RESUMEN
Viral hepatitis is caused by a heterogenous group of viral agents representing a wide range of phylogenetic groups. Many viruses can involve the liver and cause liver injury but only a subset are delineated as 'hepatitis viruses' based upon their primary site of replication and tropism for hepatocytes which make up the bulk of the liver cell population. Since their discovery, beginning with the agent that caused serum hepatitis in the 1960s, the alphabetic designations have been utilized. To date, we have five hepatitis viruses, A through E, though it is postulated that others may exist. This chapter will focus on those viruses. Note that hepatitis D is included as a subset of hepatitis B, as it cannot exist without concurrent hepatitis B infection. Pregnancy has the potential to affect all aspects of these viral agents due to the unique immunologic and physiologic changes that occur during and after the gestational period. In this review, we will discuss the most common viral hepatitis and their effects during pregnancy.
Asunto(s)
Hepatitis B , Hepatitis D , Hepatitis Viral Humana , Complicaciones Infecciosas del Embarazo , Femenino , Virus de Hepatitis , Hepatitis Viral Humana/epidemiología , Humanos , Filogenia , EmbarazoRESUMEN
The US is experiencing a major public health crisis that is fueled by the illicit use of synthetic opioids including fentanyl. While several drugs of abuse can enhance viral replication and/or antagonize immune responses, the impact of specific synthetic opioids on HIV pathogenesis is poorly understood. Thus, we evaluated the effects of fentanyl on HIV replication in vitro. HIV-susceptible or HIV-expressing cell lines were incubated with fentanyl. HIV p24 synthesis and chemokine receptor levels were quantified by ELISA in culture supernatants and cell lysates, respectively. Addition of fentanyl resulted in a dose-dependent increase in HIV replication. Fentanyl enhanced expression of the HIV chemokine co-receptors CXCR4 and CCR5 and caused a dose-dependent decrease in cell viability. The opioid antagonist naltrexone blocked the effect of fentanyl on HIV replication and CCR5 receptor levels but not CXCR4 receptor levels. TLR9 expression was induced by HIV; however, fentanyl inhibited TLR9 expression in a dose-dependent manner. These data demonstrate that the synthetic opioid fentanyl can promote HIV replication in vitro. As increased HIV levels are associated with accelerated disease progression and higher likelihood of transmission, additional research is required to enhance the understanding of opioid-virus interactions and to develop new and/or optimized treatment strategies for persons with HIV and opioid use disorder.
Asunto(s)
Infecciones por VIH , VIH-1 , Humanos , Fentanilo/farmacología , Fentanilo/metabolismo , Analgésicos Opioides/farmacología , Analgésicos Opioides/metabolismo , Receptores de Quimiocina/metabolismo , Receptor Toll-Like 9 , VIH-1/fisiología , Quimiocinas/metabolismo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Replicación ViralRESUMEN
BACKGROUND: The C-C chemokine receptor Type 5 (CCR5) is a key receptor for human immunodeficiency virus type 1 (HIV-1) entry into T-cells and a variant allele, CCR5 delta-32, is associated with decreased viral replication and disease progression. Active HIV-1 replication is highly associated with accelerated rates of hepatic fibrosis. We postulated that CCR5 plays a role in the development of hepatic fibrosis and evaluated the longitudinal effect of natural or drug-induced CCR5 mutation and blockade on biomarkers of liver fibrosis in HIV-1 patients. METHODS: To accomplish this goal, we examined 2 distinct cohorts. First, we evaluated fibrosis markers in the Multicenter Hemophilia Cohort Studies (MHCS), which included subjects with HIV and hepatitis C virus (HCV) coinfection with the CCR5 delta-32 allele. We also evaluated an HIV-1 infected cohort that was treated with a dual CCR5/CCR2 antagonist, cenicriviroc. The enhanced liver fibrosis (ELF) index was validated against liver histology obtained from HCV/HIV and HCV patients and demonstrated strong correlation with fibrosis stage. RESULTS: In both the MHCS patients and patients treated with cenicriviroc, CCR5 mutation or blockade was associated with a significant decrease in the ELF index. Among the patients with the delta-32 allele, the ELF index rate significantly decreased in sequential samples as compared to CCR5 wild-type patients (P = .043). This was not observed in control subjects treated with efavirenz nor with a lower dose of 100 mg cenicriviroc. CONCLUSION: These findings suggest that hepatic fibrosis in HIV-1 infected patients can be modulated by the mutation of CCR5 and/or use of CCR5/CCR2 blockade agents. CLINICAL TRIALS REGISTRATION: NCT01338883.
Asunto(s)
Infecciones por VIH/complicaciones , Hepatitis C/complicaciones , Imidazoles/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/inmunología , Receptores CCR5/genética , Adolescente , Adulto , Anciano , Alelos , Biomarcadores/análisis , Antagonistas de los Receptores CCR5/uso terapéutico , Niño , Preescolar , Estudios de Cohortes , Coinfección/complicaciones , Coinfección/virología , Método Doble Ciego , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Hepacivirus , Humanos , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Mutación , Estudios Observacionales como Asunto , Sulfóxidos , Adulto JovenRESUMEN
Diarrhea is one of the most common adverse side effects observed in â¼7% of individuals consuming Food and Drug Administration (FDA)-approved drugs. The mechanism of how these drugs alter fluid secretion in the gut and induce diarrhea is not clearly understood. Several drugs are either substrates or inhibitors of multidrug resistance protein 4 (MRP4), such as the anti-colon cancer drug irinotecan and an anti-retroviral used to treat HIV infection, 3'-azido-3'-deoxythymidine (AZT). These drugs activate cystic fibrosis transmembrane conductance regulator (CFTR)-mediated fluid secretion by inhibiting MRP4-mediated cAMP efflux. Binding of drugs to MRP4 augments the formation of MRP4-CFTR-containing macromolecular complexes that is mediated via scaffolding protein PDZK1. Importantly, HIV patients on AZT treatment demonstrate augmented MRP4-CFTR complex formation in the colon, which defines a novel paradigm of drug-induced diarrhea.
Asunto(s)
AMP Cíclico/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Diarrea/inducido químicamente , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Animales , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Aprobación de Drogas , Células HT29 , Humanos , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Irinotecán , Ratones , Modelos Moleculares , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/química , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/deficiencia , Conformación Proteica , Estados Unidos , United States Food and Drug AdministrationRESUMEN
The IL28B gene is associated with spontaneous or treatment-induced HCV viral clearance. However, the mechanism by which the IL28B single nucleotide polymorphism (SNP) affects the extra-hepatic HCV immune responses and its relationship to HCV pathogenesis have not been thoroughly investigated. To examine the mechanism by which IL28B affects HCV clearance. Forty Egyptian patients with chronic HCV infection receiving an Interferon/ribavirin treatment regimen were enrolled into this study. There were two groups: non-responders (NR; n = 20) and sustained virologic responders (SVR; n = 20). The initial plasma HCV viral loads prior to treatment and IL28B genotypes were determined by quantitative RT-PCR and sequencing, respectively. Liver biopsies were examined to determine the inflammatory score and the stage of fibrosis. Colonic regulatory T cell (Treg) frequency was estimated by immunohistochemistry. No significant association between IL28B genotypes and response to therapy was identified, despite an odds ratio of 3.4 to have the TT genotype in NR compared to SVR (95 % confidence interval 0.3-35.3, p = 0.3). Patients with the TT-IL28Brs12979860 genotype (unfavorable genotype) have significantly higher frequencies of colonic Treg compared to the CT (p = 0.04) and CC (p = 0.03) genotypes. The frequency of colonic Treg cells in HCV-infected patients had a strong association with the IL-28B genotype and may have a significant impact on HCV clearance.
Asunto(s)
Colon/inmunología , Interleucinas/genética , Mucosa Intestinal/inmunología , Polimorfismo de Nucleótido Simple , Linfocitos T Reguladores/inmunología , Adulto , Antivirales/uso terapéutico , Estudios Transversales , Egipto , Femenino , Hepatitis C Crónica/tratamiento farmacológico , Histocitoquímica , Humanos , Interferón-alfa/uso terapéutico , Interferones , Hígado/patología , Masculino , Persona de Mediana Edad , Plasma/virología , Ribavirina/uso terapéutico , Resultado del Tratamiento , Carga Viral , Adulto JovenRESUMEN
BACKGROUND AND AIM: Forkhead box protein P3 (FoxP3)(+) regulatory T (Treg ) cells play a fundamental role in maintaining the balance between the tissue-damaging and protective immune response to chronic hepatitis C (CHC) infection. Herein, we investigated the frequency of Treg cells in the colon and their potential relationship to the various CHC outcomes and hepatic histopathology. METHODS: Colonic biopsies were collected from three groups with CHC: treatment naïve (TN; n = 20), non-responders (NR; n = 20), sustained virologic response (SVR; n = 20), and a fourth healthy control group (n = 10). The plasma viral loads and cytokines levels were determined by quantitative real-time polymerase chain reaction, and ELISA, respectively. Liver biopsies were examined to assess inflammatory score and fibrosis stage. Colonic Treg frequency was estimated by immunohistochemistry using confocal microscopy. RESULTS: A significant increase in the frequency of colonic Treg was found in TN, and NR groups compared with the control and SVR group. The frequency of colonic Treg , plasma interleukin (IL)-10 and IL-4 levels were significantly positively correlated with viral load and negatively correlated with METAVIR inflammatory score, and fibrosis stages. CONCLUSION: Colonic Treg cells are negatively correlated with liver inflammation and hepatitis C virus (HCV) viral load, which suggests a strong linkage between gut-derived Treg cell populations and HCV infection.
Asunto(s)
Colon/inmunología , Colon/patología , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/patología , Hígado/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Adulto , Femenino , Fibrosis , Hepatitis C Crónica/sangre , Hepatitis C Crónica/virología , Humanos , Interleucina-10/sangre , Interleucina-4/sangre , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Carga Viral , Adulto JovenRESUMEN
BACKGROUND: SARS-CoV-2 vaccination induces a varied immune response among persons with chronic liver disease (CLD) and solid organ transplant recipients (SOTRs). We aimed to evaluate the humoral and T-cell-mediated immune responses to SARS-CoV-2 vaccination in these groups. METHODS: Blood samples were collected following the completion of a standard SARS-CoV-2 vaccination (2 doses of either BNT162b2 or mRNA-12732), and a subset of patients had a blood sample collected after a single mRNA booster vaccine. Three separate methods were utilized to determine immune responses, including an anti-spike protein antibody titer, neutralizing antibody capacity, and T-cell-mediated immunity. RESULTS: The cohort included 24 patients with chronic liver disease, 27 SOTRs, and 9 controls. Patients with chronic liver disease had similar immune responses to the wild-type SARS-CoV-2 compared with controls following a standard vaccine regimen and single booster vaccine. SOTRs had significantly lower anti-S1 protein antibodies (p < 0.001), neutralizing capacity (p < 0.001), and T-cell-mediated immunity response (p = 0.021) to the wild-type SARS-CoV-2 compared with controls following a standard vaccine regimen. Following a single booster vaccine, immune responses across groups were not significantly different but numerically lower in SOTRs. The neutralization capacity of the B.1.1.529 Omicron variant was not significantly different between groups after a standard vaccine regimen (p = 0.87) and was significantly lower in the SOTR group when compared with controls after a single booster vaccine (p = 0.048). CONCLUSION: The immunogenicity of the SARS-CoV-2 vaccine is complex and multifactorial. Ongoing and longitudinal evaluation of SARS-CoV-2 humoral and cellular responses is valuable and necessary to allow frequent re-evaluation of these patient populations.
Asunto(s)
COVID-19 , Hepatopatías , Humanos , Vacunas contra la COVID-19 , SARS-CoV-2 , Receptores de Trasplantes , Vacuna BNT162 , COVID-19/prevención & control , Vacunación , Inmunidad CelularRESUMEN
The US is in the midst of a major drug epidemic fueled in large part by the widespread recreational use of synthetic opioids such as fentanyl. Persons with opioid use disorder are at significant risk for transmission of injection-associated infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV). Commonly abused substances may antagonize immune responses and promote viral replication. However, the impact of synthetic opioids on virus replication has not been well explored. Thus, we evaluated the impact of fentanyl and carfentanil using in vitro systems that replicate infectious viruses. Fentanyl was used in cell lines replicating HBV or HCV at concentrations of 1 ng, 100 ng, and 10 ug. Viral protein synthesis was quantified by ELISA, while apoptosis and cell death were measured by M30 or MTT assays, respectively. HCV replicative fitness was evaluated in a luciferase-based system. RNAseq was performed to evaluate cellular gene regulation in the presence of fentanyl. Low dose fentanyl had no impact on HCV replication in Huh7.5JFH1 hepatocytes; however, higher doses significantly enhanced HCV replication. Similarly, a dose-dependent increase in HCV replicative fitness was observed in the presence of fentanyl. In the HepG2.2.15 hepatocyte cell line, fentanyl caused a dose-dependent increase in HBV replication, although only a higher doses than for HCV. Addition of fentanyl resulted in significant apoptosis in both hepatocyte cell lines. Cell death was minimal at low drug concentrations. RNAseq identified a number of hepatocyte genes that were differentially regulated by fentanyl, including those related to apoptosis, the antiviral / interferon response, chemokine signaling, and NFκB signaling. Collectively, these data suggest that synthetic opioids promote viral replication but may have distinct effects depending on the drug dose and the viral target. As higher viral loads are associated with pathogenesis and virus transmission, additional research is essential to an enhanced understanding of opioid-virus pathogenesis and for the development of new and optimized treatment strategies.
Asunto(s)
Fentanilo/efectos adversos , Hepacivirus/efectos de los fármacos , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B/virología , Hepatitis C/virología , Hepatocitos/virología , Replicación Viral , Analgésicos Opioides/efectos adversos , Apoptosis , Efecto Citopatogénico Viral , Células Hep G2 , Hepatitis B/inducido químicamente , Hepatitis B/patología , Hepatitis C/inducido químicamente , Hepatitis C/patología , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Humanos , Técnicas In Vitro , TranscriptomaRESUMEN
BACKGROUND: Hepatitis B virus (HBV) infection is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Due to their shared routes of transmission, approximately 10% of HIV-infected patients worldwide are chronically coinfected with HBV. Additionally, liver disease has become a major cause of morbidity and mortality in HBV/HIV coinfected patients due to prolonged survival with the success of antiretroviral therapy. The relationship between immune exhaustion markers (PD-1/PD-L1) and apoptotic markers such as Fas/FasL, TGFß1, TNF-α, and Th1/Th2 cytokines are not clearly delineated in HBV/HIV coinfection. METHODS: Levels of soluble Fas/FasL, TGFß1, TNF-α, and sPD-1/sPD-L1 as well as Th1 and Th2 cytokines were evaluated in the sera of HBV-monoinfected (n = 30) and HBV/HIV-coinfected (n = 15) patients and compared to levels in healthy controls (n = 20). RESULTS: HBV-monoinfected patients had significantly lower levels of the anti-inflammatory cytokine IL-4 (P < 0.05) and higher levels of apoptotic markers sFas, sFasL, and TGFß-1 (P < 0.001) compared to healthy controls. Coinfection with HIV was associated with higher levels of sFas, TNF-α, and sPD-L1 (P < 0.005), and higher levels of the pro-inflammatory cytokines IL-6, IL-8, and IL-12p70 (P < 0.05) compared to healthy controls. Patients with HBV infection had a unique biomarker clustering profile comprised of IFN-γ, IL12p70, IL-10, IL-6, and TNF-α that was distinct from the profile of the healthy controls, and the unique HIV/HBV profile comprised GM-CSF, IL-4, IL-2, IFN-γ, IL12p70, IL-7, IL-10, and IL-1ß. In HBV monoinfection a significant correlation between sFasL and PD1(r = 0.46, P = < 0.05) and between sFas and PDL1 (r = 0.48, P = <0.01) was observed. CONCLUSION: HBV-infected and HBV/HIV-coinfected patients have unique apoptosis and inflammatory biomarker profiles that distinguish them from each other and healthy controls. The utilization of those unique biomarker profiles for monitoring disease progression or identifying individuals who may benefit from novel immunotherapies such as anti-PD-L1 or anti-PD-1 checkpoint inhibitors appears promising and warrants further investigation.
RESUMEN
The efficacy of protease inhibitor drugs in hepatitis C virus (HCV) treatment is limited by the selection and expansion of drug-resistant mutations. HCV replication is error-prone and genetic variability within the dominant epitopes ensures its persistence. The aims of this study are to evaluate the role of cellular immune response in the emergence of HCV protease resistance mutations and its effects on treatment outcome. Ten chronically HCV-infected subjects were treated with boceprevir (BOC)-based triple therapy. HCV-RNA was tested for BOC resistance-associated viral variants. HCV protease resistance mutations were investigated pretreatment and 24 weeks post-treatment. Synthetic peptides representing the wild-type and the potential nonstructural (NS)3 variants were used to evaluate T cell responses and human leukocyte antigen binding. Sustained viral response was achieved in 70% of patients, two patients were treatment nonresponders (NRs) and one was classified as a relapse. Pretreatment, the proportion of drug-resistant variants within individuals was higher in sustained viral responders (SVRs) than in NR patients. However, resistance-associated variants increased in NRs after BOC combined triple therapy. In contrast to NR patients, significant stronger cell-mediated immune responses were observed at the baseline among those who achieved sustained viral response for all T cell epitopes tested. Despite the increase in cell-mediated immune responses at week 24 in NRs, they failed to control the virus replication, leading to development of overt drug-resistant variants. Our data suggest that strong NS3-specific T cell immune responses at the baseline may predict a positive outcome of directly acting antiviral-based therapy, and the presence of pre-existent resistance mutations does not play a significant role in the outcome of anti-HCV combined therapy.
Asunto(s)
Antivirales/farmacología , Farmacorresistencia Viral/genética , Hepacivirus/genética , Hepatitis C Crónica/inmunología , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/uso terapéutico , Quimioterapia Combinada , Femenino , Antígenos HLA/inmunología , Hepacivirus/efectos de los fármacos , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/sangre , Hepatitis C Crónica/genética , Hepatitis C Crónica/virología , Humanos , Inmunidad Celular , Masculino , Persona de Mediana Edad , Mutación , Proyectos Piloto , Prolina/análogos & derivados , Prolina/farmacología , Prolina/uso terapéutico , Estudios Prospectivos , Inhibidores de Proteasas/uso terapéutico , ARN Viral/genética , ARN Viral/aislamiento & purificación , Recurrencia , Linfocitos T/inmunología , Resultado del Tratamiento , Proteínas no Estructurales Virales/antagonistas & inhibidores , Adulto JovenRESUMEN
Extra-hepatic compartments might contribute to hepatitis C virus (HCV) persistence and extra-hepatic manifestations. Therefore, we investigated HCV infection in colonic tissue in patients with chronic hepatitis C (CHC) and its relationship with HCV pathogenesis. Colonic biopsies were collected from three groups with CHC infection: treatment naïve (TN; n=12), non-responders (NR; n=10) to anti-HCV therapy (pegylated interferon-α and ribavirin) and sustained virologic response (SVR; n=10) and from a fourth healthy control group (n=10). Liver biopsies were examined to assess inflammation and fibrosis. HCV infection and colonic T regulatory (Treg) frequency were detected by immunohistochemistry. HCV core and NS3 proteins were detected in B cells and macrophage/monocytes of 42 % and 25 % of TN and 50 % and 30 % of NR, respectively, but not in SVR or control group. The numbers of cells expressing HCV proteins were positively correlated with both HCV viral load and colonic Treg frequency. A significant negative correlation between HCV-expressing cells with both liver inflammation and fibrosis was identified. Our study provides evidence that HCV can infect B cells and macrophages of the colon. The correlations between HCV infection in colonic tissue and HCV viral load and liver pathology underline the significance of this extra-hepatic infection in HCV pathogenesis and response to therapy.
Asunto(s)
Colon/virología , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/virología , Adulto , Linfocitos B/virología , Biopsia , Estudios Transversales , Femenino , Humanos , Inmunohistoquímica , Hígado/virología , Macrófagos/virología , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/inmunología , Adulto JovenRESUMEN
The present study was carried out to investigate the protective effect of Physalis peruviana L. (family Solanaceae) against cadmium-induced neurotoxicity in rats. Adult male Wistar rats were randomly divided into four groups. Group 1 was used as control. Group 2 was intraperitoneally injected with 6.5 mg/kg bwt of cadmium chloride for 5 days. Group 3 was treated with 200 mg/kg bwt of methanolic extract of Physalis (MEPh). Group 4 was pretreated with MEPh 1 h before cadmium for 5 days. Cadmium treatment induced marked disturbances in neurochemical parameters as indicating by significant (p < 0.05) reduction in dopamine (DA), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in cerebellum, hippocampus, and cerebral cortex and enhanced significantly (p < 0.05) the levels of lipid peroxidation and nitric oxide in the brain. Cadmium treatment also decreased the amount of nonenzymatic and enzymatic antioxidants significantly (p < 0.05). Pretreatment with MEPh resulted in significant (p < 0.05) decreases in lipid peroxidation and nitric oxide levels and restored the amount of glutathione successfully. Although, preadministration of MEPh also brought the activities of cellular antioxidant enzymes, namely superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase significantly (p < 0.05) to the control levels, as well as the levels of Ca(2+), Cl(-), DA, 5-HT, and serotonin metabolite, 5-HIAA. These data indicated that Physalis has a beneficial effect in ameliorating the cadmium-induced oxidative neurotoxicity in the brain of rats.
Asunto(s)
Encéfalo , Cloruro de Cadmio/toxicidad , Síndromes de Neurotoxicidad , Physalis/química , Extractos Vegetales/farmacología , Animales , Antioxidantes/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Química Encefálica/efectos de los fármacos , Cadmio/toxicidad , Dopamina/metabolismo , Ácido Hidroxiindolacético/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/prevención & control , Oxidorreductasas/metabolismo , Extractos Vegetales/química , Ratas , Ratas Wistar , Serotonina/metabolismoRESUMEN
BACKGROUND: Immune activation is one of the main features of HIV/Hepatitis C virus (HCV) infections and has been linked to the disturbance of the gut-associated lymphoid tissue (GALT). In chronic HIV infection, loss of GALT integrity results in translocation of microbial products and chronic immune activation. We explored the relationship between bacterial translocation and specific colonic proteins, including liver expressed antimicrobial peptide (LEAP 2) which may play a role in modulating the bacterial translocation process. METHODS: A total of 40 subjects (10 HIV/HCV, 10 HIV, 10 HCV-infected patients and 10 controls) were enrolled and underwent serum and colonic tissue sampling. The levels of immune activation were evaluated by measuring plasma sCD27, and the levels of selected proinflammatory, Th2 and regulatory cytokines in both the plasma and supernatant of CD3-stimulated intraepithelial lymphocytes. We also evaluated LEAP-2 expression in the colon biopsies using Affymetrix Human Gene 1.0 ST (HuGene) and fluorescent immunohistochemistry. RESULTS: Increased levels of sCD27 were observed in HIV/HCV coinfected (p=0.03) and HIV monoinfected (p=0.04) patients compared with controls consistent with the presence of immune activation. The chip array identified LEAP-2 expression as a key marker associated with immune activation. LEAP-2 expression in HIV, HCV and HIV/HCV-infected patients was significantly lower compared with controls, and was significantly negatively correlated (p=0.03, r=-0.44) with sCD27. CONCLUSIONS: Our data suggests that HCV and HIV infections are associated with decreased expression of LEAP-2 in colonic tissue. This may represent a key mechanism for enhanced microbial translocation and immune activation in HIV/HCV-infected patients.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/metabolismo , Traslocación Bacteriana , Proteínas Sanguíneas/metabolismo , Infecciones por VIH/inmunología , VIH-1/inmunología , Hepacivirus/inmunología , Hepatitis C Crónica/inmunología , Adulto , Anciano , Péptidos Catiónicos Antimicrobianos/genética , Proteínas Sanguíneas/genética , Coinfección , Colon/inmunología , Colon/patología , Colon/virología , Citocinas/sangre , Citocinas/metabolismo , Perfilación de la Expresión Génica , Regulación Viral de la Expresión Génica , Infecciones por VIH/complicaciones , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/metabolismo , Hepatitis C Crónica/virología , Humanos , Hígado/inmunología , Hígado/patología , Hígado/virología , Activación de Linfocitos , Tejido Linfoide/inmunología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/sangre , Adulto JovenRESUMEN
BACKGROUND: We previously reported successful therapeutic immunization in a chimpanzee having a relatively low viral load, which was immunized with recombinant plasmid hepatitis B surface antigen (HBsAg) DNA and boosted with recombinant HBsAg encoding canarypox virus. In the present study, we attempted to confirm these findings in an animal with a high virus load. METHODS AND RESULTS: We tested three immunization strategies successively over a 3-year period. In the first of these, we administered four monthly injections of DNA encoding HBsAg + PreS2 + hepatitis B core antigen (HBcAg) + DNA encoding interleukin (IL)-12, (given 3 days later), and boosted with canarypox expressing all of the above HBV genes 6 months after initial immunization. No reduction in viral load was observed. In the second trial, we administered lamivudine for 8 weeks, and then began monthly DNA-based immunization with plasmids expressing the above viral genes; however, viral loads rebounded 1 week after termination of lamivudine therapy. In a third trial, we continued lamivudine therapy for 30 weeks and immunized with vaccinia virus expressing the above viral genes 18 and 23 weeks after the start of lamivudine therapy. Again viral loads rebounded shortly after cessation of lamivudine treatment. Analysis of cell-mediated immune responses, and their avidity, revealed that DNA-based immunization produced the strongest enhancement of high avidity T-cell responses, while recombinant vaccinia immunization during lamivudine therapy enhanced low avidity responses only. The strongest low and high avidity responses were directed to the middle surface antigen. CONCLUSIONS: Three strategies for therapeutic immunization failed to control HBV viremia in a chronically infected chimpanzee with a high viral load.
Asunto(s)
Enfermedades del Simio Antropoideo/terapia , Vacunas contra Hepatitis B/uso terapéutico , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/veterinaria , Inmunización/veterinaria , Pan troglodytes , Vacunas de ADN/uso terapéutico , Animales , Afinidad de Anticuerpos/inmunología , Antivirales/uso terapéutico , Enfermedades del Simio Antropoideo/inmunología , Enfermedades del Simio Antropoideo/virología , ADN Viral/química , ADN Viral/genética , Femenino , Antígenos del Núcleo de la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/genética , Antígenos de Superficie de la Hepatitis B/inmunología , Vacunas contra Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/terapia , Hepatitis B Crónica/virología , Inmunización/métodos , Interferón gamma/sangre , Lamivudine/uso terapéutico , Precursores de Proteínas/genética , Precursores de Proteínas/inmunología , ARN Viral/sangre , Vacunas de ADN/inmunología , Carga ViralRESUMEN
Immune correlates of protection against hepatitis C virus (HCV) infection are not well understood. Here we investigated 2 naive and 6 immunized chimpanzees before and after intravenous challenge, 12 weeks after the last immunization, with 100 50% chimpanzee infectious doses (CID(50)) of heterologous genotype 1b HCV. Vaccination with recombinant DNA and adenovirus vaccines expressing HCV core, E1E2, and NS3-5 genes induced long-term HCV-specific antibody and T-cell responses and reduced peak viral load about 100 times compared with controls (5.91 +/- 0.38 vs. 3.81 +/- 0.71 logs, respectively). There was a statistically significant inverse correlation between peak viral loads and envelope glycoprotein 2 (E2)-specific antibody responses at the time of challenge. Interestingly, one vaccinee that had sterilizing immunity against slightly heterologous virus generated the highest level of E2-specific total and neutralizing antibody responses as well as strong NS3/NS5-specific T-cell proliferative responses. The other four vaccinees with low levels of E2-specific antibody had about 44-fold reduced peak viral loads but eventually developed persistent infections. In conclusion, vaccine-induced E2-specific antibody plays an important role in prevention from nonhomologous virus infection and may provide new insight into the development of an effective HCV vaccine.