence of acute anicteric hepatitis. HCV RNA was detected in 12 of the 13 anti-HCV-positive patients. Phylogenetic analysis of the nonstructural 5A (NS5A) and E2 regions showed that 10 patients, including all 9 with acute hepatitis, were infected with a closely related HCV strain, while the remaining 2 patients harbored unrelated strains. Flushing of intravenous catheters with heparin retrieved from a multidose heparin solution in saline was carried out for all the patients involved in the hepatitis outbreak but in only 1 of 23 (4%) matched controls recruited among HCV-noninfected patients attending the emergency room on the same day, and this was the only significant difference concerning risk factors for HCV infection between patients and controls. Thus, accidental contamination of a multidose heparin solution with blood from an unrecognized HCV carrier was identified as the source of this nosocomial outbreak of hepatitis C.


Assuntos
Infecção Hospitalar/epidemiologia , Surtos de Doenças , Hepacivirus/isolamento & purificação , Hepatite C/epidemiologia , RNA Viral/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecção Hospitalar/virologia , Serviço Hospitalar de Emergência , Feminino , Hepacivirus/genética , Hepatite C/virologia , Hospitais Urbanos , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Análise de Sequência de DNA , Proteínas do Envelope Viral/genética , Proteínas não Estruturais Virais/genética
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