Discovery Of Hepatitis C Virus Research Articles

National Blood Foundation 2021 Research and Development summit: Discovery, innovation, and challenges in advancing blood and biotherapies.

National Blood Foundation 2021 Research and Development summit: Discovery, innovation, and challenges in advancing blood and biotherapies.

Treatment progress and expansion in Japan: From interferon to direct-acting antiviral.

Hepatitis C virus (HCV) was first discovered in 1989, and patients infected with HCV were initially treated with interferon (IFN) monotherapy. In the 2000s, pegylated IFN combined with ribavirin was the mainstay of therapy for infected patients, but the sustained virologic response (SVR) rate was less than 50% for patients with HCV genotype 1. To further improve the therapeutic effect, direct-acting antiviral (DAA) was developed, and combination therapy with DAA and IFN has been available since 2011. In addition, IFN-free DAA therapy became available in 2014, and SVR was achieved in more than 95% of patients with chronic hepatitis and compensated cirrhosis. Thus, in just 30 years since the discovery of HCV, we aim to eliminate HCV in almost all patients. However, there are remaining issues to be addressed. Many of the patients who achieved SVR with DAA therapy had advanced liver fibrosis, and it is necessary to verify to what extent DAA therapy improves their prognosis in terms of liver function, hepatocellular carcinoma occurrence, and mortality. Resistance-associated substitutions can cause failure of DAA therapy, and the search for an effective therapy for high-level resistant viruses such as P32 deletion is particularly important. DAA therapy was approved for use in patients with decompensated cirrhosis in Japan in 2019, which is an unmet need so far. It is also important to verify the efficacy and safety in real-world settings. The World Health Organization aims to eliminate HCV by 2030, and Japan must tackle its remaining issues to achieve this goal.

Update on Hepatitis C Epidemiology: Unaware and Untreated Infected Population Could Be the Key to Elimination.

Globally, the World Health Organization (WHO) estimates that 71 million people have chronic hepatitis C virus (HCV) infection. A significant number of these will develop cirrhosis or liver cancer. Currently, during the COVID-19 outbreak, a high mortality rate has been found in patients with COVID-19 and cirrhosis. New direct-acting antiviral agents can cure more than 90% of HCV-infected patients. The new WHO strategy has introduced global goals against viral hepatitis, including a 30% reduction in new HCV cases and a 10% reduction in mortality by 2020. HCV transmission has changed considerably, reflecting both the evolution of medicine and health and social changes. The HCV is usually spread through blood-to-blood contact. After the discovery of HCV in 1989, antibody screening has drastically decreased the incidence of post-transfusion hepatitis. Nowadays, routine blood donor screening by nucleic acid amplification testing for the presence of HCV RNA has been introduced in many countries. It is conceivable that HCV screening could be offered to people born between 1946 and 1964 in the developed world and to people at high risk for HCV infection such as those who have received blood transfusions, blood products or organ donations before the 1990s, prisoners, health care workers, drug users and infants born to HCV-infected women. To achieve HCV elimination, health programmes should include improvement to access to health care services, increased screening and new projects to identify a submerged portion of patients with HCV infection. Submerged people with HCV infection are both people who are unaware of their condition and people diagnosed with HCV but not yet treated. Based on these premises, this review will examine and discuss the epidemiological changes in contracting HCV, highlighting the ways in which to identify a submerged portion of patients with HCV infection.

The Many Difficulties and Subtleties in the Cognitive Assessment of Chronic Hepatitis C Infection.

Since the discovery of HCV in 1989, several diseases have been related to chronic infection by this virus. Often, patients with hepatitis C virus (HCV) complain of cognitive impairment even before the development of hepatic cirrhosis, which they described as “brain fog.” Several studies have proposed a link between chronic HCV infection and the development of cognitive alterations, but the inclusion of confounding factors in their samples significantly limits the analysis of the results. In this article, we will give an overview about cognitive dysfunction in patients with HCV.

Hepatitis C Virus Vaccine: Challenges and Prospects.

The hepatitis C virus (HCV) causes both acute and chronic infection and continues to be a global problem despite advances in antiviral therapeutics. Current treatments fail to prevent reinfection and remain expensive, limiting their use to developed countries, and the asymptomatic nature of acute infection can result in individuals not receiving treatment and unknowingly spreading HCV. A prophylactic vaccine is therefore needed to control this virus. Thirty years since the discovery of HCV, there have been major gains in understanding the molecular biology and elucidating the immunological mechanisms that underpin spontaneous viral clearance, aiding rational vaccine design. This review discusses the challenges facing HCV vaccine design and the most recent and promising candidates being investigated.

Should My Patient Accept a Kidney from a Hepatitis C Virus-Infected Donor?

The availability of direct-acting antiviral (DAA) agents that reliably offer cure rates exceeding 95% for patients with CKD and patients with ESKD infected with hepatitis C virus (HCV) (1) has had a significant effect on the retrieval and allocation of kidneys from HCV-infected donors. Presented with increasing numbers of kidney offers from viremic donors, the transplant community has studied the feasibility of using these kidneys in an effort to increase access to kidney transplantation. Many transplant centers are now routinely performing transplants from HCV-viremic donors into HCV-positive recipients and initiating DAA treatment early after transplantation with excellent outcomes (2,3). This approach has translated into shorter waitlist times, increased access to transplantation, and a potential decrease in long-term morbidity and mortality for this patient population (2⇓⇓–5). In the context of studies demonstrating the safety and efficacy of the DAAs in kidney recipients (2,3,6,7), there has been increased interest in transplanting kidneys from HCV-positive donors into uninfected recipients. Agreeing to accept a kidney from a Public Health Service increased risk, HCV-infected donor requires informed consent at the time of listing, and in this context, many patients are being presented with this option and often seek advice and recommendations from their nephrologist. Understanding the pertinent literature on this topic will enable the nephrologist to actively participate in this decision and offer valuable guidance. Following the discovery of HCV and the availability of an ELISA to identify anti-HCV antibody, many cases of transmission of HCV with kidney transplantation were reported (8,9). Adverse consequences of transmission at the time of transplantation with resulting de novo HCV infection in the setting of intense immunosuppression included an aggressive form of fibrosing cholestatic hepatitis (FCH) and an immune complex injury to the allograft resembling …

Nanomedicine as a Future Therapeutic Approach for Hepatitis C Virus

Hepatitis C virus (HCV) is not easily cleared from thehuman body and in most cases turned into chronic infection. This chronicity is a major cause of liver damage, cirrhosis and hepatocellular carcinoma. Therefore, immediate detection and treatment of HCV guarantees eradication of the virus and prevention of chronicity complications. Since discovery of HCV in 1989, several emerging treatments were developed such aspolyethylene glycol(PEG)-ylated interferon/ribavirin, direct acting antivirals and host targeting antivirals. Despite the progress in anti-HCV therapy, there is still a pressing need of new approaches for affordable and effective drug delivery systems using nanomedicine. In this review, the contribution of nanoparticles as a promising delivery system for HCV immunizing, diagnostic and therapeutic agents are discussed.

Hepatocellular carcinoma in patients with autoimmune hepatitis - a systematic review of the literature published between 1989-2016.

Background and aimsLiver cancer is one of the most common cause of deaths from cancer. Hepatocellular carcinoma (HCC) was reported at a frequency of 7% of patients with autoimmune hepatitis (AIH) - related cirrhosis in 1988. We aimed to provide a systematic literature review on the frequency of HCC in patients with AIH, after the discovery of hepatitis C virus (HCV), in order to avoid any possible confounding etiology.MethodsA literature search of the PubMed database between 1989–2016 was performed, using the relevant keywords “hepatocellular carcinoma” and “autoimmune hepatitis”. We followed the PRISMA statement guidelines during the preparation of this review.ResultsEleven studies (n=8,460 patients with AIH) were retained for the final analysis. HCC was diagnosed in 0–12.3% of the AIH patients included in these studies. The overall occurrence of HCC in patients with AIH was estimated in two studies, at 5.1% and 6.2%, respectively. In patients with AIH and cirrhosis, the percentage of HCC varied between 0.2%–12.3%. The proportion of HCC in patients with AIH without cirrhosis was estimated at 1.03%. The percentage of cirrhosis in AIH patients varied from 18.7% to 83.3% in Japan, and from 12% to 50.2% in the other areas. The mean follow-up of the patients with AIH was of 10 years.ConclusionsThe development of HCC in patients with AIH appeared to be similar before and after the discovery of HCV, and it was mainly associated to cirrhosis. The number of patients developing cirrhosis in relation with AIH was impressive. The long evolution of AIH to cirrhosis and, eventually, to HCC, has been be suggested.

Chronic hepatitis C: from discovery to cure

Chronic hepatitis C virus(HCV)infection is one of the leading causes of liver cirrhosis and hepatocellular carcinoma. In recent years, the treatment of HCV infection has undergone a revolutionary change. Chronic HCV infection has become a curable disease. This article reviews the developmental history of antiviral therapy for hepatitis C since the discovery of HCV.

Drug therapy for chronic hepatitis C: An update

Affecting more than 3 million Americans, the hepatitis C virus (HCV) is the most common blood-borne pathogen producing a chronic infection within our country today.1,2 Since 1994, the prevalence of chronic HCV infections has been decreasing.3 However, as our chronically infected population ages, signifi cant increases in morbidity, mortality, and health care costs will persist for many years to come. 3

Hepatitis C virus alternate reading frame protein decreases interferon-α secretion in peripheral blood mononuclear cells

The hepatitis C virus (HCV) alternate reading frame protein (ARFP or F protein) of the HCV 1b genotype is a double-frameshift product of the HCV core protein (Core). The discovery of HCV F protein challenges various biological functions attributed to Core. However, the specific characteristics of the host cellular immune response to F protein during HCV infection have yet to be fully elucidated. Therefore, the present study investigated the cytokine response to HCV Core or F protein in peripheral blood mononuclear cells (PBMCs) and plasmacytoid dendritic cells (PDCs) from patients with chronic HCV and healthy donors in vitro. The results demonstrated that the levels of interferon (IFN)-α, analyzed by an enzyme-linked immunosorbent assay, secreted by PBMCs in patients positive for the anti-F protein antibody, were lower than those of patients negative for the anti-F protein antibody. Moreover, the frequency of PDCs in patients negative for the anti-F protein antibody, were higher than in the group positive for the anti-F protein antibody. Furthermore, HCV F protein and Core not only inhibited specific unmethylated CpG oligonucleotide sequences of type A (CpG‑A)-induced IFN-α production by PBMCs and PDCs, but also upregulated the production of interleukin (IL)-10 by PBMCs in patients with chronic HCV and healthy controls. Notably, following neutralization of IL-10 in the media and in vitro Core or F protein stimulation, levels of IFN-α were increased. Moreover, the results revealed that the roles of F protein and Core were similar with regard to the induction of apoptosis of PDCs in patients with chronic HCV. These findings suggest that F protein may inhibit PBMC IFN-α secretion by regulating the production of IL-10, and may contribute to an increase in the rates of apoptosis in PDCs. In conclusion, the results have revealed a potential involvement of F protein in the mechanisms of chronic hepatitis C.

Study of hepatitis C virus entry in genetically humanized mice

Approximately 2% of the world’s population is chronically infected with hepatitis C virus (HCV). Chronic hepatitis C can culminate in end stage liver disease and liver cancer if the infection is untreated. Current therapy is only partially effective and a vaccine for HCV does not exist. Since the discovery of HCV as the etiologic agent causing hepatitis C several experimental tools have been developed which have improved our understanding of the viral life cycle and the interaction of HCV with human cells. However, it remains challenging to study HCV infection in its native liver environment given its narrow species tropism, limited to humans and chimpanzees. Mice can be rendered susceptible to HCV infection by transplanting human hepatocytes into immunocompromized liver injury strains. Such human liver chimeric mice are useful as a challenge model for human hepatotropic pathogens but their utility is hampered by their inability to mount functional immune responses and practical aspects including high costs, low throughput, and donor-to-donor variability. The barriers that restrict HCV species tropism are incompletely understood. We have previously shown that expression of human CD81 and human OCLN is required for HCV uptake into mouse cells. This led to the construction of a genetically humanized mouse model for HCV infection. Here, we provide a detailed protocol for the generation of these animals and highlight some of its applications for studying HCV biology and preclinical testing of drug and vaccine candidates.

NASPGHAN Practice Guidelines

Hepatitis C virus (HCV) is an RNA virus that affects >180 million individuals worldwide with a high propensity for chronic infection. Children with HCV infection differ from adults in several ways including some modes of transmission, rates of clearance, progression of fibrosis, and the duration of potential chronic infection when acquired at birth. Since the discovery of HCV in 1989, there have been significant advances in the understanding of the virology and natural history of chronic HCV infection in children. In addition, there are now several treatment options for children with chronic hepatitis C infection and many new therapies on the horizon. As a consequence, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition brought together experts in pediatric hepatology to review the available data in children and provide clinicians with approaches to the diagnosis, management, and prevention of HCV infection in children and adolescents. The guideline details the epidemiology and natural history of HCV infection in children, the diagnostic workup, monitoring and treatment of disease, and provides an update on future treatment options and areas of research.

Mortality rate and outcome factors in mixed cryoglobulinaemia: the impact of hepatitis C virus

Objectives: Mixed cryoglobulinaemia (MC) is a chronic small-vessel vasculitis. Shortly after the discovery of hepatitis C virus (HCV) in 1989, an association between HCV infection and MC was being increasingly reported, suggesting the potential pathogenetic implication of HCV in most of the cases that had been previously diagnosed as essential MC. A number of studies have pointed out prognostic factors linked to mortality in this disorder. None of them, however, have clarified the impact of HCV discovery on the natural history of the disease. The aim of the present study was to evaluate mortality in MC after the discovery of HCV infection.Methods: We retrospectively collected clinical and serological data in 70 unselected HCV-positive patients being followed up at our unit from 1990. Clinical and prognostic factors linked to poor outcome were evaluated.Results: Chronic hepatitis, renal involvement, and intestinal vasculitis were the most frequent causes of death.Conclusion: Compared to other series, the outcome in our MC seemed to be better. Factors linked to a poor outcome were renal involvement, widespread vasculitis, male sex, and cryocrit.

Hépatite C : la guérison

After the discovery of the hepatitis B virus in 1968 and of the hepatitis A virus in 1973, many years were needed to identify the hepatitis C virus (HCV) in 1989. The discovery of HCV was a revolution for hepatology because of the magnitude of the global burden related to HCV infection, a major cause of cirrhosis and hepatocellular carcinoma. Therapy of hepatitis C has rapidly evolved with currently nearly 60% of sustained virological response with the combination of pegylated interferon plus ribavirin. In patients with sustained virological response, viral eradication, corresponding to the cure of infection, and regression of histological liver lesions have been demonstrated. Recently, the availability of in vitro culture systems allowed to characterize viral enzymes, potential therapeutic targets. A novel therapeutic era is open with the protease and polymerase inhibitors, used as a first step in association with pegylated interferon and ribavirin, both to increase efficacy and decrease the risk of resistance. Thanks to these new molecules with a potent antiviral activity, one can reasonably predict a rapid improvement of treatments becoming more efficient and also better tolerated with the progressive replacement of interferon and ribavirin by combinations of these virus specific enzyme inhibitors.

Hepatitis C infection: recent insights relevant to transfusion safety

Hepatitis C virus (HCV) infects over 100 million persons worldwide, and is hence one of the most prevalent and clinically significant blood‐borne pathogens. The introduction of HCV antibody screening in the early 1990s led to detection of large numbers of infected donors and dramatic increases in blood safety. The seroprevalence of HCV in blood donors varies, ranging from rates as low as 0·01% in South Africa to ~0·5% in most developed countries, to > 5% in focal endemic areas such as Egypt. Studies of HCV in infected donors and recipients were instrumental in the discovery of HCV, and have yielded ongoing insights into HCV epidemiology, natural history and pathogenesis. Recent examples include detailed characterization of the dynamics of acute HCV infection based on studies of plasma donor panels, and important contributions to understanding viral and host factors influencing HCV transmission and disease outcome based on linked donor‐recipient cohort studies. The addition of nucleic acid testing (NAT) for HCV RNA to routine HCV antibody screening of donors in 1999 further reduced the risk of transfusion‐transmitted HCV. Mini‐pool (MP)‐NAT screening has led to detection of well over 500 donors in the viraemic, preseroconversion phase of primary HCV infection, as well as to discrimination of seropositive donors into those with resolved and chronic infections. Studies of donors with acute, chronic/persistent and resolved HCV infections have further contributed to our understanding of viral and host genetic and immunological determinants of spontaneous clearance of HCV and short‐ and long‐term disease outcomes. This review will highlight these past scientific contributions, and present the results of a recent survey of the yield of HCV MP‐NAT screening and estimated residual risks of MP‐NAT screened transfusions in different regions of the world. Finally, the review will discuss available evidence for the infectivity of very low‐level viraemia that may be missed by MP‐NAT, information that is pivotal to modelling the residual risk of MP‐NAT screened blood transfusions, and which will guide further strategies to reduce risk by further enhancing screening or implementation of pathogen‐inactivation technologies.

Gene expression and hepatitis C virus infection

Hepatitis C virus (HCV) is a major cause of chronic liver disease, with about 170 million people infected worldwide. Up to 70% of patients will have persistent infection after inoculation,...

The Accelerating Pace of HCV Research: A Summary of the 15th International Symposium on Hepatitis C Virus and Related Viruses

Almost 800 research scientists convened in San Antonio in early October of 2008 to share recent results and new insights concerning hepatitis C virus (HCV). The 15th International Symposium on Hepatitis C Virus and Related Viruses opened with a mini-symposium recognizing progress made over the past 20 years since the discovery of HCV. This was followed by 10 keynote talks, and 61 oral and 379 poster presentations over the succeeding 4 days. Our intent is to succinctly summarize the most notable findings reported, a task made extraordinarily difficult by the volume, diversity and quality of science presented. At best, this cursory overview vividly demonstrates the robust pace of the research that is unraveling the mysteries of this unique and potentially deadly human pathogen.

Immunité maternelle et transmission mère-enfant du VIH et du VHC

Human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) are two viral pathogens that establish chronic infections in their hosts and that are at present responsible for serious public health problems on a pandemic scale. HIV-1 and HCV can be transmitted from person to person by contact with bodily fluids. Both can also be transmitted from mother to child during the course of pregnancy and childbirth. There are currently no vaccines available to immunize against HIV-1 and HCV infection or to prevent mother-to-child transmission (MTCT), and accessible treatments have significant yet limited efficacy. However, important progresses have been made since the discovery of HCV and HIV-1 : (a) sensitive screening and detection methods have been perfected ; (b) risk factors for acquisition, replicative cycles, pathogenesis, and mechanisms of transmission have been better characterized ; (c) specific treatments, immunotherapy, and antiretroviral prophylaxis regimen were developed ; (d) immune correlates of protection are better understood ; and (e) vaccine design was undertaken. In addition, co-infection with HCV and HIV-1, which is common among high-risk groups including injection drug users, significantly increases the incidence of MTCT of both viruses. The mechanisms by which this facilitation occurs are still under investigation and may involve direct replicative facilitation, enhancement of placental transfer, and/or interference with host immune responses. Taken together, these developments could lead to the implementation of global scale strategies to prevent MTCT of HCV and HIV-1.

A milestone for hepatitis C virus research: A virus generated in cell culture is fully viable in vivo

Chronic hepatitis C virus (HCV) infection is a leading cause of end-stage liver disease in the United States, and the Centers for Disease Control has predicted that ≈10,000 Americans die annually from this disease. Since the discovery of HCV in 1989, basic research on this important pathogen has been difficult because of the lack of a robust cell-culture system. Thus, the recent development of a cell culture resulting in production of significant levels of infectious virus particles (1–3) will without doubt lead to rapid progress in our understanding of the HCV viral life cycle and, it is hoped, development of better therapies. The development of molecular clones of strain H77 (genotype 1a) infectious for chimpanzees in 1997 was an important initial advance, but these clones and subsequent infectious clones of other genotype strains did not produce viruses in cell culture (4–7). Another critical advance was the development of subgenomic replicons in 1999 that permitted studies of RNA replication (8). Efficient replication, however, depended on adaptive mutations (9, 10). In 2003, Kato et al. (11) observed that the WT JFH1 strain of HCV, belonging to genotype 2a, replicated to high levels in the replicon system. Subsequently, in 2005, Wakita and coworkers (2) demonstrated that RNA transcripts from the full-length JFH1 genome could produce viruses in a human liver hepatoma cell line (Huh-7 cells), and it was demonstrated by Chisari and coworkers (3) that this system could be developed to generate relatively high titers of HCV. In a different approach, Rice and coworkers (1) developed a chimeric genome in which the structural genes (C, E1, and E2), p7, and NS2 from an infectious clone of another genotype 2a strain (strain HC-J6) (6) were inserted into the subgenomic replicon of the JFH1 strain and demonstrated that RNA transcripts from this full-length chimeric genome could produce relatively high titers of HCV. In the current issue of PNAS, a study by Lindenbach et al. (12) demonstrated that chimeric J6/JFH1 viruses generated in vitro were fully viable also in vivo, as tested in chimpanzees and in SCID-uPA mice with human liver grafts, and that virus recovered from infected animals efficiently infected naive Huh-7 cells. An overview of this important study is shown in Fig. 1. Therefore, it appears that not only has a cell-culture system been developed for HCV, but this system produces viruses that are biologically relevant.