by endocytosis mediated by either clathrin or caveolin-1. hbv initially binds to heparin sulfate proteoglycan. the pre-s1 segment of the hbv l protein then binds tightly to the cell surface receptor sodium taurocolate cotransporting polypeptide (ntcp), encoded by the slc10a1gene. ntcp is mostly found in the sinusoidal membrane of liver cells. the presence of ntcp in liver cells correlates with the tissue specificity of hbv infection. penetrationfollowing endocytosis, the virus membrane fuses with the host cell's membrane, releasing the nucleocapsid into the cytoplasm. uncoatingbecause the virus multiplies via rna made by a host enzyme, the viral genomic dna has to be transferred to the cell nucleus. it is thought the capsid is transported on the microtubules to the nuclear pore. the core proteins dissociate from the partially double stranded viral dna, which is then made fully double stranded (by host dna polymerases) and transformed into covalently closed circular dna (cccdna) that serves as a template for transcription of four viral mrnas. replicationthe largest mrna, (which is longer than the viral genome), is used to make the new copies of the genome and to make the capsid core protein and the viral rna-dependent-dna-polymerase. assemblythese four viral transcripts undergo additional processing and go on to form progeny virions which are released from the cell or returned to the nucleus and re-cycled to produce even more copies. releasethe long mrna is then transported back to the cytoplasm where the virion p protein synthesizes dna via its reverse transcriptase activity. disease main article: hepatitis b despite there being a vaccine to prevent hepatitis b, hbv remains a global health problem. hepatitis b can be acute and later become chronic, leading to other diseases and health conditions. in addition to causing hepatitis, infection with hbv can lead to cirrhosis and hepatocellular carcinoma. it has also been suggested that it may increase the risk of pancreatic cancer. roles in disease viral infection by hepatitis b virus (hbv) causes many hepatocyte changes due to the direct action of a protein encoded by the virus, hbx, and to indirect changes due to a large increase in intracellular reactive oxygen species (ros) after infection. hbx appears to dysregulate a number of cellular pathways. hbx causes dysregulation in part by binding to genomic dna, changing expression patterns of mirnas, affecting histone methyltransferases, binding to sirt1 protein to activate transcription, and cooperating with histone methylases and demethylases to change cell expression patterns. hbx is partly responsible for the approximate 10,000-fold increase in intracellular reactive oxygen species (ros) upon chronic hbv infection. increased ros can be caused, in part, by localization of hbx to the mitochondria where hbx decreases the mitochondrial membrane potential. in addition, another hbv protein, hbsag, also increases ros through interactions with the endoplasmic reticulum. the increase in ros after hbv infection causes inflammation, which leads to a further increase in ros. ros cause more than 20 types of dna damage. oxidative dna damage is mutagenic. in addition, repair of the dna damage can cause epigenetic alterations at the site of the damage during repair of the dna. epigenetic alterations and mutations may cause defects in the cellular machinery that then contribute to liver disease. by the time accumulating epigenetic and mutational changes eventually cause progression to cancer, epigenetic alterations appear to have a larger role in this carcinogenesis than mutations. only one or two genes, tp53 and perhaps arid1a, are mutated in more than 20% of liver cancers while 41 genes each have hypermethylated promoters (repressing gene expression) in more than 20% of liver cancers, with seven of these genes being hypermethylated in more than 75% of liver cancers. in addition to alterations at the sites of dna repair, epigenetic alterations are also caused by hbx recruiting the dna methyltransferase enzymes, dnmt1 and/or dnmt3a, to specific gene loci to alter their methylation levels and gene expression. hbx also alters histone acetylation that can affect gene expression. several thousand protein-coding genes appear to have hbx-binding sites. in addition to protein coding genes, about 15 micrornas and 16 long non-coding rnas are also affected by the binding of hbx to their promoters. each altered microrna can affect the expression of several hundred messenger rnas (see microrna). history the origin of hepatitis b virus can be traced back to the 5th century bce and is even mentioned in babylonian clay tablets. hippocrates later described an epidemic of jaundice among his patients that was characterized by the yellowing of the skin and whites of the eyes. jaundice is a clinical sign of hepatitis b viral infection. however, due to the lengthy time interval, measured in weeks, between exposure of the causative agent and the development of illness prevented recognition of jaundice as an infectious disease until the 20th century. the first recorded cases of hepatitis b virus infection occurred in 1883 after the smallpox vaccine containing human lymph was administered to a group of people. the smallpox vaccine was administered to shipyard workers in germany and the workers later developed symptoms of hepatitis. serum hepatitis, now known as hepatitis b, was often observed following the use of contaminated needles and syringes. these contaminated needles and syringes were not properly cleaned and/or they were reused among patients. in 1943, transmission of hepatitis b virus via blood was further emphasized when paul beeson described jaundice occurring in patients who had just received blood transfusions. another epidemic of jaundice was observed among soldiers in 1942, after they had received a yellow fever vaccine. the distinction between hepatitis a virus and hepatitis b virus was not determined until 1947 when they were recognized as being two different filterable agents through numerous studies done of human volunteers. in 1965, the “australian antigen” was then discovered and identified as the hepatitis b virus surface antigen hbsag. this was one of the first breakthroughs in the effort to understand the pathology of viral hepatitis that instigated jaundice in those infected with hbv. it allowed industrialized countries to reliably diagnose asymptomatic carriers of hepatitis b virus and the discovery provided healthcare professionals a way to screen blood for hep b before administering blood transfusions. today, hepatitis b virus infection is easily avoided by receiving one of the hepatitis b vaccines. the plasma-derived hepb vaccine was licensed in 1981 and was subsequently replaced in 1986 with the recombinant hepb vaccine. engerix b was approved in 1989 and heplisav-b was approved in 2017. all of which provide protection against hbv. distribution rates of hepatitis b infection are equal across male and females. hepatitis b virus is more prominently found in us citizens of asian, pacific islander, or african descent and roughly 25% of these individuals will receive a diagnosis. hbv is spread more readily in groups with high risk behavior such as intravenous drug use, multiple sex partners, and men who have sex with men. hepatitis b virus causes the disease hepatitis b. hepatitis is considered to be the leading cause of liver cancer worldwide (reference). hepatitis b virus can be found in almost every region of the world but is most prevalent in countries where the virus is endemic. hbv is endemic in some countries located in asia, africa, south america, and the caribbean. approximately two billion people have been infected with hbv which means almost 1 out of 3 people have been infected. every year an estimated 1.5 million people will become newly infected and roughly 10% of those individuals will go undiagnosed. every year, an estimated 820,000 people die from hepatitis b infection and related hbv complications. the spread of hbv during pregnancy remains the highest risk for developing chronic hepatitis b later in childhood. roughly 90% of infected infants will become chronically infected. only 2%-6% of adults once infected with hbv will go on to be chronically infected. of the estimated 350 million individuals chronically infected with hbv worldwide, 50% or more of those individuals acquired the infection prenatally or during their early childhood. in countries where hbv is endemic, vertical transmission of hbv poses a major health risk due to a high number of women of childbearing age being hbeag-positive allowing them to transmit hbv to their newborn. in areas where hbv is endemic, transmission is not limited to groups with high-risk behaviors. instead, infection can occur through different routes of transmission but mostly during early childhood. the spread of hepatitis b virus in the western world occurs most often through sexual intercourse or needle sharing by intravenous drug users (ivdu). ivdu show the highest rate of hbv infection in europe and north america. there are also higher rates of hepatitis b infection among men who have sex with men (msm). risk of being infected with hbv increases with having multiple sex partners. (need reference) transmission the spread of hepatitis b virus occurs most often through vertical transmission from mother to child during birth and delivery. hbv can also be spread through contact with blood or other bodily fluids during sexual intercourse with an infected partner. it is also spread through needles shared with infected persons or exposure to sharp objects. needles of any kind can be a risk if they are not single use or are not properly sanitized, preferably in an autoclave. this includes needles used at tattooing and body piercing parlors. furthermore, hepatitis b virus can also be spread through sharing earrings and other body piercing jewelry. it is also spread through hemodialysis units that have been used by hbeag positive patients. because hd units usually treat multiple patients at a time, contamination of patients' blood can occur. incidences of hbv infection through hd units is at 1% in the united states. healthcare staff are also at an increased risk of infection. transmission of hbv can be limited by administering the hepatitis b vaccine. in areas where the virus is endemic, vaccines are limited, especially in rural areas where medical clinics are sparse. although hbv can be infectious on surfaces for up to seven days, it is not spread through breastfeeding, sharing eating utensils, hugging, kissing, holding hands, coughing, or sneezing. unlike other hepatitis viruses, hbv is not spread by contaminated food or water. however, living with a person infected with hepatitis b virus increases your risk of contracting the virus. co-infection of hbv and other viruses co-infection of hepatitis b and various other viruses can also occur. hepatitis c, hepatitis d (a satellite virus of hepatitis b), and hiv can all co-infect an individual alongside hbv. because hbv and hcv share a similar mode of transmission, co-infections are possible. most cases of hbv and hcv co-infection occurs among intravenous drug users, unscreened blood products, or exposure to dirty needles and unsterilized medical equipment. co-infection of these two viruses can cause a more severe liver disease and increase the risk for primary liver cancer (hepatocellular carcinoma). reporting of this co-infection may be underreported due to hepatitis c's ability to become the dominant liver virus during coinfection, reducing the detectable amount of hbv found in the body. recent statistics show that 10% of all persons infected with hiv are also infected with hepatitis b. however, this statistic increases to almost 20% for southeast asia. hepatitis b infection is one of the leading causes of hospitalizations and death among patients with hiv since the development and use of antiretroviral therapies. those who are infected with hiv and hbv are six times more likely to develop chronic hepatitis b. some studies suggest this may be due to co-infected individuals having lower cd4+ t cell counts.