RESUMO
Arthritogenic alphaviruses are mosquito-borne viruses that are a major cause of infectious arthropathies worldwide, and recent outbreaks of chikungunya virus and Ross River virus (RRV) infections highlight the need for robust intervention strategies. Alphaviral arthritis can persist for months after the initial acute disease, and is mediated by cellular immune responses. A common strategy to limit inflammation and pathology is to dampen the overwhelming inflammatory responses by modulating proinflammatory cytokine pathways. Here, we investigate the contribution of interleukin-17 (IL-17), a cytokine involved in arthropathies such as rheumatoid arthritis, in the development RRV-induced arthritis and myositis. IL-17 was quantified in serum from RRV-infected patients, and mice were infected with RRV and joints and muscle tissues collected to analyse cellular infiltrates, tissue mRNA, cytokine expression, and joint and muscle histopathology. IL-17 expression was increased in musculoskeletal tissues and serum of RRV-infected mice and humans, respectively. IL-17-producing T cells and neutrophils contributed to the cellular infiltrate in the joint and muscle tissue during acute RRV disease in mice. Blockade of IL-17A/F using a monoclonal antibody (mAb) reduced disease severity in RRV-infected mice and led to decreased proinflammatory proteins, cellular infiltration in synovial tissues and cartilage damage, without affecting viral titers in inflamed tissues. IL-17A/F blockade triggered a shift in transcriptional profile of both leukocyte infiltrates and musculoskeletal stromal cells by downregulating proinflammatory genes. This study highlights a previously uncharacterized role for an effector cytokine in alphaviral pathology and points towards potential therapeutic benefit in targeting IL-17 to treat patients presenting with RRV-induced arthropathy.
Assuntos
Artrite Reumatoide/imunologia , Imunidade Celular , Inflamação/imunologia , Interleucina-17/imunologia , Miosite/imunologia , Ross River virus/imunologia , Infecções por Alphavirus/imunologia , Infecções por Alphavirus/virologia , Animais , Artrite Reumatoide/virologia , Chlorocebus aethiops , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miosite/virologia , Células Vero , Carga ViralRESUMO
HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5-10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6-6.4%; p = 0.002); and in chronic HIV-1 infection to 1.9% (IQR: 1.1-3%; p < 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and ß7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects.
Assuntos
Antígenos CD/imunologia , Proliferação de Células/genética , Infecções por HIV/genética , Terapia de Alvo Molecular , 5'-Nucleotidase/genética , 5'-Nucleotidase/imunologia , Antígenos CD/genética , Antígenos CD/uso terapêutico , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Infecções por HIV/imunologia , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/patogenicidade , Humanos , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/imunologia , Memória de Longo Prazo/fisiologiaRESUMO
BACKGROUND: In hepatitis C virus (HCV) infection, virus-specific CD8+ T cells are recruited to the liver for antiviral activity. Multiple chemokine ligands are induced by the infection, notably interferon-inducible chemokine, CXCL10. In HCV, intrahepatic T cells express chemokine receptors (CCRs), including CXCR3, CXCR6, CCR1, and CCR5, but CCR expression on antigen-specific effector and memory T cells has not been investigated. METHODS: Paired blood and liver samples were collected from subjects with chronic HCV for flow cytometric analysis of CCR expression on CD8+ T cells. Expression of these CCRs was then examined on HCV-specific CD8+ T-cell subpopulations in the blood from subjects with acute or chronic HCV. RESULTS: Relative to peripheral blood, the liver was enriched with CD8+ T cells expressing CCR2, CCR5, CXCR3, and CXCR6 either singly or in combinations. CXCR3 was preferentially expressed on HCV-specific CD8+ T cells in both acute and chronic phases of infection in blood. Both CXCR3 and CCR2 were overexpressed on HCV-specific CD8+CCR7+CD45RO+ (central memory) cells, whereas effector memory (CD8+CCR7-CD45RO+) cells expressed more CXCR6. CONCLUSIONS: CXCR3-mediated signals support the accumulation of HCV-specific CD8+ memory T cells in the infected liver, and emphasize the importance of the CXCL10/CXCR3 trafficking pathway during acute and chronic HCV infection.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Quimiocinas/metabolismo , Hepatite C Crônica/imunologia , Hepatite C Crônica/metabolismo , Receptores de Quimiocinas/metabolismo , Doença Aguda , Adulto , Quimiocina CXCL10/metabolismo , Feminino , Hepatite C Crônica/sangue , Humanos , Antígenos Comuns de Leucócito/metabolismo , Fígado/imunologia , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores CCR2/metabolismo , Receptores CCR5/metabolismo , Receptores CCR7/metabolismo , Receptores CXCR3/metabolismo , Receptores CXCR6/metabolismoRESUMO
Despite significant reductions in morbidity and mortality secondary to availability of effective combination anti-retroviral therapy (cART), human immunodeficiency virus (HIV) infection still accounts for 1.5 million deaths annually. The majority of deaths occur in sub-Saharan Africa where rates of opportunistic co-infections are disproportionately high. In this review, we discuss the immunopathogenesis of five common infections that cause significant morbidity in HIV-infected patients globally. These include co-infection with Mycobacterium tuberculosis, Cryptococcus neoformans, hepatitis B virus, hepatitis C virus, and Plasmodium falciparum. Specifically, we review the natural history of each co-infection in the setting of HIV, the specific immune defects induced by HIV, the effects of cART on the immune response to the co-infection, the pathogenesis of immune restoration disease (IRD) associated with each infection, and advances in the areas of prevention of each co-infection via vaccination. Finally, we discuss the opportunities and gaps in knowledge for future research.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/imunologia , Infecções por HIV/imunologia , Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , África Subsaariana , Animais , Criptococose/imunologia , Criptococose/prevenção & controle , Infecções por HIV/tratamento farmacológico , Hepatite B/imunologia , Hepatite B/prevenção & controle , Hepatite C/imunologia , Hepatite C/prevenção & controle , Humanos , Malária/imunologia , Malária/prevenção & controle , Tuberculose/imunologia , Tuberculose/prevenção & controleRESUMO
UNLABELLED: The interaction between hepatitis C virus (HCV) and cellular immune responses during very early infection is critical for disease outcome. To date, the impact of antigen-specific cellular immune responses on the evolution of the viral population establishing infection and on potential escape has not been studied. Understanding these early host-virus dynamics is important for the development of a preventative vaccine. Three subjects who were followed longitudinally from the detection of viremia preseroconversion until disease outcome were analyzed. The evolution of transmitted/founder (T/F) viruses was undertaken using deep sequencing. CD8(+) T cell responses were measured via enzyme-linked immunosorbent spot (ELISpot) assay using HLA class I-restricted T/F epitopes. T/F viruses were rapidly extinguished in all subjects associated with either viral clearance (n = 1) or replacement with viral variants leading to establishment of chronic infection (n = 2). CD8(+) T cell responses against 11 T/F epitopes were detectable by 33 to 44 days postinfection, and 5 of these epitopes had not previously been reported. These responses declined rapidly in those who became chronically infected and were maintained in the subject who cleared infection. Higher-magnitude CD8(+) T cell responses were associated with rapid development of immune escape variants at a rate of up to 0.1 per day. Rapid escape from CD8(+) T cell responses has been quantified for the first time in the early phase of primary HCV infection. These rapid escape dynamics were associated with higher-magnitude CD8(+) T cell responses. These findings raise questions regarding optimal selection of immunogens for HCV vaccine development and suggest that detailed analysis of individual epitopes may be required. IMPORTANCE: A major limitation in our detailed understanding of the role of immune response in HCV clearance has been the lack of data on very early primary infection when the transmitted viral variants successfully establish the acute infection. This study was made possible through the availability of specimens from a unique cohort of asymptomatic primary infection cases in whom the first available viremic samples were collected approximately 3 weeks postinfection and at regular intervals thereafter. The study included detailed examination of both the evolution of the viral population and the host cellular immune responses against the T/F viruses. The findings here provide the first evidence of host cellular responses targeting T/F variants and imposing a strong selective force toward viral escape. The results of this study provide useful insight on how virus escapes the host response and consequently on future analysis of vaccine-induced immunity.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Hepacivirus/imunologia , Hepacivirus/patogenicidade , Hepatite C/imunologia , Hepatite C/virologia , Doença Aguda , Adulto , Sequência de Aminoácidos , Anticorpos Antivirais/sangue , Progressão da Doença , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Evolução Molecular , Hepacivirus/genética , Antígenos de Hepatite/genética , Antígenos de Hepatite/imunologia , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Celular , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Seleção Genética , Fatores de Tempo , Vacinas contra Hepatite Viral/imunologia , Carga Viral , Adulto JovemRESUMO
BACKGROUND: T cells have been implicated in neuropathic pain that is caused by peripheral nerve injury. Immunogenic myelin basic protein (MBP) peptides have been shown to initiate mechanical allodynia in a T cell-dependent manner. Antagonistic altered peptide ligands (APLs) are peptides with substitutions in amino acid residues at T cell receptor contact sites and can inhibit T cell function and modulate inflammatory responses. In the present study, we studied the effects of immunization with MBP-derived APL on pain behavior and neuroinflammation in an animal model of peripheral nerve injury. METHODS: Lewis rats were immunized subcutaneously at the base of the tail with either a weakly encephalitogenic peptide of MBP (cyclo-MBP87-99) or APL (cyclo-(87-99)[A(91),A(96)]MBP87-99) in complete Freund's adjuvant (CFA) or CFA only (control), following chronic constriction injury (CCI) of the left sciatic nerve. Pain hypersensitivity was tested by measurements of paw withdrawal threshold to mechanical stimuli, regulatory T cells in spleen and lymph nodes were analyzed by flow cytometry, and immune cell infiltration into the nervous system was assessed by immunohistochemistry (days 10 and 30 post-CCI). Cytokines were measured in serum and nervous tissue of nerve-injured rats (day 10 post-CCI). RESULTS: Rats immunized with the APL cyclo-(87-99)[A(91),A(96)]MBP87-99 had significantly reduced mechanical pain hypersensitivity in the ipsilateral hindpaw compared to cyclo-MBP87-99-treated and control rats. This was associated with significantly decreased infiltration of T cells and ED1+ macrophages in the injured nerve of APL-treated animals. The percentage of anti-inflammatory (M2) macrophages was significantly upregulated in the APL-treated rats on day 30 post-CCI. Compared to the control rats, microglial activation in the ipsilateral lumbar spinal cord was significantly increased in the MBP-treated rats, but was not altered in the rats immunized with the MBP-derived APL. In addition, immunization with the APL significantly increased splenic regulatory T cells. Several cytokines were significantly altered after CCI, but no significant difference was observed between the APL-treated and control rats. CONCLUSIONS: These results suggest that immune deviation by active immunization with a non-encephalitogenic MBP-derived APL mediates an analgesic effect in animals with peripheral nerve injury. Thus, T cell immunomodulation warrants further investigation as a possible therapeutic strategy for the treatment of peripheral neuropathic pain.
Assuntos
Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Neuropatia Ciática/complicações , Vacinação/métodos , Animais , Chaperonina 60/imunologia , Citocinas/sangue , Modelos Animais de Doenças , Adjuvante de Freund/efeitos adversos , Lateralidade Funcional , Gânglios Espinais/citologia , Macrófagos/metabolismo , Masculino , Proteína Básica da Mielina/efeitos adversos , Proteína Básica da Mielina/imunologia , Limiar da Dor/efeitos dos fármacos , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/imunologia , Ratos , Ratos Endogâmicos Lew , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Fatores de TempoRESUMO
BACKGROUND & AIMS: In chronic hepatitis C virus infection (CHC), expression of suppressor of cytokine signalling-3 (SOCS3) has been shown to be associated with obesity and non-response to antiviral therapy. In this study, we aimed to determine the effect of SOCS3 induction on the cytokine response in patients receiving Pegylated interferon (PegIFN) and ribavirin (RBV) therapy. METHODS: Peripheral blood mononuclear cells (PBMC) collected at baseline and at 12 weeks from CHC patients receiving PegIFN/RBV therapy were examined for mRNA and protein SOCS3 expression. Immunological assays were employed to examine cytokine production. RESULTS: There was increased expression of SOCS3 in PBMC of non-responders at week 12 of therapy, when compared to treatment responders (P = 0.0001). The expression of SOCS3 correlated with body mass index (BMI) (r = 0.54; P = 0.01). Patients with low SOCS3 expression at week 12 of therapy had lower HCV-specific IFN-γ production in enzyme-linked immunosorbent spot (ELISpot) assays (P = 0.01), and reduced ex-vivo production of the anti-HCV effector cytokines interleukin (IL)-2 and tumour necrosis factor (TNF)-α(P = 0.01 and P = 0.04 respectively). Analysis of serum cytokine levels revealed higher levels of IL-6 at week 12 in the high SOCS3 expression group (P = 0.02) while IL-6 levels correlated with SOCS3 expression in the entire cohort (P = 0.04). Ex-vivo studies confirmed that IL-6 induced SOCS3, and neutralisation of IL-6 reduced levels of SOCS3. CONCLUSION: In subjects with increased BMI and non-response to antiviral therapy, the IL-6/SOCS3 axis appears to play a crucial role in altering the anti-HCV-cytokine response associated with antiviral therapy.
Assuntos
Citocinas/sangue , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Proteínas Supressoras da Sinalização de Citocina/imunologia , Western Blotting , Índice de Massa Corporal , Estudos de Coortes , Primers do DNA/genética , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática , ELISPOT , Humanos , Interferon-alfa/uso terapêutico , Interferon gama/sangue , Interleucina-2/sangue , Interleucina-6/sangue , Leucócitos Mononucleares/metabolismo , Polietilenoglicóis/uso terapêutico , RNA Viral/sangue , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Estatísticas não Paramétricas , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/metabolismoRESUMO
BACKGROUND & AIMS: HCV seroprevalence surveys in longstanding injecting drug users (IDUs) reveal a small minority who remain seronegative, with some exhibiting HCV-specific cellular immunity. This study aimed to characterise this immunity, assess associations with risk behaviours and protection against infection. METHODS: A nested case-control series from a prospective cohort of seronegative IDUs was selected with incident cases (IN; n = 28) matched by demographics and risk behaviour to exposed uninfected (EU) subjects (n = 28). Samples were assayed for natural killer (NK) cell phenotypes and function, HCV-specific IFNγ in ELISpot, and HCV-specific CD4 T effector responses. IL28B and HLA-C/KIR2DL3 genotypes were tested. RESULTS: Numbers of activated (CD69(+)) NK cells in the mature CD56(dim)CD16(+) subset, and cytotoxic (NKp30(+)) cells in the CD56(bright)CD16(+) subset were higher in the EU subjects (p = 0.040, p = 0.038 respectively). EU subjects had higher frequencies of interferon gamma (IFNγ) producing NK cells, and lower frequencies of CD107a expression (p = 0.003, p = 0.015 respectively). By contrast, the frequency, magnitude, and breadth of HCV-specific CD4 and CD8 T cell responses did not differ, nor did IL28B, HLA-C, or KIR2DL3 allele frequencies. CONCLUSIONS: Sustained NK cell activation contributes to protection against HCV infection. HCV-specific cellular immunity is prevalent in EU subjects but does not appear to be protective.
Assuntos
Hepatite C , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Abuso de Substâncias por Via Intravenosa , Adulto , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Usuários de Drogas/psicologia , Feminino , Perfilação da Expressão Gênica , Hepatite C/etiologia , Hepatite C/genética , Hepatite C/imunologia , Hepatite C/prevenção & controle , Humanos , Interferons , Interleucinas/genética , Interleucinas/imunologia , Lectinas Tipo C/imunologia , Masculino , Receptor 3 Desencadeador da Citotoxicidade Natural/imunologia , Receptores KIR2DL3/genética , Receptores KIR2DL3/imunologia , Assunção de Riscos , Abuso de Substâncias por Via Intravenosa/complicações , Abuso de Substâncias por Via Intravenosa/genética , Abuso de Substâncias por Via Intravenosa/imunologia , Abuso de Substâncias por Via Intravenosa/psicologiaRESUMO
BACKGROUND AND AIM: Chronic hepatitis C virus infection is characterized by infiltration of a mixed population of leukocytes into portal tracts and infiltration almost exclusively by CD8+ T cells into lobules of the liver. This pattern of leukocyte recruitment is likely to be orchestrated in a cell-specific fashion by local chemokine expression. METHODS: Portal or lobular tissues were isolated by laser capture microdissection from 17 liver biopsy specimens to examine regional gene expression of a panel of chemokine ligands and receptors. The biopsies were also stained immunohistochemically to enumerate regional cell numbers. RESULTS: Expression of multiple chemokine ligands and receptors was evident, although few correlated with leukocyte numbers. In the lobule, expression of CXCL10 correlated with T-cell subsets (CD3+, P = 0.0002; CD4+, P = 0.0053; and CD8+, P = 0.0061), as did CCL5 (CD3+, P = 0.0005; CD8+, P = 0.0199) and CCL3 (CD3+, P = 0.0016; CD8+, P = 0.008). In the portal tracts, expression of CXCL10 and CCL5 was correlated with CD8+ T-cell numbers (P = 0.0040 and P = 0.0114, respectively), whereas CXCL13 was strongly correlated with CD20+ B-cell numbers (P < 0.0001). CXCR3 expression correlated with CD3+ and CD4+ T cells (P < 0.0001 and P = 0.0208, respectively), CCR5 with CD8+ T cells (P < 0.0001), and CXCR5 with CD20+ B-cell infiltration (P = 0.0022). CONCLUSION: CXCR3, CCR5, and CXCR5 and their ligands form key elements of the "zip code" responsible for regional localization of specific lymphocyte subsets in the HCV-infected liver.
Assuntos
Quimiocinas/genética , Quimiocinas/metabolismo , Expressão Gênica , Hepatite C Crônica/genética , Hepatite C Crônica/imunologia , Fígado/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Antígenos CD/imunologia , Feminino , Humanos , Fígado/metabolismo , Masculino , Receptores CCR5/genética , Receptores CCR5/metabolismo , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Receptores CXCR5/genética , Receptores CXCR5/metabolismoRESUMO
Hepatitis C is a pandemic human RNA virus, which commonly causes chronic infection and liver disease. The characterization of viral populations that successfully initiate infection, and also those that drive progression to chronicity is instrumental for understanding pathogenesis and vaccine design. A comprehensive and longitudinal analysis of the viral population was conducted in four subjects followed from very early acute infection to resolution of disease outcome. By means of next generation sequencing (NGS) and standard cloning/Sanger sequencing, genetic diversity and viral variants were quantified over the course of the infection at frequencies as low as 0.1%. Phylogenetic analysis of reassembled viral variants revealed acute infection was dominated by two sequential bottleneck events, irrespective of subsequent chronicity or clearance. The first bottleneck was associated with transmission, with one to two viral variants successfully establishing infection. The second occurred approximately 100 days post-infection, and was characterized by a decline in viral diversity. In the two subjects who developed chronic infection, this second bottleneck was followed by the emergence of a new viral population, which evolved from the founder variants via a selective sweep with fixation in a small number of mutated sites. The diversity at sites with non-synonymous mutation was higher in predicted cytotoxic T cell epitopes, suggesting immune-driven evolution. These results provide the first detailed analysis of early within-host evolution of HCV, indicating strong selective forces limit viral evolution in the acute phase of infection.
Assuntos
Evolução Molecular , Genes Virais , Hepacivirus/genética , Hepatite C/imunologia , Hepatite C/virologia , Regiões 3' não Traduzidas , Regiões 5' não Traduzidas , Doença Aguda , Adulto , Sequência de Aminoácidos , Clonagem Molecular , Feminino , Marcadores Genéticos , Variação Genética , Haplótipos , Hepacivirus/isolamento & purificação , Hepatite C/transmissão , Humanos , Estudos Longitudinais , Masculino , Dados de Sequência Molecular , Filogenia , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , RNA Viral/genética , RNA Viral/isolamento & purificação , Análise de Sequência de DNA , Linfócitos T Citotóxicos/imunologia , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Adulto JovemRESUMO
Cytokine concentrations are thought to be affected by methods of sampling and processing and by storage conditions. In this study we compared 17 cytokine concentrations obtained from plasma and serum at baseline and after a controlled thaw condition. We found that absolute agreement was poor between concentrations of cytokines in plasma and serum, except for MIP1 ß . A thaw condition significantly changed the concentrations of most cytokines, but serum appeared less affected by this than plasma was. Closer examination using Bland-Altman analyses revealed that for each comparison, agreement was moderately good for many cytokine concentrations. This is important because measures of agreement must be interpreted based on the required precision, which may differ between clinical and research demands. We also identified that for some cytokines, the relationship between serum and plasma is affected by concentration, thus advocating for the use of appropriate methods when performing such comparisons in studies such as systematic reviews and meta-analyses.
Assuntos
Citocinas/sangue , Imunoensaio/métodos , Imunoensaio/normas , Manejo de Espécimes , Adolescente , Adulto , Idoso , Quimiocina CCL4/sangue , Feminino , Congelamento , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Hepatitis C virus (HCV) infection is a global pandemic associated with a growing disease burden due to cirrhosis and the consequent morbidity and mortality. Transmission is largely via blood-to-blood contact. Following primary infection, a minority of individuals clear the infection predominantly via cellular immune mechanisms, whereas the majority become chronically infected. Recent data suggest that a third outcome may also be possible, termed 'occult' infection in which subjects who are known, or suspected to have previously been infected with HCV, no longer have viral RNA in their serum at levels detectable by sensitive commercial assays, but do have virus detected by ultra-sensitive techniques. Occult infection has also been detected in peripheral blood mononuclear cells, which may indicate an extra-hepatic reservoir of the virus. Although the clinical significance of occult infection remains unknown, most authors have raised concerns of recrudescent infection. Here we critically review the published literature, suggest further avenues of investigation and propose that occult infection may be beneficial to the host by maintaining immunological memory to protect against reinfection.
Assuntos
Hepacivirus/fisiologia , Hepatite C/diagnóstico , Hepatite C/virologia , Animais , Antivirais/uso terapêutico , Técnicas e Procedimentos Diagnósticos , Hepacivirus/imunologia , Hepacivirus/isolamento & purificação , Hepatite C/tratamento farmacológico , Hepatite C/imunologia , Humanos , RNA Viral/sangue , RNA Viral/genética , Tropismo/imunologiaRESUMO
BACKGROUND: Several infections trigger postinfective fatigue syndromes, which share key illness characteristics with each other and with chronic fatigue syndrome (CFS). Previous cross-sectional case-control studies of CFS have suggested that unique gene expression signatures are evident in peripheral blood samples. METHODS: Peripheral blood transcriptomes in samples collected longitudinally, in 18 subjects with a fatigue syndrome lasting ≥ 6 months after acute infection due to Epstein-Barr virus, Ross River virus, or Coxiella burnetii (Q fever), and 18 matched control subjects who had recovered promptly, were studied by microarray (n = 127) and confirmatory quantitative polymerase chain reaction (PCR). Gene expression patterns associated with CFS were sought by univariate statistics and regression modeling. RESULTS: There were 23 genes with modest differential expression (0.6-2.3-fold change) in within-subject comparisons of early, symptomatic time points with late, recovered time points. There were modest differences found in 63 genes, either in cross-sectional comparison of cases and controls at 6 months after infection onset or in the regression model. There were 223 genes significantly correlated with individual symptom domains. Quantitative PCR confirmed 33 (73%) of 45 genes-none were consistent across cohorts. CONCLUSIONS: Although the illness characteristics of patients with postinfective fatigue syndromes have more similarities than differences, no reliable peripheral blood gene expression correlate is evident.
Assuntos
Infecções por Alphavirus/complicações , Infecções por Vírus Epstein-Barr/complicações , Síndrome de Fadiga Crônica/genética , Expressão Gênica , Febre Q/complicações , Ross River virus , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Síndrome de Fadiga Crônica/virologia , Feminino , Perfilação da Expressão Gênica , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Adulto JovemRESUMO
The cause of liver enzyme elevation during combination antiretroviral therapy in people with human immunodeficiency virus and hepatitis C virus co-infection is unclear. We followed 12 subjects (five with alanine transaminase elevation) for 24 weeks after combination antiretroviral therapy commencement. Immune responses against hepatitis C virus, human immunodeficiency virus and other viruses were assessed by interferon-γ ELISpot. Plasma cytokines, chemokines and anti-hepatitis C virus antibody levels were measured. Those with liver enzyme elevation had higher ELISpot responses both against hepatitis C virus non-structural regions and other viral antigens, and their anti-hepatitis C virus antibody levels were consistently higher, suggesting that reconstitution of both hepatitis C virus-specific and non-hepatitis C virus-specific immune responses may be associated with liver transaminase elevation during combination antiretroviral therapy.
Assuntos
Infecções por HIV/tratamento farmacológico , HIV-1/imunologia , Hepacivirus/imunologia , Hepatite C/tratamento farmacológico , Fígado/efeitos dos fármacos , Adulto , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Anticorpos Antivirais/metabolismo , Antígenos Virais/imunologia , Terapia Antirretroviral de Alta Atividade , Células Cultivadas , Coinfecção , ELISPOT , Seguimentos , Regulação da Expressão Gênica/imunologia , Infecções por HIV/enzimologia , Infecções por HIV/imunologia , HIV-1/patogenicidade , Hepacivirus/patogenicidade , Hepatite C/enzimologia , Hepatite C/imunologia , Humanos , Fígado/enzimologia , Fígado/imunologia , Fígado/virologia , Masculino , Pessoa de Meia-IdadeRESUMO
Multiple previous studies have sought evidence for ongoing, active infection with, or reactivation of, Herpesviruses in patients with chronic fatigue syndrome (CFS), with conflicting results. This study aimed to clarify this by studying 20 patients enrolled in a well-characterized model of the onset and evolution of CFS, the prospective cohort of the Dubbo Infection Outcomes Study (DIOS). The patients selected for examination included five CFS patients with primary Epstein-Barr virus (EBV) infection; five CFS patients with acute viral infection not caused by EBV; and 10 matched controls with prompt resolution of primary EBV infection. Serum samples from three timepoints were assayed using a comprehensive range of serological assays for EBV, HHV-6, and CMV. Viral genomes were assessed using quantitative PCR assays. All patients were seropositive for HHV-6, and 10 were seropositive for CMV at infection baseline (five patients and five controls). Low titer CMV IgM antibodies were found at infection baseline in two of these cases and three control patients. HHV-6 IgG antibody titers were highest at infection baseline but did not differ between the CFS cases and the control patients. There were increases in EBV IgG VCA p18, EBNA-1 IgG, and EA IgG titers over time, but these did not differ between CFS cases and control patients. EBV and HHV6 DNA levels were at control levels in a minority of samples, and CMV was undetectable in all samples. These data do not support the hypothesis of ongoing or reactivated EBV, HHV-6, or CMV infection in the pathogenesis of CFS.
Assuntos
Citomegalovirus/isolamento & purificação , Síndrome de Fadiga Crônica/virologia , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 6/isolamento & purificação , Adolescente , Adulto , Anticorpos Antivirais/sangue , Citomegalovirus/genética , Citomegalovirus/imunologia , DNA Viral/genética , DNA Viral/isolamento & purificação , Feminino , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 6/genética , Herpesvirus Humano 6/imunologia , Humanos , Técnicas Imunoenzimáticas , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Adulto JovemRESUMO
INTRODUCTION: Despite an effective vaccine, hepatitis B virus (HBV) infection continues to impose a large burden of disease globally. Until childhood immunisation achieves high adult population coverage, people who inject drugs (PWID), including prison inmates remain at risk. PWID have a higher prevalence of HBV than the wider population, and lower rates of vaccine-conferred immunity. This study sought to identify the incidence and predictors of HBV transmission and uptake of immunisation in PWID prisoners in Australia. METHODS: Longitudinally collected, stored sera from subjects previously enrolled in a prospective study of hepatitis C in recently incarcerated PWID prisoners (n = 590) were serologically tested for HBV. Interviews recording demographic and behavioural risks were analysed. Multivariate statistical analyses were applied to identify associations of incident infection or immunisation. RESULTS: Upon imprisonment there were n = 373 (63%) individuals who were HBV susceptible, of whom 140 remained susceptible at the subsequent enrolment into the cohort, and had one or more follow-up visits (a total of 406.73 person years [p.y.]), and so were included in this analysis. There were 7 incident cases of HBV infection (1.7 per 100 p.y.) in this group, with transmission being associated with injecting drug use daily or more often. There were 48 individuals who were successfully immunised (11.8 per 100 p.y.) with younger age and continuous imprisonment predicting this outcome. CONCLUSIONS: The Australian prison environment poses a high risk for HBV infection, and also provides an opportunity for immunisation for PWID. Further efforts are required to improve coverage and prevent ongoing transmissions.
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Hepatite B , Hepatite C , Prisioneiros , Abuso de Substâncias por Via Intravenosa , Adulto , Austrália/epidemiologia , Criança , Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Vírus da Hepatite B , Hepatite C/epidemiologia , Hepatite C/prevenção & controle , Humanos , Prevalência , Prisões , Estudos Prospectivos , Fatores de Risco , Abuso de Substâncias por Via Intravenosa/complicações , Abuso de Substâncias por Via Intravenosa/epidemiologiaRESUMO
BACKGROUND: Functional polymorphisms in immune response genes are increasingly recognized as important contributors to the marked individual differences in susceptibility to and outcomes of infectious disease. The acute sickness response is a stereotypical set of illness manifestations mediated by the proinflammatory cytokines induced by many different pathogens. The genetic determinants of severity of the acute sickness response have not previously been explored. METHODS: We examined the impact of functional polymorphisms in cytokine genes with critical roles in the early immune response (tumor necrosis factor-alpha, interleukin-6, interleukin-10, and interferon-gamma) on the severity and duration of illness following acute infection with Epstein-Barr virus, Coxiella burnetii (the causative agent of Q fever), or Ross River virus. RESULTS: We found that the interferon-gamma +874T/A and the interleukin-10 -592C/A polymorphisms significantly affected illness severity, cytokine protein levels, and the duration of illness. These cytokine genotypes acted in synergy to potentiate their influence on disease outcomes. CONCLUSIONS: These findings suggest that genetically determined variations in the intensity of the inflammatory response underpin the severity of the acute sickness response and predict the recovery time across varied infections.
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Infecções por Alphavirus/imunologia , Citocinas/genética , Citocinas/imunologia , Mononucleose Infecciosa/imunologia , Polimorfismo Genético , Febre Q/imunologia , Adolescente , Adulto , Idoso , Infecções por Alphavirus/patologia , Infecções por Alphavirus/fisiopatologia , Sequência de Bases , Coxiella burnetii/imunologia , Suscetibilidade a Doenças , Feminino , Herpesvirus Humano 4/imunologia , Humanos , Mononucleose Infecciosa/patologia , Mononucleose Infecciosa/fisiopatologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Febre Q/patologia , Febre Q/fisiopatologia , Ross River virus/imunologiaRESUMO
Peripheral blood specimens and clinical data were obtained over a 12-month period from subjects in the Dubbo Infection Outcomes Study to examine cytokine production in postinfective fatigue syndrome. Ex vivo production of 8 cytokines was examined in 22 case patients and in 42 control subjects who recovered promptly. No significant differences were found. Ongoing production of the cytokines examined does not play a role in postinfective fatigue syndrome.
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Citocinas/sangue , Síndrome de Fadiga Crônica/sangue , Adolescente , Adulto , Síndrome de Fadiga Crônica/patologia , Feminino , Humanos , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangueRESUMO
Peripheral immunity plays a key role in maintaining homeostasis and conferring crucial neuroprotective effects on the injured nervous system, while at the same time may contribute to increased vulnerability to neuropathic pain. Little is known about the reciprocal relationship between entrapment neuropathy and peripheral immunity. This study investigated immune profile in patients with carpal tunnel syndrome (CTS), the most prevalent entrapment neuropathy. All patients exhibited neurophysiological abnormalities in the median nerve, with the majority reporting neuropathic pain symptoms. We found a significant increase in serum CCL5, CXCL8, CXCL10 and VEGF, and in CD4+ central and effector memory T cells in CTS patients, as compared to healthy controls. CCL5 and VEGF were identified as having the highest power to discriminate between patients and controls. Interestingly, and contrary to the prevailing view of CCL5 as a pro-nociceptive factor, the level of circulating CCL5 was inversely correlated with neuropathic pain intensity and median nerve motor latency. In contrast, the level of central memory T cells was positively associated with abnormal neurophysiological findings. These results suggest that entrapment neuropathy is associated with adaptive changes in the homeostasis of memory T cells and an increase in systemic inflammatory modulating cytokines/chemokines, which potentially regulate neuropathic symptoms.
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Síndrome do Túnel Carpal/imunologia , Imunidade , Adulto , Idoso , Biomarcadores , Síndrome do Túnel Carpal/sangue , Síndrome do Túnel Carpal/diagnóstico , Citocinas/sangue , Feminino , Humanos , Memória Imunológica , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Avaliação de Sintomas , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Acute infection is known to perturb psycho-neuroendocrine-immune (PNI) gene expression. Oligonucleotide microarrays were used to examine PNI gene expression in the peripheral blood of 13 subjects with infectious mononucleosis (IM). Novel peripheral blood gene expression activity was correlated with central-nervous-system-mediated symptoms including fatigue and sleep disturbance. Of note, expression of the MADS box transcription enhancer factor 2 polypeptide C (MEF2C) gene, previously implicated in skeletal muscle myogenesis, correlated with symptoms of musculo-skeletal pain and fatigue. Expression of the hypocretin/orexin receptor HCRTR2, which has been implicated in narcolepsy, correlated with sleep disturbance. And, VACHT, the vesicular acetylcholine transporter, was highly correlated with neurocognitive disturbance. The expression of both HCRTR2 and MEF2C in the peripheral blood was validated by reverse transcription PCR. Thus, investigation of the PNI response in peripheral blood may provide novel insights into the complex pathophysiology of centrally mediated disease states.