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Skip to main content. Home Infections. Cytomegalovirus CMV. Actions for this page Listen Print. Summary Read the full fact sheet. On this page. Cytomegalovirus CMV is a member of the herpes family. Related viruses include Epstein-Barr causes glandular fever , varicella-zoster causes chicken pox and herpes simplex causes cold sores. Before widespread screening of the blood supply in , hepatitis C was also spread through blood transfusions and organ transplants. Symptoms Many people with hepatitis C do not have symptoms and do not know they are infected.
People can live with hepatitis C without symptoms or feeling sick. Getting tested is the only way to know if you have hepatitis C. CDC recommends you get tested for hepatitis C if you:. Are 18 years of age and older Are pregnant get tested during each pregnancy Currently inject drugs get tested regularly Have ever injected drugs, even if it was just once or many years ago Have HIV Have abnormal liver tests or liver disease Are on hemodialysis Received donated blood or organs before July Received clotting factor concentrates before Have been exposed to blood from a person who has hepatitis C Were born to a mother with hepatitis C.
Hepatitis C can be prevented. Avoid sharing or reusing needles, syringes or any other equipment used to prepare and inject drugs, steroids, hormones, or other substances. Do not get tattoos or body piercings from an unlicensed facility or in an informal setting. Hepatitis A. Hepatitis B. Hepatitis D. Hepatitis E. Viral Hepatitis Home. What is cytomegalovirus CMV? Once you have the virus, it stays in your body for the rest of your life.
Your immune system usually controls the virus and most people do not realise they have it. Some people get flu-like symptoms the first time they get CMV, including: a high temperature aching muscles tiredness skin rash feeling sick sore throat swollen glands If you do have symptoms, they usually get better without treatment within about 3 weeks.
Non-urgent advice: See a GP if you have flu-like symptoms and:. For example, membrane derived microvesicles MVs can be nm in diameter, so as large as lipid droplets[ , ]. Analysis of cell supernatant by gradient density centrifugation demonstrated that the MVs subpopulations are different, depending on the cell line.
It is known, that MVs are intensively released by primary hepatocytes and immortalized cells of hepatic origin[ ]. The release from hepatocytes might be increased by an undergoing lipotoxicity[ ]. Thus, MVs are actively used by the hepatocytes as delivery system and the amounts of MVs might be increased in response to lipotoxicity and likely other complications.
In this regard, we speculate that during acute phase of infection or high rate of replication the virus can trigger the MV release and that might be an additional pathway for the virus. In fact, MV containing different amount of viruses may contribute to observed diversity of buoyant densities of HCV, especially when plasma or serum is investigated.
It is known, that the diffusion of spherical particle through a viscous liquid is dependent on the particle diameter. It is described by Stokes-Einstein equation:. Another parameter that influences the diffusion is the mass of spherical particle and the equation counting these parameters looks as follows:. So, the diffusion of a spherical particle is decreased with the increase of diameter and mass.
Thus, if MVs besides the regular cargo mRNA, miRNA, modulators, peptides, proteins have in addition a different particle load, it might explain why MVs of the same sizes might be recovered in fractions with different densities, and vice versa. Thus, when supernatants or plasma are examined by density gradient centrifugation, MVs of different size and different virus loaded, can increase the amount of virus-containing fractions.
The picture is based on the known buoyant densities of analyzed elements[ 15 , , - ]. The initial material that has been used for the virus isolation, contributes greatly to the associated lipid content of the virions and, as a consequence, it influences the buoyant density[ , - ].
Because of an irregular protein to cholesterol amounts, high density lipoproteins HDL of nm in diameter can be detected in the different fractions 1. The family of HDL is given as dark blue spheres. The buoyant density of microvesicles MVs may vary from 1. If hepatitis C virus HCV is released in MVs with similar diffusion parameters size and mass , the buoyant density of vesicle should be viral cargo-dependent.
Small grey spheres - VLDL. Light blue spheres - LDL. Orange arrows indicated fractions of the gradient that are most likely to contain viruses and viral cores. What might be the advantage, for the virus to use the MVs secretory pathway? That effect might be even more prominent, if the MV loaded with viruses would be endocytosed by the cell. We suggest, that the MV pathway might be used during active virus replication of the virus. The possible implication of MVs for the virus delivery might be interesting to investigate using in vitro models.
The progress in HCV research is completely dependent on model systems[ ]. In vitro , ex vivo and in vivo models to study hepatitis C virus. The HCV genome was identified in by cloning it from infected chimpanzee, while in humans the amounts were too low for detection[ ].
However, these HCV clones were found to replicate inefficiently in vitro. This limitation was resolved by the group of Prof. After transfection of this subgenomic clone into the Huh7 cells, it was found that in drug-resistant cells a high-level of the HCV RNA replication occurred.
The replication of the HCV subgenomic replicon was confirmed in several cell lines, but the hepatocarcinoma cell line Huh7 was the most permissive. The interferon treatment of the replicon inoculated Huh7 cell clones, made them more permissive to support both subgenomic and full-length HCV replication, these so-called cured cell lines are Huh7.
Afterwards, several studies demonstrated that the virus and host factors were important for the HCV replication in cells. Some mutations in the wide-type wt consensus sequence efficiently enhanced the HCV replicon replication, some mutations in the non-structural protein efficiently contributed to the replication and the adaptation to the host cells[ - ].
The mechanism of improved replication caused by adaptive mutations is still unknown. Although these replicons with adaptive mutations could replicate with a high efficiency, they were not able to produce infectious particles in vitro. This problem was solved with development of the genotype 2a infectious clone JFH Based on this infectious clone, several different genotypes chimeric clones genotype 1a, 1b, 2a and 3b where the non-structural genes have been replaced by those of JFH-1 were constructed and were shown to be infectious in Huh-7 cells.
The HCV subgenomic replicons containing reporter genes luciferase, secreted alkaline phosphatase and chloramphenicol transferase facilitated the study of the HCV infection. This high-throughput screening assay allowed the visualization and tracking of the HCV replication complex in living host cells without affecting the HCV replication[ 47 , ]. The pseudotyped particles allowed a detailed study of the role of HCV receptors in the early steps of HCV infection adsorption, and viral entry in Huh7 cells and primary human hepatocytes[ - ].
The system is useful for testing of new antiviral drugs[ ]. However, the high replication rate in cells was not correlated with amount of released infectious virions. However, the main disadvantage of these in vitro systems is that the viruses released from these cells are not infectious. The major reason of that might be that the adaptive mutations enhancing HCV replication rates are deleterious for HCV particles assembly and release.
The problem was solved when a genotype 2a subgenomic replicon was established in the Huh-7 cell lines. It contained a full-length genotype 2a clone JFH-1 derived from serum of a Japanese patient with fulminant hepatitis.
The replication rate was about 20 times greater than Con1 gt1b when transfected into Huh-7 cells. In addition, this replicon could replicate efficiently without amino acid mutations[ 47 ]. By means of passages in infected cells, they demonstrated that JFH-1 transfected cells had continuous HCV replication. In this study, it was also shown, that the HCV viral particles HCVcc secreted in the culture supernatant had a density of approximately 1.
The released particles have a spherical morphology and a diameter of about 55 nm. In addition it was found that the secreted particles could also infect chimpanzee[ ]. Later, several groups observed that JFH-1 could efficiently infect and replicate without adaptive gene mutation in different cell types and HCV infectious particles could be produced in the culture supernatant[ 25 , , - ].
Zhong et al[ ] established a robust highly infectious in vitro system with JFH-1 and Huh The advantage of this model, compared to that established by the group of Prof. Wakita, was the possibility of HCV to undergo serial passages without losing of infectivity. Although JFH-1 in vitro system provides a powerful tool to study anti-viral drugs and vaccines, it has some limitations: HCV JFH-1 derived from an exceptional case of HCV-related fulminant hepatitis belongs to genotype 2a which is not the dominant genotype worldwide.
That is why since , different chimeric JFH-1 clones were constructed to transfect Huh The reason why JFH-1 is more permissive to Huh In summary, the HCVcc model allowed to understand the entire life cycle of HCV and that serves as a background for development of numerous antivirals[ ]. Chimpanzee could be a good model to study the HCV infection[ , ].
However, these animals are rare, difficult to handle, very costly and limited in their use by ethical issues[ ]. Few data obtained using chimpanzee model indicated a specific immune response at the acute phase of infection, resulting in inconsistent specific neutralization and viral eradication. Tupaia Treeshrew, Anathana ellioti is potentially a good model to study the HCV infection, but the instability of the infection and its low level limit the use of these animals.
The immunotolerized rat model supports the HCV replication. Histological and biochemical evidence of infection were present, but viremia was relatively low as compared with viral load in humans[ ]. Mouse models compared with other animal models, have some advantages, such as producing animals in a short time short gestation period , lower breeding cost and their small size making them easy to manipulate[ , - ].
Heterotopic liver graft mouse model seemed to be suitable to evaluate the putative effect of anti-HCV drugs, but the short and low viremia and loss of the liver graft were limiting factors. The main limitation of the model is the absence of a normal immune system, which may be overcome by combining the model with a human hemato-lymphoid system, the value and reproducibility of which has yet to be established[ ].
The main limitations of these models are the low number of animals that can be generated and the high cost[ - ]. Recent study demonstrated that hepatocyte-like cells differentiated from human embryonic stem cells and patient-derived induced pluripotent stem cells could be engrafted in the liver parenchyma of immune-deficient transgenic mice carrying the urokinase-type plasminogen activator gene driven by the major urinary protein promoter.
This efficient engraftment and in vivo HCV infection of human stem cell-derived hepatocytes provide a model to study chronic HCV infection in patient-derived hepatocytes, action of antiviral therapies, and the biology of HCV infection[ - ]. Established human hepatocarcinoma cell line Huh-7 and its derivatives support the HCV replication. However, as every transformed cell line, they resemble the primary cells only partially.
Thus, results of experiments performed on these cells might not be always appropriated[ ]. The primary human hepatocytes and human fetal hepatocytes are more clinically and physiologically relevant. Thus, they are used to test the susceptibility of HCV to drugs and drug-metabolizing enzymes. Another in vitro model, the micropatterned co-cultures of primary human hepatocytes surrounded by a supportive stroma that expressed all known HCV entry factors.
Using this method in combination with the highly sensitive luminescence-based and fluorescence reporter systems, the efficiency of anti-HCV therapeutics has been evaluated[ ]. Recent studies show that both embryonic[ ] and induced pluripotent[ , ] stem cells can be differentiated into hepatocytes, that are phenotypically similar to human fetal liver.
Study of genetic defects that impact the HCV infection could be performed in a human iPS-derived hepatocyte-like cell-based model[ ]. Induced human liver-like cells supported the entire life cycle of HCV genotype 2a reporter virus. Produced infectious particles were able to infect HuH Thus, the evaluation of antiviral drugs using these cells was possible[ ]. Analysis of precision-cutting adult human liver slices from infected or non-infected individuals represents another promising model.
In fact, this model allowes to maintain the tridimensional structure of liver and analyse gene and protein expression. Thus, this approach allowed to validate the efficiency of the new antiviral drugs[ , ].
The HCV causes damage to the liver cells, but the exact mechanism of this phenomenon is unknown. It is believed, that the damage is largely mediated by the host immune response.
In immunocompetent and immunocompromised patients with little, or no intrahepatic damage, including inflammation, high levels of the HCV replication have been reported[ , , ]. However, high levels of an intrahepatic HCV replication are usually tolerated by the host immune system. However, why in most patients the immune response cannot resolve the infection remains obscure.
The liver fibrosis is caused by inflammatory cells of the intrahepatic infiltrate secreting cytokines and chemokines to activate hepatic stellate cells HSC to secrete collagen[ ]. HSCs may exist as several different phenotypes with distinct molecular and cellular functions and features, each of which contributes significantly to the liver homeostasis and the disease.
The quiescent stellate cells are critical to the normal metabolic functioning of the liver. The liver injury provokes the transdifferentiation of quiescent stellate cells to their activated phenotype, leading to a metabolic reprogramming. Through these changes, the activated stellate cells drive the fibrotic response to injury and the development of cirrhosis.
As liver injury subsides, the activated stellate cells can be eliminated by one of three pathways: Apoptosis, senescence or reversion to an inactivated phenotype.
Reduction in the number of activated stellate cells contributes to the regression of fibrosis or cirrhosis and the liver repair in most, but not all patients. The relative inputs of these three pathways on the fibrosis regression are not clearly defined[ ].
In response to HCV antigens, the PD-1 blockade enhanced an interleukin-2 IL-2 —dependent proliferation of intrahepatic Tregs and enhanced the overall ability of Tregs to inhibit T-effector cells. An increase in Treg proliferation with PD-1 blockade was linked to this effect[ ].
A typical model of the wound-healing response to a persistent liver injury is the hepatic fibrosis occurring in the chronic hepatitis C[ ]. Cytokines and chemokines capable of activating hepatic stellate cells to secrete collagen are secreted by the inflammatory cells of the intrahepatic infiltrate[ , ].
Thus, the fibrogenesis seems to be linked to the HCV expression through indirect mechanisms, mediated by a virally driven inflammation, but the direct role of viral factors in the disease progression should be investigated in more details.
The cell injury, such as an oxidative stress and a steatosis, may be induced specifically by several viral proteins alone which could directly activate the hepatic stellate cells[ , ]. Moreover, a reduced portal pressure and a decreased all-cause mortality are improved when the reversal occurs[ ].
The stellate cells can respond to cytokines and growth factors after priming stimuli. Then the proliferation, contractility, fibrogenesis, matrix degradation and proinflammatory signaling are enhanced. Now, it is clear that there are disease-specific pathways of fibrosis, without all activated cytokine pathways[ , ].
This is especially relevant to NAFLD, where there are many convergent pathogenic routes[ - ]. Importantly, different families of inflammatory cell types and their subsets may either promote or inhibit fibrosis[ - ]. Lipids are required for the HCV replication and particles assembly. As mentioned above, HCV can modify the host serum lipid profile and this ese modification s can provoke the steatosis[ ]. On one hand, in HCV-infected patients, the steatosis can be considered as a marker of the liver disease progression[ ] and, on the other hand, as an indication of the reduced response to therapy[ ].
However, if it is not metabolic or alcoholic steatosis, an efficient antiviral therapy is capable to reduce it[ , ]. Using sensitive PCR assays, the HCV was revealed in leukocytes and there are evidences that these cells may represent a reservoir of the virus after treatment[ , ].
Interestingly, the pool of the HCV quasi-species differs between the plasma and peripheral blood monocytes, suggesting an independent spread of HCV within different cell types[ , ].
A cell line established from transformed lymphocytes supported the HCV replication and also enable production of infectious viral particles capable to infect peripheral blood B cells[ ]. The significance of these extrahepatic HCV reservoirs is not well understood, although one could speculate that the leukocyte compartments might represent an additional route by which HCV can directly manipulate the immune system and also another means by which the virus avoids the eradication.
The most frequent associated pathology is a mixed cryoglobulinemia. They are produced by HCV activated B cells. The cryoglobulins deposed in small and medium vessels are the cause of systemic vasculitis which can manifest in level joint, skin, renal or peripheral nerves[ ]. Other observed extrahepatic manifestations are the following: lymphoma, thyroid disorders, diabetes, xerostomia and xerophthalmia[ - ].
The HCV infection cure leads to a gradual decrease of the cryoglobulin level in serum, followed by the remission of cryoglobulin-related symptoms and pathologic lesions[ ]. Interestingly, as a result of treatment the incidence of type 2 diabetes is also reduced by approximately two thirds[ , ]. In some cases, asthenia, fever and muscle, and joint pain can appear. While, signs of jaundice are not frequent. Acute hepatitis C is characterized by a transient increase in the rate of serum transaminases.
The first detectable virus marker is viral RNA that appears one to two weeks after exposure. The viral RNA becomes undetectable within three to four months after infection. Various factors could promote the viral clearance. Similarly, hepatitis acute symptoms would reflect a significant immune response of the host. The gene polymorphism of interleukin IL 28B also influences the host immune response[ , ]. The fulminant hepatitis C is exceptional[ ]. When the viral replication persists for more than six months after acute infection, the hepatitis is considered chronic.
At the stage of chronic hepatitis, most patients are asymptomatic and may have no non-specific symptoms such as fatigue, arthralgia or myalgia. The transaminase levels may be moderately increased or even normal[ ].
The long-term evolution of chronic infection is variable. The factors that accelerate the disease progression are the following: acquisition of more than 40 years, male gender, co-infection by HIV, higher body mass index, fatty liver and alcohol consumption[ ].
The cirrhosis may be associated with a liver failure, as a decompensation following a portal hypertension ascites, gastrointestinal bleeding, etc. Thirty-three percent of patients with HCC die within one year after diagnosis[ , ]. Natural history of hepatitis C virus infection and start to treat. The Child—Pugh score employs five clinical measures of liver disease: Total bilirubin, Serum albumin, Prothrombin time, Ascites, Hepatic encephalopathy.
The letter F refers to the scars of the liver caused by the aggression. It is classified from F0 to F4: F1, F2 are minimal to moderate fibrosis, F3 corresponds to a pre-cirrhotic stage and F4 corresponds to cirrhosis.
Red arrows indicated the time to start treatment[ ]. For HCV diagnosis both serologic and nucleic acid-based tests were developed[ , ]. When an acute hepatitis C is considered, a serologic screening alone is insufficient, because mature anti-HCV antibodies are developed late after transmission of the virus. Morphological methods like immunohistochemistry, in situ hybridization or PCR from liver specimens play no relevant role in the diagnosis of hepatitis C because of their low sensitivity, poor specificity and low efficacy compared to serologic and nucleic acid-based approaches.
This assay comprises 5 different antibodies targeted the HCV core. The test is highly specific However, HCV core antigen correlated well, but not fully linearly, with HCV RNA serum levels, and false-negative results might be obtained in patients with an impaired immunity[ - ].
Another study has shown that the HCV core antigen quantification could be an alternative to the HCV RNA quantification for on-treatment antiviral response monitoring[ ]. Here, a HCV core antigen below the limit of quantification at treatment 1 wk was strongly predictive of RVR, whereas patients with a less than 1 log10 decline in HCV core antigen at treatment 12 wk had a high probability of achieving nonresponse.
The new HCV core antigen assay could be a cheaper, though somewhat less sensitive, alternative for nucleic acid testing. Since the HCV RNA is detectable within a few days of infection; the nucleic acid-based tests are efficient in an early diagnostic of acute hepatitis C and should be considered as mandatory.
The HCV RNA measurement is furthermore important in determination of the HCV genotype, selection of treatment strategy, therapy duration and evaluation of the treatment success[ ]. For a number of antiviral combination therapies, the HCV RNA follow-up studies are essential to define the outcome of the treatment and further therapeutic strategies, if necessary. Traditionally, the tests should be repeated 24 wk after treatment completion to assess whether a sustained virologic response SVR has been achieved.
However, as the probability of a virologic relapse is similar after 12 and 24 wk, the new time point for assessment of final virological treatment outcome is 12 wk after the end-of-treatment[ , ]. Both qualitative and quantitative PCR-based detection assays are available. The measurements are essential in the treatment monitoring when the virus load is gradually reducing. HCV genotyping is mandatory for every patient who considers antiviral therapy[ ].
For DAA-based therapies, the determination of HCV genotypes and even subtypes is important because of significantly distinct barriers to resistance on the HCV subtype level. However, the importance for the HCV genotyping may decline with the availability of highly and broadly effective all oral combination therapies in the future.
Both direct sequence analysis and reverse hybridization technology allow the HCV genotyping. Current assays were improved by additionally analyzing the coding regions, in particular the genes encoding core protein and the NS5B, both of which provide non-overlapping sequence differences between the genotypes and subtypes[ , ]. All people with confirmed chronic HCV infection should be offered a high-quality care as soon as possible. Simultaneously, the screening and management of alcohol use is essential to prevent the progression to cirrhosis[ , ].
The modelling suggests that the treatment early in the course of HCV disease for all or specific populations could prevent the disease progression and onward transmission[ - ].
In fact, not all people with chronic HCV infection will progress to fibrosis[ ]. So, medical authorities of a country to should decide when to start anti-HCV treatment. It should be emphasized that the transmission has been documented among people recently cured who lacked access to prevention services[ ]. More research is needed to determine cost-effective eligibility criteria for both key and other populations that maximize reductions in the HCV-related morbidity, mortality, and transmission in different epidemiological contexts.
The WHO guidelines recommend the prioritizing treatment among people with an advanced fibrosis or cirrhosis in order to prevent a liver cancer[ ].
However, the liver biopsy test is expensive and can lead to complications such as infections, excessive bleeding, pain, or accidental injury to other organs. The use of liver function tests and platelet counts to determine the degree of liver fibrosis, such as the aminotransferase-to-platelet ratio index and the Fibrosis-4 score could be a non-invasive alternative and a more useful approach for gauging treatment eligibility across different tiers of health systems[ , ].
Monitoring systems should be put in place for people who do not initiate treatment immediately. In the course of the last two decades, treatment of the HCV infection has significantly improved.
For nearly 15 years, the combination of pegylated interferon alfa and ribavirin PR allowed a moderate sustain virologic response SVR. It revolutionized the treatment of chronic hepatitis C[ , ]. In , telaprevir and boceprevir obtained a market approval. From the standard of care is a combination of DAAs.
These medicines are much more effective, safer and better-tolerated than the older therapies. The estimation of a putative virus resistance profile prior to an antiviral therapy can help to select the optimal treatment regimen for individual patients[ , ].
Selected directly acting antiviral agents and host targeting agents in the pipeline[ 63 ]. Selected directly acting antiviral agents and host targeting agents whose development has been stopped or temporarily halted[ 63 ].
A prominent genetic diversity of HCV in combination with non-trivial replication cycle poses serious problems in virus research and therapy of virus-associated diseases. However, during the last several years a significant progress in understanding of the HCV molecular biology and pathogenesis has been achieved. In many aspects that allows to making a great step forward towards antivirals design, that result in DAA therapy.
However, even with the new drugs the HCV-associated problems, of both fundamental and applied origin, are not solved. In fact, the resolution of these problems is going hand in hand. First, in the absence of direct cytopathic effect, the mechanism of lipid deregulation, that results in liver pathologies, is not completely understood.
Second, the system of the HCV control during latency and putative triggers of virus active replication were poorly investigated. Third, design of prophylactic vaccine is still in its infancy. Finally, the access to drugs and therapies for the people leaving in the third world is very restricted.
Indeed, an easy access to diagnosis and treatment is still missing to drug users, people in difficult socio-economic situations, migrants, prisoners, because of themselves or health policy. Therefore, fundamental studies on virus-cell interactions and studies directing towards development of the prophylactic vaccine should be intensified. Conflict-of-interest statement: The authors have no conflict of interest to declare.
Manuscript source: Invited manuscript. Peer-review started: December 5, First decision: December 11, Article in press: February 7, Specialty type: Gastroenterology and hepatology. Country of origin: France. Peer-review report classification. Grade A Excellent : A.
Grade B Very good : B. National Center for Biotechnology Information , U.
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