Success and failure of virus-specific T cell responses in hepatitis C virus infection

Hepatitis C virus (HCV) infection is only cleared in a minority of infected individuals, the majority of patients develop chronic infection. Chronic HCV infection potentially leads to liver fibrosis, cirrhosis and finally hepatocellular carcinoma. The host immune response is an important determinant in the outcome of HCV infection. Innate as well as adaptive cellular and humoral immune responses mediate important antiviral actions; however, virus-specific T cell responses appear to be most critical. Indeed, strong and multispecific CD4+ as well as CD8+ T cell responses are required for viral clearance. Interestingly, individuals who express certain HLA alleles (which are important for antigen presentation to CD4+ and CD8+ T cells) have a higher chance to clear the virus. The mechanisms of protection by HLA class I alleles such as HLA-B27 have been characterized recently. In most individuals, however, the HCV-specific immune response fails to clear the virus. Several mechanisms underlying this HCV-specific T cell failure have been identified. These include viral factors such as viral escape mutations and immunological factors such as the expression of inhibitory receptors, which lead to CD8+ T cell dysfunction. An in-depth understanding of the determinants of success or failure of the HCV-specific T cell response is critical for the development of prophylactic as well as therapeutic vaccination regimes against HCV. Here, we will discuss the virological and immunological determinants of HCV clearance and persistence.     

Host and viral factors contributing to CD8＋ T cell failure in hepatitis C virus infection

Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epitopes. In the chronic phase of infection, HCV-specific CD8+ T cell responses are usually weak, narrowly focused and display often functional defects regarding cytotoxicity, cytokine production, and proliferative capacity. In the last few years, different mechanisms which might contribute to the failure of HCV-specific CD8+ T cells in chronic infection have been identified, including insufficient CD4+ help, deficient CD8+ T cell differentiation, viral escape mutations, suppression by viral factors, inhibitory cytokines, inhibitory ligands, and regulatory T cells. In addition, host genetic factors such as the host’s human leukocyte antigen (HLA) background may play an important role in the efficiency of the HCV- specific CD8+ T cell response and thus outcome of infection. The growing understanding of the mechanisms contributing to T cell failure and persistence of HCV infection will contribute to the development of successful immunotherapeutical and -prophylactical strategies.     

CD4＋ T cell responses in hepatitis C virus infection

Hepatitis C virus (HCV) infection is a major cause of liver damage, with virus-induced end-stage disease such as liver cirrhosis and hepatocellular carcinoma resulting in a high rate of morbidity and mortality worldwide. Evidence that CD4+ T cell responses to HCV play an important role in the outcome of acute infection has been shown in several studies. However, the mechanisms behind viral persistence and the failure of CD4+ T cell responses to contain virus are poorly understood. During chronic HCV infection, HCV-specific CD4+ T cell responses are rela- tively weak or absent whereas in resolved infection these responses are vigorous and multispecific. Persons with a T-helper type I profile, which promotes cellular effec- tor mechanisms are thought to be more likely to experi- ence viral clearance, but the overall role of these cells in the immunopathogenesis of chronic liver disease is not known. To define this, much more data is required on the function and specificity of virus-specific CD4+ T cells, especially in the early phases of acute disease and in the liver during chronic infection. The role and possible mechanisms of action of CD4+ T cell responses in deter- mining the outcome of acute and chronic HCV infection will be discussed in this review.     

Regulatory T cells in viral hepatitis

The pathogenesis and outcome of viral infections are significantly influenced by the host immune response. The immune system is able to eliminate many viruses in the acute phase of infection. However, some viruses, like hepatitis C virus (HCV) and hepatitis B virus (HBV), can evade the host immune responses and establish a persistent infection. HCV and HBV persistence is caused by various mechanisms, like subversion of innate immune responses by viral factors, the emergence of T cell escape mutations, or T cell dysfunction and suppression. Recently, it has become evident that regulatory T cells may contribute to the pathogenesis and outcome of viral infections by suppressing antiviral immune responses. Indeed, the control of HCV and HBV specific immune responses mediated by regulatory T cells may be one mechanism that favors viral persistence, but it may also prevent the host from overwhelming T cell activity and liver damage. This review will focus on the role of regulatory T cells in viral hepatitis.     

HIV type 1 persistence in CD4- /CD8- double negative T cells from patients on antiretroviral therapy

The establishment of reservoirs of latently infected cells is thought to contribute to the persistence of HIV-1 infection in the host. Studies so far have mainly focused on the long-lived reservoir of HIV-infected resting CD4+ T cells. A discrete population of HIV-infected CD4-/CD8- double negative (DN) T cells has recently been shown to exist and may also play a role in HIV-1 persistence. DN T cells are CD3 positive, either TCRalphabeta or TCRgammadelta positive, but lack both CD4 and CD8 surface markers. We developed a novel, magnetic bead column-based cell fractionation procedure for isolating >99% pure DN T cells. CD4+, CD8+, and DN T cells were purified from 23 samples of a cohort of 18 HIV-1-infected patients. Each cell fraction was analyzed for levels of total and integrated HIV-1 DNA. A correlation was observed between the presence of HIV-1 DNA in the DN T cell fraction and plasma viral load (VL). Using a micrococulture technique, we saw an initial release of virus from DN T cells of a patient with high VL. Analysis of env and nef sequence data suggested that the HIV-1 present in CD4+ and DN T cells originated from a common infecting strain. Different from the published literature, we have demonstrated the presence of HIV-1 DNA in DN T cells only in patients who are experiencing HAART failure. While these cells may have a limited role in viral persistence in high VL patients, our results suggest DN T cells are unlikely to be a major reservoir in patients on HAART with clinically undetectable plasma viral RNA.     

Hepatitis C virus strategies to evade the specific-T cell response: a possible mission favoring its persistence

Hepatitis C virus (HCV) is a small, enveloped RNA virus. The number of HCV-infected individuals worldwide is estimated to be approximately 200 million. The vast majority of HCV infections persist, with up to 80% of all cases leading to chronic hepatitis associated with liver fibrosis, cirrhosis, and hepatocellular carcinoma. The interaction between HCV and the host have a pivotal role in viral fitness, persistence, pathogenicity, and disease progression. The control of HCV infection requires both effective innate and adaptive immune responses. The HCV clearance during acute infection is associated with an early induction of the innate and a delayed initiation of the adaptive immune responses. However, in the vast majority of acute HCV infections, these responses are overcome and the virus persistence almost inexorably occurs. Recently, several host- and virus-related mechanisms responsible for the failure of both the innate and the adaptive immune responses have been recognized. Among the latter, the wide range of escape mutations to evade the specific-T-and B-cell responses as well as the T cell anergy and the CD8+ T cell exhaustion together with the interference with its function after prolonged virus exposure hold a pivotal role. Other HCV strategies include the modification or manipulation of molecules playing key roles in the induction of the interferon response and its induced effector proteins. In this review, we attempt to gain insights on the main T cell immune evasion strategies used by the virus in order to favor its persistence.     

Antivirale Therapie bei viraler Herzerkrankung

Several investigations showed that in addition to genetic factors also virological and chronic inflammatory aspects are relevant pathogenic mechanisms for the development of dilated cardiomyopathy (DCM). Based on the etiopathogenic importance of viral persistence and chronic myocardial inflammation for disease progression, novel rational therapeutic strategies have been developed. The diagnosis of chronic myocardial inflammation and viral persistence has been a controversial issue for a long time due to diagnostic pitfalls. Detection of persistence of viral genomes with adequate sensitivity and specificity succeeded only by the establishment of sensitive molecular biological techniques such as in situ hybridization and nested polymerase chain reaction (nPCR). By the use of these molecular biological methods, further viruses have been detected in DCM patients in addition to the classic cardiotropic viruses (entero- and adenoviruses), particularly parvovirus B19, human herpes virus type 6 (HHV-6), and Epstein-Barr virus. Considering these different cardiotropic viruses, viral persistence can be proven in > 50% of the DCM patients, consistent with the diagnosis of viral heart disease.This differentiated diagnosis enables, in addition to symptomatic therapy of heart failure, novel rational therapeutic regimens (e. g., beta-interferon) in the setting of randomized trials such as the BICC Study (Betaferon In Patients with Chronic Viral Cardiomyopathy).     

Immunology of hepatitis B infection

The immune response initiated by the T-cell response to viral antigens is thought to be fundamental for viral clearance and disease pathogenesis in hepatitis B virus (HBV) infection. The T-cell response during acute self-limited hepatitis B in people is characterised by a vigorous, polyclonal, and multispecific cytotoxic and helper-T-cell response. By contrast, the immune response in chronic carriers, not able to eliminate the virus, is weak or undetectable. Thus a dominant cause of viral persistence could be the existence of a weak antiviral immune response. Methodological progress in animal models allows more precise investigation of the mechanisms by which the immune system resolves viral infection or develops chronic infection. Although clearance of most virus infections is widely thought to indicate the killing of infected cells by virus-specific T cells, data suggest that non-cytolytic intracellular viral inactivation by cytokines released by virus-inactivated lymphomononuclear cells could have an important role in the clearance of this virus without killing the infected cell. Additional factors that could contribute to viral persistence, which have been partly proven in animal models, are viral inhibition of antigen processing or presentation, modulation of the response to cytotoxic mediators, immunological tolerance to viral antigens, viral mutations, and infection of immunologically privileged sites. In view of the central role of cellular immunity in disease pathogenesis, strategies have been proposed to manipulate this cellular immune response in favour of protection from disease.     

Hepatitis C virus infection: virus/host interactions

Infection with the hepatitis C virus (HCV) is a leading cause of chronic liver disease world-wide. This paper examines our current understanding of the complex relationship between HCV and its host, especially potential mechanisms of viral persistence and resistance to interferon therapy, and the pathogenesis of liver injury in chronic HCV infection. HCV infection leads to viral persistence and chronic disease in a very high proportion of cases, despite broad humoral and cellular immunological responses to viral proteins. These responses may be thwarted by the high rate of mutation, which leads to the generation of a highly variable mixture of closely related genomes, referred to as a quasispecies, that persists and continuously evolves in infected individuals. Understanding this, and other mechanisms of viral persistence and immune escape, will be essential in developing effective future therapeutic and preventive strategies. As far as the pathogenesis of chronic hepatitis C is concerned, two non-mutually exclusive hypotheses have been raised: first, that HCV can be cytopathic and induce liver lesions by replicating in infected hepatocytes, and second, that liver lesions could be the result of specific or non-specific immune responses. In the absence of a cell-culture model, the direct cytopathogenicity of the virus cannot be assessed confidently. Recent data suggest that cytotoxic T cells and cytokines produced by both CD4 + (T helper) and cytotoxic T cells may be responsible for much of the damage that occurs in the livers of infected patients.     

T cell responses in hepatitis C: the good, the bad and the unconventional

Over recent years, it has become increasingly accepted that virus-specific CD4+ and CD8+ T cell responses play a major role in outcome and pathogenesis of hepatitis C virus (HCV) infection. Indeed, while the emergence of strong and multispecific T cell responses may correlate with spontaneous viral clearance, the virus has developed several mechanisms to avoid T cell control in the majority of acutely HCV-infected patients that subsequently develop persistent HCV infection. In this review, we will discuss the current knowledge about the role of cellular immune responses in HCV infection. Specifically, we will emphasise recent new insights into the effector functions of T cells, possible mechanisms of their failure and the host-virus interactions occurring at the site of the disease, the liver.     

Basis of HBV persistence and new treatment options

The majority of the morbidity and mortality associated with hepatitis B virus infection is due to viral persistence and its consequences. The heterogeneity of outcomes from HBV infection suggests that both viral and host factors influence the development of chronic infection. Study of host genetic susceptibility has revealed a number of genes including MHC class II loci and cytokine receptors, which decrease the risk of persistence. On the viral side, the replication system is adapted to generate high levels of virions without stimulating the innate immune system. Secreted viral proteins (HBsAg and HBeAg) suppress innate responses through inhibition of TLR signaling, which leads to a weak adaptive immune response with an exhausted phenotype that is incapable of inducing viral elimination. However, even when the adaptive immune system begins to take effect after HBe seroconversion, the ability of the virus to mutate and evade T and B cell-mediated responses helps to sustain persistent infection. Understanding the mechanisms of persistence is important for the design of therapeutic strategies. Although there are currently no specific drugs that target the viral minichromosome (cccDNA), it is expected that in the future we will be able to use existing drugs more effectively to eliminate the infection.     

Autoimmune cardiac-specific T cell responses in dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a common cause of congestive heart failure and commonly occurs in the setting of autoimmune cardio-inflammatory processes. Consistent with this notion myocardial damage and dilatory remodeling consistent with DCM occurs upon adoptive transfer of T cell subsets reactive to self-antigens abundantly expressed in cardiac tissue. In this review we discuss etiologic mechanisms by which cardio-destructive T cells are generated during T cell ontogeny, and we review accumulated work identifying myocardial-derived T cell epitopes. Additionally, we describe several possible mechanisms whereby autoimmune T cell responses are sustained during chronic DCM. Epitope spreading, intra-cardiac persistence of pathogen-derived proteinaceous determinants, and generation of long-lived memory T cells are discussed as putative processes operative in the chronic maintenance of DCM.     

Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies

Helicobacter pylori infects the stomach of half of the human population worldwide and causes chronic active gastritis, which can lead to peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. The host immune response to the infection is ineffective, because the bacterium persists and the inflammation continues for decades. Bacterial activation of epithelial cells, dendritic cells, monocytes, macrophages, and neutrophils leads to a T helper cell 1 type of adaptive response, but this remains inadequate. The host inflammatory response has a key functional role in disrupting acid homeostasis, which impacts directly on the colonization patterns of H pylori and thus the extent of gastritis. Many potential mechanisms for the failure of the host response have been postulated, and these include apoptosis of epithelial cells and macrophages, inadequate effector functions of macrophages and dendritic cells, VacA inhibition of T-cell function, and suppressive effects of regulatory T cells. Because of the extent of the disease burden, many strategies for prophylactic or therapeutic vaccines have been investigated. The goal of enhancing the host's ability to generate protective immunity has met with some success in animal models, but the efficacy of potential vaccines in humans remains to be demonstrated. Aspects of H pylori immunopathogenesis are reviewed and perspectives on the failure of the host immune response are discussed. Understanding the mechanisms of immune evasion could lead to new opportunities for enhancing eradication and prevention of infection and associated disease.     

Immunosuppression in Patients with Chronic Hepatitis B

After hepatitis B virus (HBV) infection, HBV DNA persists in minute amounts in hepatocyte nuclei even in individuals with “resolved” infection. Viral replication and development of liver disease depend on the balance between viral mechanisms promoting persistence and host immune control. Patients with active or inactive disease or resolved HBV infection are at risk for reactivation with immunosuppressive therapy use. HBV reactivation varies from a clinically asymptomatic condition to one associated with acute liver failure and death. We review recent studies on HBV reactivation during immunomodulatory therapies for oncologic, gastroenterological, rheumatic, and dermatologic disorders. Risk calculation should be determined through HBV screening and assessment of immunosuppressive therapy potency. We also discuss monitoring for reactivation, prophylactic antiviral therapy, and treatment of reactivation. Prophylactic antiviral treatment is needed for all HBsAg carriers and selected patients who have anti-HBc without HBsAg and is critical for preventing viral reactivation and improving outcomes.     

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

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.     

The nature of interferon-alpha resistance in hepatitis C virus infection

PURPOSE OF REVIEW: HCV infection becomes chronic in 50-85% of cases. The treatment of chronic hepatitis C is currently based on a combination of pegylated interferon (IFN)-alpha and ribavirin. With this regimen, a failure to eradicate infection occurs in 18-24% of patients infected by genotype 2 or 3, and in 54-58% of patients infected by genotype 1. IFN resistance, i.e. the capacity of HCV strains to attenuate IFN antiviral responses in order to evade them, could play a role in the establishment of chronic infection at the acute stage of infection. IFN resistance could also play a role in the virological response to IFN therapy through similar or different mechanisms. The involved mechanisms however remain unclear. RECENT FINDINGS: Several viral proteins were recently shown to mediate IFN resistance through inhibition of IFN antiviral effectors in vitro, but the relevance of such mechanisms in vivo is not proven. Whatever the mechanisms, IFN resistance could play a role at the early stages of infection, but a qualitative and quantitative defect of both CD4-positive and CD8-positive immune responses appears as the main determinant of viral persistence. IFN treatment failure to eradicate infection is multifactorial. IFN resistance could play a partial role through unclear mechanisms. However, immune clearance of infected cells appears to be the principal determinant of IFN treatment success. SUMMARY: In spite of active research, the role and the mechanisms of IFN resistance in HCV persistence and IFN treatment failure remain partly unknown. A better understanding is needed in order to further improve IFN treatment strategies.     

Myocarditis: the immunologist's view on pathogenesis and treatment

Viral myocarditis is a frequent and often unrecognised cause of post-inflammatory cardiomyopathy. The role of viral persistence and heart-specific autoimmunity in the development of myocarditis and heart failure is still controversial. This review updates the current view on the immunological mechanisms of disease development and addresses the current and future role of immunomodulation and immunosuppression as treatment options for defined subgroups of patients with myocarditis or dilated cardiomyopathy.     

Specific cellular immune response and cytokine patterns in patients coinfected with hepatitis C virus and Schistosoma mansoni

Patients coinfected with hepatitis C virus (HCV) and Schistosoma mansoni show high incidence of viral persistence and accelerated fibrosis. To determine whether immunological mechanisms are responsible for this alteration in the natural history of HCV, the HCV-specific peripheral CD4(+) T cell responses and cytokines were analyzed in patients with chronic hepatitis C monoinfection, S. mansoni monoinfection, or HCV and S. mansoni coinfection. An HCV-specific CD4(+) proliferative response to at least 1 HCV antigen was detected in 73.3% of patients infected with HCV, compared with 8.6% of patients coinfected with HCV and S. mansoni. Stimulation with HCV antigens produced a type 1 cytokine profile in patients infected with HCV alone, compared with a type 2 predominance in patients coinfected with HCV and S. mansoni. In contrast, there was no difference in response to schistosomal antigens in patients infected with S. mansoni alone, compared with those coinfected with HCV and S. mansoni. These findings suggest that the inability to generate an HCV-specific CD4(+)/Th1 T cell response plays a role in the persistence and severity of HCV infection in patients with S. mansoni coinfection.