Journal of Medicinal Chemistry , 57 12 , DOI: Santseharay Ramirez, Jens Bukh. Current status and future development of infectious cell-culture models for the major genotypes of hepatitis C virus: Essential tools in testing of antivirals and emerging vaccine strategies.
Antiviral Research , , Gottwein, Jens Bukh. Recombinant hepatitis C virus genotype 5a infectious cell culture systems expressing minimal JFH1 NS5B sequences permit polymerase inhibitor studies. Virology , , Emerson, Patrizia Farci,. Infection with hepatitis C virus depends on TACSTD2, a regulator of claudin-1 and occludin highly downregulated in hepatocellular carcinoma.
PLOS Pathogens , 14 3 , e Hepatitis C Vaccines.
Small RNA fragments derived from multiple RNA classes — the missing element of multi-omics characteristics of the hepatitis C virus cell culture model. Tree shrew, a potential animal model for hepatitis C, supports the infection and replication of HCV in vitro and in vivo. Journal of General Virology , 98 8 , Scipione, Rocco Romagnuolo, Marlys L.
Apolipoprotein a inhibits hepatitis C virus entry through interaction with infectious particles. Hepatology , 65 6 , Perelson, Shingo Iwami, Koichi Watashi. Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection.
Proceedings of the National Academy of Sciences , 8 , Annual Review of Pathology: Mechanisms of Disease , 12 1 , Rice, Ralf Bartenschlager, Volker Lohmann. Tuning a cellular lipid kinase activity adapts hepatitis C virus to replication in cell culture. Nature Microbiology , 2 , Production of infectious HCV genotype 1b virus in cell culture using a novel Set of adaptive mutations.
Jens Bukh. The history of hepatitis C virus HCV : Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control. Journal of Hepatology , 65 1 , S2-S Corinne L.
Hepatitis C Virus: From Molecular Virology to Antiviral Therapy
Journal of Clinical Investigation , 10 , Robert E. Schwartz, Yaron Bram, Angela Frankel. Current Pathobiology Reports , 4 3 , Development of a rapid phenotypic test for HCV protease inhibitors with potential use in clinical decisions. Genetics and Molecular Biology , 39 3 , Nicholas A. Portoghese Medicinal Chemistry Lectureship. Journal of Medicinal Chemistry , 59 16 , Emmanuel Thomas, T. Jake Liang. Experimental models of hepatitis B and C — new insights and progress. Joshua A. Klemme, Nathan J.
Small , 12 9 , Genomics Data , 7 , David Paul, Ralf Bartenschlager. Hepatitis C virus's next top models?. Nature Microbiology , 1 , Wallace, Denise A. Viral Oncogenesis. Micropatterned coculture of primary human hepatocytes and supportive cells for the study of hepatotropic pathogens.
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Nature Protocols , 10 , Viruses , 7 11 , Human norovirus culture in B cells. Viruses , 7 10 , Clair M. NK cell function and receptor diversity in the context of HCV infection. Frontiers in Microbiology , 6 DOI: Effects of short RNA structural analogues against hepatitis C virus genotypes 2, 3 and 4 in replicon cells. Journal of Digestive Diseases , 16 The recommended duration of therapy 48 weeks for Peg-Intron may be unnecessarily long for individuals with genotypes 2 and 3. The full range and upper limit for weight-based dosing of Peg-Intron have not been adequately defined. Obese individuals typically have lower response rates, but it is unclear whether this is due to inadequate dosing of peg-interferon and ribavirin or to other poor prognostic factors, viral resistance, or a combination of these elements.
For some, peg-interferon dosing may be too high, and dose reduction may be necessary to reduce hematologic problems. In the absence of more effective and less toxic therapies for hepatitis C, questions about dosing variability must be addressed. More research needs to be conducted on optimal dosing and duration of therapy in other understudied populations, including individuals with acute hepatitis C infection, those with renal disease, advanced liver disease, non-responders to prior HCV treatment, those who have relapsed after treatment, children, individuals with autoimmune disorders, and transplant recipients.
It is still unclear when antiretroviral therapy should be initiated in coinfected individuals. Thus, for coinfected individuals, it is now critical to investigate whether earlier initiation of HAART -- possibly earlier than today's recommended thresholds of CD4 cells -- will decrease the incidence and progression of ESLD among coinfected individuals. Answering these questions will require allocation of resources for long-term treatment strategy studies. Coinfected individuals often have elevated liver enzyme levels, which may be due to liver disease, the hepatotoxicity of anti-HIV medications, or both Staples A universal definition of hepatotoxicity for research and clinical practice is needed to increase the consistency and interpretability of results from clinical trials, to guide antiretroviral treatment decisions and to enable the collection of consistent adverse event data.
Some individuals must discontinue HAART altogether because of liver toxicity; in other instances, only one drug must be switched.
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Hepatotoxicity has multiple causes, such as underlying liver diseases unrelated to HCV, fatty liver, alcohol consumption, genetic variation, antiretrovirals, or other medications. We need more research to understand if HAART-related hepatotoxicity worsens HCV disease, and to differentiate between transient elevations in liver enzymes and clinically significant indications of clinical progression. The potential for drug interactions in HIV-positive individuals is abundant even without hepatitis C coinfection; often, these individuals may be taking lipid lowering agents, methadone, anti-anxiety medications, prophylaxis against opportunistic infections, vitamins, herbs, supplements, and antiretrovirals.
Several important antiretrovirals are metabolized by the liver. HCV-related liver damage may diminish the liver's ability to metabolize these drugs. Drug levels may be elevated in individuals with liver disease, increasing side effects, interactions, and toxicities. The incidence of complications from antiretroviral therapy among coinfected individuals needs further investigation and documentation. The contribution of specific classes and drugs to interactions, side effects, and complications needs further study.
Despite the emerging reports of favorable outcomes in HIV-positive individuals, insurers have sometimes denied reimbursement for transplants when HIV is involved, deeming it "experimental. Prospective studies of transplantation in HIV-positive individuals will provide vitally important information about the specific risks for those undergoing transplantation, as well as help to identify the optimal clinical management strategies for improved and extended survival of HIV-positive organ recipients.
The initial identification of hepatitis C Choo ushered in a decade of productive virology and immunology research, as scientists began investigating the genetic structure of the virus, the role of viral proteins in HCV replication, the immune response to HCV, and how HCV causes disease. During the s, researchers made significant inroads into understanding the structure and genetics of HCV. Scientists cloned the genome of various HCV strains Choo ; Kato ; Takamizawa and characterized the morphology of HCV through isolation of virions using electron microscopy Kaito ; Li ; Shimizu Immunologists identified major epitopes recognized by HCV-specific cytotoxic T lymphocytes Battegay ; Cerny ; Kita ; Koziel ; Koziel , cells which are believed to play a key role in liver injury and cell death.
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Other groups made preliminary attempts at developing a cell culture system to model the HCV replication cycle using infectious complementary DNA clones Kholykhalov ; Yanagi and subgenomic RNA replicons Lohmann In recent years, researchers have provided detailed evaluations of cell-mediated immune responses to HCV Day ; Godkin ; Lauer ; Penna ; Rosen a and further clarified the viral replication cycle and viral-host cell interactions Bartenschlager ; Shirota ; Spahn ; Takikawa ; Tellinghuisen ; Walewski Researchers still lack an efficient, reproducible cell culture system that can support viral replication and infection.
However, the refinement of cell culture models, including more robust replicon systems Blight ; Ikeda , as well as a surrogate tissue culture system using GBV-B in tamarin hepatocytes Beames , enables the examination of the expression and function of viral proteins. Replicon systems have facilitated drug development efforts by allowing researchers to screen compounds for activity against viral proteins involved in the replication cycle, with the significant limitation that these replicons cannot infect new cells. While chimpanzees are the only other animals aside from human beings known to support HCV replication, progress has been made towards making a viable chimeric mouse model of hepatitis C infection Mercer Despite these advances, numerous challenges remain.
Key aspects of HCV pathogenesis and the viral replication cycle are not fully understood, and further work on cell culture systems and animal models remains an urgent priority. Continued elucidation of the pathogenesis of HCV will be critical in leading to new therapies. The potential roles of HCV proteins -- particularly the core protein and NS5A -- in the pathogenesis of fibrosis progression, hepatic steatosis, and hepatocellular carcinoma require investigation Gimenez-Barcons ; Shi ; Tsutsumi ; Yoshida Key foci in immunology research include clarifying the correlates of the protective immune responses that enable clearance of acute infection as well as defining mechanisms of long-term virological control in chronic infection Bassett ; Major ; Shata ; Thomson Immunologists should also continue to explore the associations between HCV disease progression, cytokines such as IL and TNF-alpha, and genetic polymorphisms Rosen b; Tokushige ; Yee , and further investigate the possible contributions of interactions among HCV and gamma-delta T cells, NK cells, and dendritic cells to pathogenesis and immune evasion Tseng ; Crotta ; Tseng ; Auffermann-Gretzinger ; Bain Finally, efforts must be made to increase the utility of the mouse model and enhance the efficiency and reproducibility of in vitro cell culture systems.
Hepatitis C Viruses: Genomes and Molecular Biology
The chimeric mouse model incorporating human hepatocytes shows promise, though further work is necessary to better mimic the human immune response to HCV in this model. The standard HCV treatment using pegylated interferon and ribavirin has limited efficacy, suboptimal tolerability, and significant expense. New treatment options that are more potent, less toxic, and effective in those who relapse or do not respond to current regimens are desperately needed.
Anecdotal reports suggest that many people with HCV are choosing -- often based on the advice of their doctors -- to defer treatment due to the limitations of interferon and ribavirin. The complicated calculus of when and whether to initiate HCV treatment begins with an assessment of one's current disease state and risk of disease progression.
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However, for many, these considerations are superseded by the difficulties of managing treatment including the duration of treatment, the necessity of injecting interferon, the risk of depression, and the potential impairment of quality of life as well as the lower likelihood of a sustained virological response SVR among those with genotype 1, high viral loads, and HIV coinfection. New and better treatments could mitigate many of these concerns and make therapy for HCV more widely acceptable and, ultimately, more successful. The mechanisms of action of interferon and ribavirin as treatment for HCV -- as well as the causes of viral resistance and treatment failure -- are not fully understood, and most likely involve multiple immunomodulatory and antiviral effects Gretch ; Lau ; Taylor Researchers and drug companies are exploring several new viral targets and drug candidates informed by a substantial body of basic research into the molecular biology of HCV.
Progress here has been delayed by the lack of standard tools to screen potential drugs -- an efficient, reproducible cell culture system that can sustain viral replication and infection of new cells, and a small animal model. Chimpanzees, the only other animal model known to support HCV replication, have been used to study pathogenesis and immune response, yielding data that may inform efforts at finding a vaccine against HCV. However, chimpanzee research is prohibitively expensive and ethically challenging, and the supply of chimpanzees is extremely limited Grakoui ; Lanford ; Lanford Current drugs in development include those targeting translation initiation antisense oligonucleotides and synthetic ribozymes , viral enzymes serine protease and helicase , and inhibitors of RNA synthesis RdRp inhibitors and IMPDH inhibitors , as well as antifibrotic compounds and immunomodulators Di Bisceglie b; Tan Most of these drugs are in very early stages of preclinical or clinical development.
Vaccine development has not advanced beyond a few animal studies Himoudi ; Matsui ; Pancholi During the s, some drug and vaccine studies were delayed by lawsuits initiated by Chiron against other companies, claiming that their drug development programs infringed Chiron's patents related to HCV Cohen While these issues appear to be largely resolved for now, the potential inhibitory effect of intellectual property disputes on the development of new drugs and diagnostics calls for scrutiny and vigilance.
Speeding the development of new therapeutic strategies for HCV will require a coordinated effort involving government, industry, research institutions, private foundations supporting biomedical research, and HCV advocates, especially people infected with hepatitis C. A strategic partnership between public and private sectors could support exploration of new targets and a better understanding of viral-host interactions through techniques such as microarray analysis Aizaki ; Bigger , an intensive research and development program on tools for rapid and high-throughput screening of candidate compounds, preclinical research, and the establishment of a network to facilitate the recruitment of patients into clinical trials.
Preliminary data suggest a poorer response rate to HCV treatment in coinfected persons Chung ; Perronne Because HCV is more aggressive in HIV-positive individuals, the need for new, more effective treatments is particularly urgent. Research on the safety and efficacy of HCV treatment in coinfected persons has lagged; usually, patients and clinicians must wait for a couple of years before these data are available to them. Coinfected individuals must be offered the opportunity to participate in clinical trials of new agents as soon as it is safe to do so. A good benchmark here would be to ensure enrollment of coinfected persons as soon as a safe and virologically active dose is defined.
Such a network would fill a void in current research efforts, providing better data regarding pathogenesis, natural history, long-term clinical outcomes, and determinants of variations in response rates to current treatment. A clinical research network could also provide a mechanism to test new therapies alone and in combination with the standard of care. A well-designed network should support investigation into optimizing the use of current treatments in understudied populations, including injection drug users, cirrhotics, and people with a history of depression.
The existing multicenter networks that have studied HCV have a narrow focus or limited capacity for large-scale, long-term research. This work should be supported and expanded, given the pressing need for increased resources, strong leadership, and strategic direction. Recommendations from TAG's Hepatitis Report are listed below, with progress on achieving them and comments on their place in the current recommendations.
More research should be conducted to completely understand the immunologic responses associated with control of HCV infection. This is still an important recommendation; see recommendations 5a and 6a Investigate sequencing of treatment for HIV and HCV and Support and intensify research into the molecular biology and immunopathogenesis of HCV. The findings should be widely distributed to patients and community physicians in a timely manner.