Hepatitis b virus treatment beyond the guidelines,herpes 1 eye symptoms nhs,neonatal hsv treatment guidelines,hsv 1 and 2 blood test results - PDF Review

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Chronic hepatitis B virus (HBV) infection, affecting approximately 240 million people worldwide, is a major public health problem that elevates the risk of developing liver cirrhosis and hepatocellular carcinoma. AcknowledgmentsThe authors are grateful to all of the members of the Department of Virology II, National Institute of Infectious Diseases, the Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, and the Li lab at the National Institute of Biological Sciences, Beijing, for their research, technical support and discussions. More than 1 million sexually transmitted infections (STIs) are acquired every day worldwide. Each year, there are an estimated 357 million new infections with 1 of 4 STIs: chlamydia, gonorrhoea, syphilis and trichomoniasis.
More than 500 million people are estimated to have genital infection with herpes simplex virus (HSV).
The majority of STIs have no symptoms or only mild symptoms that may not be recognized as an STI. Drug resistance, especially for gonorrhoea, is a major threat to reducing the impact of STIs worldwide. More than 30 different bacteria, viruses and parasites are known to be transmitted through sexual contact.
Mother-to-child transmission of STIs can result in stillbirth, neonatal death, low-birth-weight and prematurity, sepsis, pneumonia, neonatal conjunctivitis, and congenital deformities.
STIs such as gonorrhoea and chlamydia are major causes of pelvic inflammatory disease (PID) and infertility in women. Counselling and behavioural interventions offer primary prevention against STIs (including HIV), as well as against unintended pregnancies. In addition, counselling can improve peoplea€™s ability to recognize the symptoms of STIs and increase the likelihood they will seek care or encourage a sexual partner to do so. When used correctly and consistently, condoms offer one of the most effective methods of protection against STIs, including HIV. Several rapid tests for other STIs are under development and have the potential to improve STI diagnosis and treatment, especially in resource-limited settings. Three bacterial STIs (chlamydia, gonorrhoea and syphilis) and one parasitic STI (trichomoniasis) are generally curable with existing, effective single-dose regimens of antibiotics. For herpes and HIV, the most effective medications available are antivirals that can modulate the course of the disease, though they cannot cure the disease. For hepatitis B, immune system modulators (interferon) and antiviral medications can help to fight the virus and slow damage to the liver. Resistance of STIsa€”in particular gonorrhoeaa€”to antibiotics has increased rapidly in recent years and has reduced treatment options. Low- and middle-income countries rely on identifying consistent, easily recognizable signs and symptoms to guide treatment, without the use of laboratory tests. Syndromic management is simple, assures rapid, same-day treatment, and avoids expensive or unavailable diagnostic tests.
HPV vaccine is available as part of routine immunization programmes in 65 countries, most of them high- and middle-income. Research to develop vaccines against herpes and HIV is advanced, with several vaccine candidates in early clinical development.
Other biomedical interventions to prevent some STIs include adult male circumcision and microbicides.
Male circumcision reduces the risk of heterosexually acquired HIV infection in men by approximately 60% and provides some protection against other STIs, such as herpes and HPV.
Tenofovir gel, when used as a vaginal microbicide, has had mixed results in terms of the ability to prevent HIV acquisition, but has shown some effectiveness against HSV-2.
Despite considerable efforts to identify simple interventions that can reduce risky sexual behaviour, behaviour change remains a complex challenge. In many countries, STI services are provided separately and not available in primary health care, family planning and other routine health services. In many settings, services are often unable to provide screening for asymptomatic infections, lacking trained personnel, laboratory capacity and adequate supplies of appropriate medicines. Marginalized populations with the highest rates of STIsa€”such as sex workers, men who have sex with men, people who inject drugs, prison inmates, mobile populations and adolescentsa€”often do not have access to adequate health services.
WHO develops global norms and standards for STI treatment and prevention, strengthens systems for surveillance and monitoring, including those for drug-resistant gonorrhoea, and leads the setting of the global research agenda on STIs.
Our work is currently guided by the Global Strategy for the Prevention and Control of Sexually Transmitted Infections: 2006-2015, adopted by the World Health Assembly in 2006, and the 2015 United Nations Global Strategy for Women's, Children's and Adolescentsa€™ Health, which highlight the need for a comprehensive, integrated package of essential interventions, including information and services for the prevention of HIV and other sexually transmitted infections. Ari Nowain, MD has years of experience as a gastroenterologist, and is uniquely specialized in the treatment and prevention of Hepatitis B. Not be confused with hepatitis C, hepatitis B is a liver infection caused by the hepatitis B virus (HBV).
In addition to being aware of how HBV can spread, it is important to understand risk factors that make you more susceptible to HBV infection.
If you believe you may have come into contact with the hepatitis B virus or are experiencing symptoms of HBV infection, it is important to undergo several diagnostic tests. The hepatitis B vaccine is the most effective preventative treatment against HBV.  All children should receive the hepatitis B vaccine in a series of three shots by the age of six months. If you or someone you know has experience symptoms associated with Hepatitis B, or if you think you may have been exposed, please contact Beverly Hills gastroenterologist Ari Nowain, MD by calling (310) 657-4444. Hepatitis C is not a death sentence and you are NOT helpless.  There are 8 ways you can help your body fight Hepatitis C right now to make a difference in your liver health.
When I was diagnosed with Hep C it was overwhelming to learn the damage the virus does to the liver.  I researched and talked with my physician and a registered dietitian about how I could help my liver fight HCV. Medications, vitamins, and supplements you take pass through your liver.  Your liver is responsible for processing all of these substances.
Be discerning when taking vitamins, minerals, and supplements.  A good rule of thumb to remember, everything you take has to an effect on your liver and immune system. Vitamins, minerals and supplements if taken correctly can play a part in good health, but when taken incorrectly can harm your liver.  Be especially careful with herbal and alternative liver treatments. Toxins can injure your liver cells.  Avoid direct contact with chemicals from cleaning products, insecticides, fumes from paint thinners and aerosol sprays. A depressive state can chemically affect your health in a negative way and suppress your immune system, leaving you at greater risk for infections and other health issues.  See your doctor if you are experiencing depression, or problems with anxiety or insomnia.
No reference links, or contact information are to be posted without prior approval from website administration.
It helps to hear encouragement and inspiration from others who are walking the steps to taking charge of good liver health. I have lost a website that treated Hepatitis C for those who had no insurance or were of low income.
Depending on your genotype, liver condition and any past treatment history, will help determine which treatment is best suited for you.
You have to be diligent and persevere with going down the list to see which resources is the right one for you. PS: I removed your contact information from being visible on the website to help protect you. Free guidebookSign up to receive my blog posts and other updates via email and get a Free copy of 3 Phases of Hep C Treatment. Prayer RequestsFeel free to send your prayer request privately or place on our Hep C Prayer Board so others may join in praying for you. FDA approves New Hep C Combo Harvoni, October 10th the first once-daily single tablet regimen for Hepatitis C genotype 1.  Harvoni by Gilead Sciences may be dubbed “the one hit wonder” which combines the brand new drug Ledipasvir, an NS5A inhibitor with the nucleotide analog polymerase inhibitor Sofosbuvir (Sovaldi) which was approved December 2013. Shortens treatment duration to just 8 weeks for certain treatment-naive patients without cirrhosis and a baseline viral load below 6 million.
Standard treatment duration with Harvoni is 12 or 24 weeks depending on prior treatment history, cirrhosis status and baseline viral load. An SVR12 stands for sustained virological response after 12 weeks of treatment which means, after patients complete the course of treatment a blood test for viral load test is taken again after 12 weeks of post treatment to see if the Hep C virus is still present, if it remains Non-Detected, the patient is cured. There are at least 6 known genotypes for Hepatitis C (genotypes 1–6) and more than 50 subtypes have been identified.
December 2013 until now, the treatment offered with Sovaldi for genotype 1 is used in combination with Ribavirin and Interferon, 12 weeks of treatment and a 90% cure rate. December 2013 Gilead Sciences opened the door to the first Hep C treatment offered without Interferon to patients with Genotype 2 with Sovaldi and Ribavirin, 12 weeks of treatment and a 90% cure rate. Today, we are waving goodbye to Interferon and severe side effects of the past and ushering in a new generation of effective treatments for Hep C. Other side effects listed by the FDA reports less than 10% of patients reported additional side effects of nausea, diarrhea and insomnia. Laboratory Abnormalities of elevations of Bilirubin and Lipase in a small percentage of patients were observed. I totally agree my friend, I am Praising the Lord for this new treatment and many more to follow.
Thank you for sharing your update with getting your paperwork done and waiting for approval.
This is the day the lord have made and we shall rejoice and be glad in it you shall overcome this with God grace. I LOVE the saying, Wag More and Bark Less, I have heard that before and it is written on my office bulletin board as a reminder to face each day with a smile and see each day filled with blessings and wonder. But Sovaldi which is one of the meds in the Harvoni combo is available for Genotype 2 with combo Sovaldi & Ribavirin which has a 93% cure rate.
Infectious MononucleosisIt is a common infection, but often it causes no symptoms, especially when children have it. Heart Abnormalities In Chronic Fatigue SyndromeChronic fatigue syndrome is considered a multi-system illness with dysfunction in the That makes them feel lightheaded and sometimes causes fainting (syncope). EVALUATION OF BIO-RAD RDT EBV ASSAYS (VCA IGG, EBNA IGG AND …Epstein Barr Virus (EBV) is a member of the herpes virus family that causes acute mononucleosis and is a candidate causative agent for many human cancers. Astrovirus – Wikipedia, The Free EncyclopediaThere is, as with most viral causes of gastroenteritis, a peak of incidence in the winter. Hepatitis B – Wikipedia, The Free EncyclopediaThe acute illness causes liver inflammation, vomiting, jaundice and, rarely, death.
Herpes Simplex – Wikipedia, The Free EncyclopediaFor the virus that causes herpes simplex, see Herpes simplex virus.
Given that current anti-HBV drugs are limited to interferon-based regimens and nucleos(t)ide analogs, the development of new anti-HBV agents is urgently needed. IntroductionHepatitis B virus (HBV) infection constitutes a serious public health problem, affecting approximately 240 million carriers worldwide [1].
Common symptoms of STIs include vaginal discharge, urethral discharge or burning in men, genital ulcers, and abdominal pain. Unfortunately, lack of public awareness, lack of training of health workers, and long-standing, widespread stigma around STIs remain barriers to greater and more effective use of these interventions. Female condoms are effective and safe, but are not used as widely by national programmes as male condoms.
The emergence of decreased susceptibility of gonorrhoea to the a€?last linea€? treatment option (oral and injectable cephalosporins) together with antimicrobial resistance already shown to penicillins, sulphonamides, tetracyclines, quinolones and macrolides make gonorrhoea a multidrug-resistant organism.
However, this approach misses infections that do not demonstrate any syndromes - the majority of STIs globally. HPV vaccination could prevent the deaths of more than 4 million women over the next decade in low- and middle-income countries, where most cases of cervical cancer occur, if 70% vaccination coverage can be achieved. Research into vaccines for chlamydia, gonorrhoea, syphilis and trichomoniasis is in earlier stages of development. Research has demonstrated the need to focus on carefully defined populations, consult extensively with the identified target populations, and involve them in design, implementation and evaluation.
These include limited resources, stigmatization, poor quality of services, and little or no follow-up of sexual partners.


At the Center for GI Health in the heart of Beverly Hills, we offer the latest testing and treatments to help prevent the spread of Hepatitis B. Some patients with hepatitis B do not require treatment beyond routine follow-ups with a doctor while others require treatment and follow-ups.
When your body’s immune system detects the infection, it mounts a systemic response to fight off the disease. The Center for GI Health offers state-of-the-art facilities and technology to test for HBV infection.
In most patients, acute symptoms subside in a few weeks, with liver function returning to normal within a period of about six months. Anyone under the age of 19 who has not been vaccinated as well as those at high risk of infection should also get the hepatitis B vaccine.
Nowain is a double board certified Gastroenterologist in Beverly Hills with expertise in advanced diagnostic and therapeutic techniques for digestive disorders.
This information is not intended to replace a medical consultation where a physician's judgment may advise you about specific disorders, conditions and or treatment options.
According to the American Liver Foundation, it is important to understand exactly how you should be taking your medications in order to avoid putting undue stress on your liver. Talk to your doctor about treatment for Hep C.  Don’t be afraid to get a second opinion if you don’t feel right about their advice. Reading the Bible daily along with devotions and listening to Christian radio brings peace and spiritual insight. Many times if treatment has been denied then appeals can be made, but in case of no insurance or non-coverage, these patient assistance programs can help guide you on which resource is available to help you. Always feel free to contact me privately and your contact information will be protected and kept private. Director of Hepatology at Beth Israel Deaconess Medical Center, Professor of Medicine at Harvard Medical School states, “By providing very high cure rates in as little as eight weeks and completely eliminating the need for interferon and ribavirin, which are challenging to take and tolerate, Harvoni significantly advances treatment for patients with the most common form of hepatitis C in the United States.
Genotype 1 is the most common HCV genotype in the United States and the hardest type to fight. For those who cannot tolerate the side effects of Interferon and Ribavirin and off label combo of Sovaldi and Olysio, by Janssen (Johnson & Johnson) has been prescribed by physicians.
John’s Wort are not recommended for use with Harvoni as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations.
Fix-It he would probably tell you I’m no saint, but Bless You for the sweet sentiment.
I personally believe the Lord gives us an opportunity to see things from His perspective if we will only see our life through His eyes and not our own. Well looks like I am about to get back into the arena again for another round of treatment. However, for adolescents and young adults it is a frequent cause of illness and missed school.
Persisting illness and fatigue in adults with evidence of Epstein–Barr virus infection. Jaundice might develop rarely during the clinical course of Epstein– Barr virus infection. EBV also establishes a lifelong dormant infection in some cells of the body’s immune system. Patients with T-cell CAEBV had a shorter survival time than those with NK-cell type of disease.
MONO)Infectious mononucleosis (Mono) is an illness caused by several viral agents, most commonly the Epstein–Barr virus (EBV). However, in adolescents and young adults an Epstein–Barr virus infection can cause mononucleosis, a more serious illness. The viral entry process is generally an attractive target implicated in antiviral strategies. Chronic HBV infection significantly elevates the risk for developing liver cirrhosis and hepatocellular carcinoma. Global epidemiology of hepatitis B virus infection: New estimates of age-specific HBsAg seroprevalence and endemicity. Many STIsa€”including chlamydia, gonorrhoea, primarily hepatitis B, HIV, and syphilisa€”can also be transmitted from mother to child during pregnancy and childbirth.
The test is accurate, can provide results in 15 to 20 minutes, and is easy to use with minimal training.
Antimicrobial resistance for other STIs, though less common, also exists, making prevention and prompt treatment critical.
The vaccine against hepatitis B is included in infant immunization programmes in 93% of countries and has already prevented an estimated 1.3 million deaths from chronic liver disease and cancer. Some patients may potentially be cured of the virus, while others will require treatment to suppress the virus in order to prevent complications. The primary test for Hepatitis B is a blood test, which will detect the presence of specific HBV markers within your blood stream. Some patients with hepatitis B will not be able to fight off the infection and develop chronic HBV. Infants born to mothers with HBV should receive a modified vaccination known as hepatitis B immune globulin (HBIG). Nowain is trained in the latest HBV treatment and prevention, as well as the treatment of liver disease that may result from HBV infection.
We hope the information will be useful for you to become more educated about your health care decisions. BTW, have you noticed in the US that HepC is getting into mainstream news reports more often?
I don't live with it." Connie shares how God empowers us to live beyond our circumstances and walk in faith and victory daily. Just want to say that I am so grateful in finding this website when I started looking for a support group this past yr. A early program for the drug I finished on Saturday not secondary effects at all I have as we’ll ribavirin secret pray and listening Joyce meyer I see on my ipad every day. I was never afraid of dying, I know my life is secure in Christ and either the Lord would heal me through whatever means he chose here on earth or in heaven and either way I would be a winner. Using primary cells from humans and Tupaia belangeri, as well as HepaRG cells, important determinants of viral entry have been achieved. Currently, conventional interferon-? (IFN?) or PEGylated-IFN? and nucleos(t)ide analogs are available as anti-HBV agents [2,3]. At any point in time, more than 290 million women have an HPV infection, one of the most common STIs.
Where testing is available, it is often expensive and geographically inaccessible; and patients often need to wait a long time (or need to return) to receive results.
Rapid syphilis tests have been shown to increase the number of pregnant women tested for syphilis. The hepatitis B vaccine and HBIG may help to prevent infection if given within 24 hours of exposure. Lifestyle measures, including practicing safe sex and avoiding shared drug needles, can go a long way towards stopping the spread of hepatitis B. There are great improvements in Hep C treatment with Higher cure rates, less treatment side effects and shorter treatment times. I cleared the virus after the first week I did ok had aweful nightmares and insomnia and a constant headache for three months and a wicked RASH ! Recently, sodium taurocholate cotransporting polypeptide (NTCP) was identified as an HBV entry receptor and enabled the establishment of a susceptible cell line that can efficiently support HBV infection. However, IFN-based therapies, which cause significant side effects, yields long-term clinical benefits in less than 40% of treated patients [4]. However, increased efforts are still needed in most low- and middle-income countries to ensure that all pregnant women receive a syphilis test.
This finding will allow a deeper understanding of the requirements for efficient HBV infection, including the elucidation of the molecular entry mechanism. Nucleos(t)ide analogs suppress an essential step in virus replication and thereby provide biochemical and histological improvement, but some of the early drugs give rise to drug-resistant viruses, which adversely affect long-term clinical outcome. Optimal management of chronic hepatitis B patients with treatment failure and antiviral drug resistance. In addition, pharmacological studies suggest that NTCP is able to serve as a therapeutic target. Thus, in order to approach curative treatments, new anti-HBV agents targeting different molecules involved in HBV infection and propagation are needed. In my 5th month post treatment, I am much more aware of everything I eat and am exposed to, even skin lotions, makeup, shampoo and other hair products.
So he has given me a prescription now for Harvoni,and he said I need to take it for 6 months.Today I got a call from ACARIA Health they said my Doctor called in the order AND I will know in 48 hours if they approve it.
This article summarizes our current knowledge on the mechanisms of HBV entry and the role of NTCP in this process.
Nucleos(t)ide analogs suppress HBV replication mainly by inhibiting the reverse transcription process in the viral lifecycle (Figure 1) [3]. IFN functions as an immunomodulator and is also reported to directly interfere with HBV replication at multiple steps of the lifecycle [5]. I was so excited to hear from them today and I pray that I am given another chance to fight .I hope if I do I can finally get this awful virus out of me once and for all and for real too !
Given that HBV encodes only one viral protein carrying enzymatic activity, polymerase, in its genome, strategies for inhibiting viral enzyme are limited. I hope I can take another 6 months of treatment I had done intepheron too for a few months as well.
Although capsid or envelope protein assembly and the regulatory X-protein are possible future targets, it is critical for developing new classes of anti-HBV agents to identify cellular factors serving as possible drug targets.In general, the viral entry step is an attractive target for the development of antiviral agents [6–8]. I read about the side effects of the new drug and I hope I dont get the insomnia thing and headache cause I had a hard time with it for 3 months and now 6 months YIKES ?
The early HBV lifecycle, including the entry step, has gained significant attention very recently with regard to molecular mechanisms, triggered by the identification of sodium taurocholate cotransporting polypeptide (NTCP) as a cellular entry receptor [9].
This article summarizes the molecular evidence related to HBV entry, mainly focusing on recent findings, and its implications. Hepatitis B surface antigen levels: Association with 5-year response to peginterferon alfa-2a in hepatitis B e-antigen-negative patients.
I read about drug interactions with Harvoni Hope I am strong enough at this point.,I do have stage 3-4 fibrosis, so I do need to treat,I have genotype 1a. Both initial attachment and, probably more importantly, specific receptor recognition contribute to host specificity and tissue tropism [10]. The initial attachment step is at least partly mediated by heparan sulfate proteoglycans [11–14]. IFN-alpha inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. The third internalization step is reported to involve caveolae-, clathrin- or macropinocytosis-dependent endocytosis, depending on the cell types and experimental systems [15–18]. The molecular requirement of HBV envelope proteins for HBV infection has been studied for more than a decade using primary hepatocytes from humans and Tupaia belangeri, as well as HepaRG cells [21]. A series of analyses using neutralizing antibodies and introduced point mutations suggested that the S and preS1, but not the preS2, regions play a significant role in HBV infection [22–27]. In a direct approach, the preS1 region in the LHBs has been shown to be essentially involved in the HBV infection process. This was demonstrated by the introduction of mutations in the viral context, infection competition with anti-preS1 antibodies and with peptides mimicking this region [28–34].


A myristoylated peptide encompassing amino acids 2–48 of the preS1 region turned out to be the most efficient in infection inhibition of HBV and also the envelope protein-related hepatitis D virus (HDV) [30,31]. Such a peptide has been used as a tool for characterizing the early infection step, including the identification of NTCP as an entry receptor [9] and as a lead substance (Myrcludex-B) presently in the clinical development (see below) [10,35,36].
Sodium Taurocholate Co-Transporting Polypeptide (NTCP) as a Bona Fide HBV ReceptorOne of the recent milestones in the field in HBV molecular biology is the identification of NTCP as a host entry receptor, as reported by Yan and Zhong et al.
By affinity purification and mass spectrometry analysis using an HBV preS1-derived lipopeptide as bait, they identified Tupaia belangeri NTCP (tsNTCP) as a cellular factor interacting with this lipopeptide. NTCP is a transporter residing in the basolateral membrane of hepatocytes and is involved in the hepatic uptake of mostly conjugated bile salts (see below). Hepatitis C virus entry into hepatocytes: Molecular mechanisms and targets for antiviral therapies.
Interestingly, this result also correlated with the in vitro binding activity of the peptide to the respective primary hepatocytes [10] and their in vivo hepatotropism [37]. The role of NTCP in the viral infection of HBV, its satellite virus, HDV, and a closely related primate hepadnavirus wooly monkey HBV was further examined by knockdown and overexpression analyses [9,38,39]. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus.
The introduction of NTCP into Huh-7 and undifferentiated HepaRG cells conferred HBV infection to these cells to some extent [38]. Myristoylated PreS1-domain of the hepatitis B virus L-protein mediates specific binding to differentiated hepatocytes. Although the total expressions in these transduced cells were comparable, hNTCP-expressing HepG2 cells showed much higher infection efficiency when compared with other human hepatocyte cell lines [38,43,44]. In the initial study, infection efficiency was ~10% in NTCP-overexpressing HepG2 cells cultured with medium containing 2% dimethyl sulfoxide (DMSO) [9]. Subsequent analysis showed that increasing the DMSO concentration to more than 2.5%~3% augmented infection efficiency to 50%~70%, as evaluated by immunofluorescence of HBV proteins, although the virus inoculum was different in these studies [38,43]. The speculations include that DMSO augmented the gene expression of NTCP, promoted the membrane localization of NTCP and changed the post-translational modification of NTCP, but the detailed molecular mechanisms for DMSO-mediated promotion of HBV infection is open for further studies. It remains unknown why not all of the cells were infected with HBV in these reports, but it is possible that the NTCP function for supporting HBV entry is reflected by post-translational modification, subcellular localization or other factors that are governed by cell conditions or by more general conditions, such as the cell cycle, cellular microenvironment or architecture. Another open question is on the high susceptibility for HDV, but not HBV, in Huh-7 cells overexpressing hNTCP [9,38]. Future analysis of this issue is necessary in order to establish a cell culture model that is 100% susceptible to HBV infection.Crucial amino acid sequences in NTCP involved in HBV infection have been analyzed. Thus, amino acids 157–165 of NTCP are crucial for NTCP-mediated HBV binding and infection [9,45].
These data indicate that the 84–87 aa residues are a determinant for NTCP function as an HBV entry receptor. It is possible that the binding of HBV to NTCP is not sufficient and requires an additional molecule or mechanism to trigger the following early infection process.HDV is a virusoid-like particle, which depends on HBV for assembly and propagation [46]. Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans. Due to its completely different replication strategy, it is very likely that it depends on different cellular factors and follows different pathways after membrane fusion.
Clathrin-mediated endocytosis and lysosomal cleavage of hepatitis B virus capsid-like core particles. This suggests that HBV requires additional host factors for infection or is restricted at a post-entry step prior to covalently closed circular DNA (cccDNA) formation. It is of particular interest to clarify the molecular mechanisms underlying the different cellular requirements between infection by HBV and HDV, especially when trying to establish a susceptible mouse model in the future. Other Factors Essential for HBV Infection?It is presently unclear whether there are additional cellular factors besides NTCP required for viral infection and determining the tissue and species tropism of HBV.
These include factors essentially involved in the viral lifecycle during attachment, internalization, endocytosis, membrane fusion, uncoating, nuclear translocation and cccDNA formation and those affecting post-entry restriction. Overexpression of hNTCP in mouse hepatocyte cell lines, such as Hepa1-6 and MMHD3 cells, did not confer susceptibility to HBV infection, in contrast to the HBV infection observed after NTCP introduction into HepG2 cells [44]. Proceedings of the 2013 International Meeting on Molecular Biology of Hepatitis B Viruses, Shanghai, China, 20–23 October 2013; p. We also showed that different HepG2 clone isolates that similarly expressed high levels of ectopic NTCP, but were likely to have different cellular genetic backgrounds, had diverse efficiencies of HBV infection [43]. Entry of hepatitis B virus into immortalized human primary hepatocytes by clathrin-dependent endocytosis. These observations favor the existence of additional host factors determining susceptibility to HBV infection. For hepatitis C virus (HCV) infection, multiple cellular factors are required for efficient viral entry, including low density lipoprotein receptor (LDLR), scavenger receptor class B type I (SR-BI), CD81, occludin (OCLN) and claudin-1 (CLDN-1) as viral entry receptors and Niemann-Pick C1-like 1 (NPC1L1), epidermal growth factor receptor (EGFR) and ephrin A2 (EphA2) as other factors involved in entry [21,47,48]. It has been reported that the complementation of both hCD81 and hOCLN are required for rendering high HCV susceptibility in mice [49]. Furthermore, in the case of duck hepatitis B virus (DHBV), multiple factors are suggested to be essential for efficient viral infection. Hepatitis B virus requires intact caveolin-1 function for productive infection in HepaRG cells. Carboxypeptidase D was confirmed to bind the DHBV envelope and function in viral attachment and entry [50].
However, overexpression of this protein alone in Huh-7 cells did not support DHBV infection [51].
Carboxypeptidase D was able to bind to DHBV and heron HBV, which did not infect primary duck hepatocytes, and this protein is also expressed in non-liver tissues [52]. Thus, additional factors are likely to be required to explain DHBV susceptibility, one candidate of which can include duck NTCP [53]. These examples in viruses that utilize multiple receptors favor pursuing the identification of additional cellular factors crucial for HBV entry.
General Characteristic Features of NTCPNTCP, also designated as solute carrier family 10A1 (SLC10A1), is a member of the SLC10 transporter gene family.
Among these, NTCP and apical sodium-dependent bile salt transporter (ASBT), also known as SLC10A2, are sodium-dependent transporters for bile acids [54]. NTCP is mainly distributed at the basolateral membrane of hepatocytes and plays a major role in the hepatic influx of conjugated bile salts from portal circulation [55,56]. NTCP on the plasma membranes in hepatocytes binds two sodium ions together with one molecule of preferentially conjugated bile salt for uptake.
While the structure of NTCP has not been resolved, the crystal structures of the ASBTs from Neisseria meningitis (ASBTNM) and Yersinia frederiksenii (ASBTYf) were recently reported [62,63]. This structure is different from the model for hASBT currently favored based on bioinformatic prediction and experimental data, which carry seven to nine transmembrane helices with N-terminal extracellular and the C-terminal cytoplasmic domain [60,64,65]. A structural analysis of ASBTYf proposed two conformations, inward- and outward-open structures of bile salt transporters by rotating two core helices transmembrane (TM)-4 and TM9 [63]. Entry of hepatitis delta virus requires the conserved cysteine residues of the hepatitis B virus envelope protein antigenic loop and is blocked by inhibitors of thiol-disulfide exchange. As non-synonymous SNPs, I223T, a variant seen in 5.5% of allele frequencies in African Americans, decreased plasma membrane-localized NTCP and reduced its transporter activity. The S267F variant, seen in 7.5% of allele frequencies in Chinese Americans, exhibited almost complete loss of function for bile acid uptake, but possessed normal transport activity for the non-bile acid substrate, estrone sulfate. N-terminal myristoylation-dependent masking of neutralizing epitopes in the preS1 attachment site of hepatitis B virus.
However, there have been no reports of serious diseases associated with defects in the NTCP gene. Thus, it is difficult to draw conclusions on whether the physiological roles of NTCP are complemented by other factors that share the redundant physiological function and whether NTCP inhibition is able to safely serve as an anti-HBV drug target.Importantly, it was very recently reported that molecular determinants for the transporter function of NTCP overlapped with those for the ability to support HBV entry [68]. Neutralization of hepatitis B virus infectivity by a murine monoclonal antibody: An experimental study in the chimpanzee. The S267F variant of NTCP could neither bind to the preS1 region nor support HBV infection in cell culture. NTCP as a Target for Anti-HBV AgentsIn general, the viral entry process is an attractive target for the development of antiviral agents. As noted above, the 2–48 aa region of preS1 in the LHBs protein is important for HBV infection [31]. The pre-s2 domain of the hepatitis B virus is dispensable for infectivity but serves a spacer function for l-protein-connected virus assembly. Myrcludex-B, which is an optimized synthetic lipopeptide consisting of the myristoylated 2–48 aa region of preS1, is able to strongly inhibit HBV infection in both cell culture and an in vivo mouse model [36]. Mechanistically, Myrcludex-B binds hNTCP and inactivates its receptor function for HBV and HDV (Figure 1).
Remarkably, IC50 to the transporter activity of NTCP was approximately 4 nM [38], showing that binding saturation is not required for receptor inactivation, thus allowing a therapeutic window for infection inhibition without a complete abrogation of bile salt transportation [38]. Thus, agents targeting NTCP are expected to be potent candidates that act as anti-HBV drugs.Cyclosporin A (CsA) is the first line of such compounds revealed to inhibit HBV infection by targeting NTCP [42,45]. CsA is known to be an immunosuppressant classified as a calcineurin inhibitor and is clinically used for the suppression of the immunological failure of xenografts after tissue transplantation [71]. In cell culture analyses, CsA was also reported to suppress the replication of numerous viruses, including HIV, HCV, influenza virus, severe acute respiratory syndrome coronavirus, human papillomavirus, flaviviruses and HBV [72–79]. Structural characterization of viral neutralizing monoclonal antibodies to hepatitis B surface antigen. However, the anti-HBV entry activity of CsA was not mediated by the inhibition of CyP, but rather, via direct targeting of NTCP. CsA bound to NTCP on the plasma membrane and inhibited transporter activity (Figure 1) [42,45].
This suggests that CsA interacted with NTCP, thus inhibiting the recruitment of LHBs of incoming HBV to NTCP on the plasma membrane and blocking HBV entry. Moreover, our derivative analysis identified a series of CsA analogs having a stronger anti-HBV entry activity with a submicromolar IC50 [42]. Given that non-immunosuppressive CsA analogs, including alisporivir (Debio 025) and SCY-635, have significant activity in decreasing HCV viral load in clinical trials and are regarded as promising anti-HCV drug candidates [80,81], further derivative analysis of CsA may be a reasonable approach for drug development.As other examples, compounds known to be NTCP inhibitors, including progesterone, propranolol and bosentan, have been shown to block HBV infection (Figure 1) [42]. NTCP substrates, such as taurocholate, tauroursodeoxycholate and bromosulfophthalein, also inhibited HBV infection [38,42,68]. An anticholesteremic drug, ezetimibe, has been shown to block HBV entry [82], and this drug was reported to inhibit the NTCP transporter [83].
Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and tupaia hepatocytes. These results indicate that compounds modulating NTCP function could substantially inhibit HBV infection. HepG2 cells engineered to overexpress NTCP are also useful for high-throughput screening to identify compounds targeting NTCP and inhibiting HBV infection. One example identified in such chemical screening is the oxysterols, which are oxidized derivatives of cholesterol or by-products of cholesterol biosynthesis [43].Host-targeting antivirals are generally expected to have significant advantages, including a much lower frequency drug resistance, universal antiviral effects beyond viral genotypes and complementary mechanisms of action that might act in a synergistic manner with currently available antiviral agents [48]. More importantly, they offer an additional therapeutic choice, given that only IFNs and nucleoside analogs are currently available as anti-HBV agents.
ConclusionsIdentification of NTCP as an HBV entry receptor has accelerated the understanding of HBV molecular biology and offered useful experimental systems to analyze the HBV and HDV lifecycle, including the identification of host restriction and dependency factors.
Further analyses using a new cell culture system are necessary in order to clarify the molecular mechanisms underlying NTCP-mediated HBV infection and to establish an in vivo small animal model that fully supports HBV infection.



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