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Adaptive immune response during hepatitis C virus infection

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World Journal of Gastroenterology 2014年第13期20卷 3418-3430页

作者： juan ramon larrubia Elia Moreno-Cubero Megha Uttam Lokhande Silvia Garcia-Garzon Alicia Lazaro Joaquin Miquel Cristian Perna Eduardo Sanz-de-Villalobos Translational Hepatology Unit Guadalajara University HospitalUniversity of AlcalaE-19002 GuadalajaraSpain Department of Medicine and Medical Specialities School of MedicineUniversity of AlcalaE-28801 Alcala de HenaresSpain

Hepatitis C virus(HCV)infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular *** is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune *** damage and disease progression during HCV infection are driven by both viral and host ***,adaptive immune response carries out an essential task in controllingnon-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic *** is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and *** impair HCV-specific T cell reactivity,HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro-and antiapoptotic *** this review,the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.

关键词： Hepatitis C, Adaptive immune response, Hepatitis C virus-specific cytotoxic T cells, Hepatitis C virus-specific T helper cells, T regs, Hepatitis C virus escape mutations, Anergy, Apoptosis, Chemotaxis

Specific CD8^+ T cell response immunotherapy for hepatocellular carcinoma and viral hepatitis

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World Journal of Gastroenterology 2016年第28期22卷 6469-6483页

作者： Elia Moreno-Cubero juan-Ramón larrubia Translational Hepatology Unit Guadalajara University Hospital University of Alcalá Department of Biology of Systems University of Alcalá Department of Medicine and Medical Specialties University of Alcalá

Hepatocellular carcinoma (HCC), chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are characterized by exhaustion of the specific CD8+ T cell response. This process involves enhancement of negative co-stimulatory molecules, such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), 2B4, Tim-3, CD160 and LAG-3, which is linked to intrahepatic overexpression of some of the cognate ligands, such as PD-L1, on antigen presenting cells and thereby favouring a tolerogenic environment. Therapies that disrupt these negative signalling mechanisms represent promising therapeutic tools with the potential to restore reactivity of the specific CD8+ T cell response. In this review we discuss the impressive in vitro and in vivo results that have been recently achieved in HCC, CHB and CHC by blocking these negative receptors with monoclonal antibodies against these immune checkpoint modulators. The article mainly focuses on the role of CTLA-4 and PD-1 blocking monoclonal antibodies, the first ones to have reached clinical practice. The humanized monoclonal antibodies against CTLA-4 (tremelimumab and ipilimumab) and PD-1 (nivolumab and pembrolizumab) have yielded good results in testing of HCC and chronic viral hepatitis patients. Trelimumab, in particular, has shown a significant increase in the time to progression in HCC, while nivolumab has shown a remarkable effect on hepatitis C viral load reduction. The research on the role of ipilimumab, nivolumab and pembrolizumab on HCC is currently underway.

关键词： Hepatocellular carcinoma CD8+ T cells Immune checkpoint modulation Chronic viral hepatitis Cytotoxic T-lymphocyte antigen-4 Programmed cell death protein-1

Hepatitis C virus-specific cytotoxic T cell response restoration after treatment-induced hepatitis C virus control

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World Journal of Gastroenterology 2015年第12期21卷 3480-3491页

作者： juan-Ramón larrubia Elia Moreno-Cubero Joaquín Miquel Eduardo Sanz-de-Villalobos Translational Hepatology Unit Guadalajara University Hospital University of Alcalá Department of Medicine and Medical Specialties University of Alcalá Department of Biology of Systems University of Alcalá

Hepatitis C virus(HCV)-specific cytotoxic T cell(CTL) response plays a major role in viral control during spontaneous infection resolution. These cells develop an exhausted and pro-apoptotic status during chronic onset, being unable to get rid of HCV. The role of this response in contributing to sustained viral response(SVR) after anti-HCV is controversial. Recent studies show that after successful interferon-based anti-HCV treatment, HCV traces are still detectable and this correlates with a peak of HCV-specific CTL response activation, probably responsible for maintaining SVR by subsequent complete HCV clearing. Moreover, SVR patients' serum is still able to induce HCV infection in na?ve chimpanzees, suggesting that the infection could be under the control of the immune system after a successful treatment, being transmissible in absence of this adaptive response. At least theoretically, treatmentinduced viral load decrease could allow an effective HCV-specific CTL response reestablishment. This effect has been recently described with anti-HCV interferonfree regimes, based on direct-acting antivirals. Nevertheless, this is to some extent controversial with interferon-based therapies, due to the detrimental immunoregulatory α-interferon effect on T cells. Moreover, HCV-specific CTL response features during anti-HCV treatment could be a predictive factor of SVR that could have clinical implications in patient management. In this review, the recent knowledge about the role of HCV-specific CTL response in the development of SVR after anti-HCV treatment is discussed.

关键词： Hepatitis C virus Chronic hepatitis Hepatitis C vi

Costimulatory molecule programmed death-1 in the cytotoxic response during chronic hepatitis C

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World Journal of Gastroenterology 2009年第41期15卷 5129-5140页

作者： juan Ramón larrubia Selma Benito-Martínez Joaquín Miquel Miryam Calvino Eduardo Sanz-de-Villalobos Trinidad Parra-Cid Translational Hepatology Unit Guadalajara University Hospital University of Alcalá

Hepatitis C virus（HCV）-specific CD8^＋ T cells play an important role in the resolution of HCV infection. Nevertheless, during chronic hepatitis C these cells lack their effector functions and fail to control the virus. HCV has developed several mechanisms to escape immune control. One of these strategies is the upregulation of negative co-stimulatory molecules such us programmed death-1 （PD-1）. This molecule is upregulated on intrahepatic and peripheral HCV-specific cytotoxic T cells during acute and chronic phases of the disease, whereas PD-1 expression is low in resolved infection. PD-1 expressing HCV-specific CD8^＋ T cells are exhausted with impairment of several effector mechanisms, such as： type-1 cytokine production, expansion ability after antigen encounter and cytotoxic ability. However, PD-1 associated exhaustion can be restored by blocking the interaction between PD-1 and its ligand （PD-L1）. After this blockade, HCV-specific CD8^＋ T cells reacquire their functionality. Nevertheless, functional restoration depends on PD-1 expression level. High PD-l-expressing intrahepatic HCV-specific CD8^＋ T cells do not restore their effector abilities after PD-1/ PD-L1 blockade. The mechanisms by which HCV is able to induce PD-1 up-regulation to escape immune control are unknown. Persistent TCR stimulation by a high level of HCV antigens could favour early PD-1 induction, but the interaction between HCV core protein and gClq receptor could also participate in this process. The PD-1/PD-L1 pathway modulation could be a therapeutic strategy, in conjunction with the regulation of others co-stimulatory pathways, in order to restore immune response aclainst HCV to succeed in clearing the infection.

关键词： Chronic hepatitis Exhaustion Hepatitis C virus core Hepatitis C virus Programmed death-1 Programmed death-1 ligand

Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection

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World Journal of Gastroenterology 2008年第47期14卷 7149-7159页

作者： juan R larrubia Selma Benito-Martínez Miryam Calvino Eduardo Sanz-de-Villalobos Trinidad Parra-Cid Department of Gastroenterology Guadalajara University HospitalUniversity of AlcaláDonante de Sangre st.19002 GuadalajaraSpain Guadalajara University Hospital University of AlcaláDonante de Sangre st.19002 GuadalajaraSpain

Chemokines produced in the liver during hepatitis C virus(HCV) infection induce migration of activated T cells from the periphery to infected *** milieu of chemokines secreted by infected hepatocytes is predominantly associated with the T-helper cell/Tc1 T cell(Th1/Tc1) *** chemokines consist of CCL3(macrophage inflammatory protein-1α;MIP-1α),CCL4(MIP-1β),CCL5(regulated on activation normal T cell expressed and secreted;RANTES),CXCL10(interferon-γ-inducible protein-10;IP-10),CXCL11(interferon-inducible T-cell α chemoattractant;I-TAC),and CXCL9(monokine induced by interferon γ;Mig) and they recruit T cells expressing either CCR5 or CXCR3 chemokine *** and peripheral blood levels of these chemokines are increased during chronic hepatitis *** interaction between chemokines and their receptors is essential in recruiting HCV-specific T cells to control the *** the adaptive immune response fails in this task,non-specific T cells without the capacity to control the infection are also recruited to the liver,and these are ultimately responsible for the persistent hepatic *** modulation of chemokine receptor expression and chemokine secretion could be a viral escape mechanism to avoid specific T cell migration to the liver during the early phase of infection,and to maintain liver viability during the chronic phase,by impairing non-specific T cell *** chemokines and their receptors correlate with liver damage,and CXCL10(IP-10) and CXCR3 levels have shown a clinical utility as predictors of treatment response *** regulation of chemokines and their receptors could be a future potential therapeutic target to decrease liver inflammation and to increase specific T cell migration to the infected liver.

关键词： Chemokines Chemokine receptors Hepatitis C virus Viral hepatitis pathogenesis Persistentinfection Viral escape mechanism

Tumor necrosis family receptor superfamily member 9/tumor necrosis factor receptor-associated f

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World Journal of Hepatology 2020年第10期12卷 754-765页

作者： Julia Peña-Asensio Eduardo Sanz-de-Villalobos Joaquín Miquel juan Ramón larrubia Department of Systems Biology Guadalajara University Hospital.University of AlcaláGuadalajara E-19002GuadalajaraSpain Translational Hepatology Unit Guadalajara University HospitalUniversity of AlcaláGuadalajara E-19002GuadalajaraSpain

Hepatitis C virus(HCV)infection is an excellent immunological model for understanding the mechanisms developed by non-cytopathic viruses and tumors to evade the adaptative immune *** antigen-specific cytotoxic T cell response is essential for keeping HCV under control,but during persistent infection,these cells become exhausted or even *** exhaustion process is progressive and depends on the infection duration and level of *** high antigenic load and long duration of infection,T cells become extremely exhausted and ultimately disappear due to *** development of exhaustion involves the impairment of positive co-stimulation induced by regulatory cytokines,such as transforming growth factor beta *** cytokine downregulates tumor necrosis factor receptor(TNFR)-associated factor 1(TRAF1),the signal transducer of the T cell co-stimulatory molecule TNFR superfamily member 9(known as 4-1BB).This impairment correlates with the low reactivity of T cells and an exhaustion *** with interleukin-7 in vitro restores TRAF1 expression and rescues T cell effector *** process of TRAF1 loss and its in vitro recovery is hierarchical,and more affected by severe disease *** conclusion,TRAF1 dynamics on T cells define a new pathogenic model that describes some aspects of the natural history of HCV,and sheds light on novel immunotherapy strategies for chronic viral infections and cancer.

关键词： Hepatitis C virus Tumor necrosis factor receptor-associated factor 1 CD8 Exhaustion Tumor necrosis family receptor superfamily member 9 Chronic hepatitis

Role of T cell death in maintaining immune tolerance during persistent viral hepatitis

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World Journal of Gastroenterology 2013年第12期19卷 1877-1889页

作者： juan Ramón larrubia Megha Uttam Lokhande Silvia García-Garzón Joaquín Miquel Dolores Subirá Eduardo Sanz-de-Villalobos Translational Hepatology Unit Guadalajara University Hospital University of Alcalá

Virus-specific T cells play an important role in the resolution of hepatic infection. However, during chronic hepatitis infection these cells lack their effector functions and fail to control the virus. Hepatitis B virus and hepatitis C virus have developed several mechanisms to generate immune tolerance. One of these strategies is the depletion of virus-specific T cells by apoptosis. The immunotolerogenic liver has unique property to retain and activate na ve T cell to avoid the over reactivation of immune response against antigens which is exploited by hepatotropic viruses to persist. The deletion of the virus-specific T cells occurs by intrinsic (passive) apoptotic mechanism. The pro-apoptotic molecule Bcl-2 interacting mediator (Bim) has attracted increasing attention as a pivotal involvement in apoptosis, as a regulator of tissue homeostasis and an enhancer for the viral persistence. Here, we reviewed our current knowledge on the evidence showing critical role of Bim in viral-specific T cell death by apoptotic pathways and helps in the immune tolerance.

关键词： T cell death Specific cytotoxic T lymphocytes Hepatitis C virus immune tolerance Apoptosis Bcl-2 interacting mediator Liver tolerance Apoptotic pathways Viral hepatitis

Is it possible to stop nucleos(t)ide analogue treatment in chronic hepatitis B patients?

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World Journal of Gastroenterology 2018年第17期24卷 1825-1838页

作者： Elia Moreno-Cubero Robert T Sánchez del Arco Julia Pena-Asensio Eduardo Sanz de Villalobos Joaquín Míquel juan Ramón larrubia Translational Hepatology Unit Guadalajara University HospitalUniversity of AlcaláGuadalajara 19002Spain Internal Medicine Service Guadalajara University HospitalUniversity of AlcaláGuadalajara 19002Spain Department of Biology of Systems University of AlcaláAlcaláde Henares(Madrid)28805Spain Department of Medicine and Medical Specialties University of AlcaláAlcaláde Henares(Madrid)28805Spain

Chronic hepatitis B(CHB) remains a challenging global health problem, with nearly one million related deaths per year. Nucleos(t)ide analogue(NA) treatment suppresses viral replication but does not provide complete cure of the hepatitis B virus(HBV) infection. The accepted endpoint for therapy is the loss of hepatitis B surface antigen(HBs Ag), but this is hardly ever achieved. Therefore, indefinite treatment is usually required. Many different studies have evaluated NA therapy discontinuation after several years of NA treatment and before HBs Ag loss. The results have indicated that the majority of patients can remain off therapy, with some even reaching HBs Ag seroconversion. Fortunately, this strategy has proved to be safe, but it is essential to consider the risk of liver damage and other comorbidities and to ensure aclose follow-up of the candidates before considering this strategy. Unanswered questions remain, namely in which patients could this strategy be effective and what is the optimal time point at which to perform it. To solve this enigma, we should keep in mind that the outcome will ultimately depend on the equilibrium between HBV and the host's immune system. Viral parameters that have been described as good predictors of response in HBe Ag(+) cases, have proven useless in HBe Ag(-) ones. Since antiviral immunity plays an essential role in the control of HBV infection, we sought to review and explain potential immunological biomarkers to predict safe NA discontinuation in both groups.

关键词： CD8 Lamivudine Nucleos(t)ide analogues Tenofovir Chronic hepatitis B Entecavir hepatitis B virus Treatment cessation

Prevalence of hepatocarcinoma-related hepatitis B virus mutants in patients in grey zone of treatment

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World Journal of Gastroenterology 2019年第38期25卷 5883-5896页

作者： Ana Isabel Gil-García Antonio Madejón Irene Francisco-Recuero Ana López-López Emiliana Villafranca Miriam Romero Araceli García Antonio Olveira Rocío Mena juan Ramón larrubia Javier García-Samaniego Hepatology Unit Hospital Universitario La PazMadrid 28046Spain Centro de Investigación Biomédica en Red Instituto de Salud Carlos IIIMadrid 28029Spain Instituto de Investigación del Hospital Universitario la Paz Madrid 28046Spain Biochemistry Department Faculty of MedicineUniversidad Autónoma de MadridMadrid 28029Spain Instituto de Genética Médica y Molecular Hospital Universitario La PazMadrid 28046Spain Translational Hepatology Unit Hospital General Universitario de GuadalajaraGuadalajara 19002Castilla-La ManchaSpain

BACKGROUND Antiviral treatment of patients with chronic hepatitis B(CHB)in the grey zone of treatment comands risk management in order to optimize the health *** this sense,the identification of HBV mutants related with an increased risk of hepatocellular carcinoma(HCC)could be useful to identify subpopulations with potential indication of antiviral *** To analyze the prevalence/persistence of hepatitis B virus(HBV)preS and basal core promoter(BCP)/precore/core variants associated to HCC development in CHB patients in the grey *** Work was designed as a longitudinal retrospective study,including 106 plasma samples from 31 patients with CHB in the grey zone of treatment:Hepatitis B e antigen negative,HBV-DNA levels between 12-20000 IU/mL,normal or discordant transaminase levels during follow up and mild/moderate necroinflammatory activity in liver biopsy or Fibroscan(up to 9.5 kPa).Serum HBVDNA was tested using the Abbott Real Time HBV Assay and the BCP/precore/core and the hepatitis B surface antigen(HBsAg)coding regions were analyzed in positive samples by PCR/bulk-sequencing to identify the HCCrelated HBV *** High-risk HCC related mutants were detected in 24(77%)patients:19(61%)in the BCP/precore/core,and 7(23%)in the HBsAg coding region(2 preS1 and 5 preS2 deletions).The prevalence of preS deletions was genotype-dependent:3/5(60%)patients with preS2 deletions and 1/2 with preS1 deletions were infected with the HBV-E *** HBV-E was the most prevalent in sub-Saharan patients,a correlation between preS deletions and ethnicity was also found:6/8(75%)sub-Saharan vs 1/19(5%)Caucasian patients had preS deletions(P=0.00016).Remarkably,this correlation was maintained in those patients infected with HBV-A,a minor genotype in sub-Saharan patients:2/2 patients infected with HBV-A from West Africa vs 0/6 of Caucasian origin had preS *** HCC related variants were the major strains and persisted over time(up to 48 mo).Pa

关键词： Hepatitis B virus Hepatocellular carcinoma PreS deletions Hepatitis B virus treatment Grey zone