Most of the world’s hepatitis B carriers are HBeAg negative, positive patients are only prevalent in young people, a recent community survey showed that e antigen negative chronic HBV infection accounts for 70%-100% of total infections, e antigen disappearance is often accompanied by improvement in hepatitis biochemistry and histology, and there is a marked suppression of HBV replication, but why is there a disappearance of e antigen? After gene sequencing, most of the residual viruses in these patients are mutated and have lost the ability to produce e antigen, and a few are heterozygous viral populations of such mutated and wild strains. In the past, classical hybridization methods have revealed that few e-antigen negative patients are positive for HBVDNA, but after current sensitive PCR and nested PCR methods, most of these e-antigen negative patients are positive for HBV DNA. When HBV undergoes anterior C-region mutation there will be e antigen-negative chronic infection, which is the main e antigen-negative etiology, and there are two possibilities to consider: 1. This HBV sequence is a stable virus capable of causing hepatitis and chronicity. 2, This case is nothing more than a viral sequence that is part of the typical wild-type HBV infection process and is eventually selected by the immune clearance period. Soon, the first possibility was disproved both clinically and experimentally, with data showing that compared to the wild type, this virus is barely able to establish chronic infection, and that infections acquired by e-antigen-negative mothers as well as from e-antigen-negative adults where not chronic. This pre-C region variant of the virus can only cause acute and fulminant hepatitis. During the immune clearance period, it appears that wild-type HBV is more readily cleared compared with pre-C variant virus, which is likely related not to the ability of the wild-type virus to replicate but to the decreased ability of the host’s immunity to clear this wild-type virus during the immune tolerance period.The presence of the E antigen in the circulation is the most important factor in the induction of immune tolerance to the virus in the host. There has been evidence of a specific immune tolerance for the e antigen. It is hypothesized that it reaches the fetal body through the placenta during pregnancy causing chronic infection. There are two mechanisms by which E antigen causes a decrease in the body’s antiviral immunity. 1, is to increase the Th2 immune response, 2, is to reduce the apoptotic response caused by Th1 cell immunity. What is not clear is what factors, at what point in chronic infection, cause the loss of immune tolerance to fight wild-type HBV and clear HBe antigen? Once this occurs, the wild-type is cleared and the e antigen-negative variants are selected by this immune pressure and accelerated to become the predominant viral population in the patient. But why the virus that disappears the e antigen is selected by this situation and thus breaks through the wild strain to become the dominant strain is not clear. What is clear is that without immune-mediated hepatocellular injury, the e antigen-negative variant would not have been selected. It is difficult to detect viral variants in genetic analysis of e antigen-positive patients with high viral titers and normal ALTs, so this selection is not the most likely time to begin, suggesting a period of immune clearance of HBV, and it is most likely that this selection would be secondary to an immune attack on the wild HBV that is already present. It is likely that E antigen-negative variants have a specific biological property that enables them to be less susceptible to clearance by the body compared with wild-type HBV, and this advantage can be summarized as follows: 1. The immune pressure that begins in patients with HBeAg-positive wild-type viremia is likely to be the result of humoral immune-mediated attacks against antigenic epitopes specific for the e protein, which can be detected in the years prior to and during the period in which e antigen is cleared Antibodies directed against spatial and linear epitopes of the e antigen are capable of triggering humoral immunity to develop pressure against wild-type e antigen-positive viruses and are capable of causing hepatic injury through antibody-dependent cytotoxic mechanisms. However, the results of a recent animal study do not support a direct cytotoxic effect of these specific antibodies on e antigen-expressing infected hepatocytes. 2. CD4-mediated mechanisms may also be involved in this process. Diepolder et al. recently showed that CD4-positive T cells attack e antigen more strongly than c antigen, and therefore, expression of both e and c antigens by wild-type virus-infected cells elicits a stronger CD4-positive T cell-mediated immune clearance than does the expression of only HBcAg by mutant strains of virus-infected hepatocytes, and that such CD4-positive T cells are effector cells that elicit hepatic inflammation in vivo. Continued immune pressure on hepatocytes against wild-type virus gradually causes the screening out of mutant strains of the virus. In contrast, the function of cytotoxic T-lymphocytes is less well defined because e-antigens and c-antigens share common CTL epitopes, and CTL cells cannot truly distinguish between the two viral proteins. Although this occurs during periods of high viral replication, the persistence of low levels of viral replication after e antigen seroconversion may be beneficial for the screening of e antigen-negative mutant strains, since the CTL epitopes of cells infected with both e and c antigens (wild-type viruses) are more likely to be targeted for immune attack than cells with CTL epitopes that express only HBcAg (mutant viruses). Some recent studies have also demonstrated that mutations, deletions or some changes in the c region of the virus can also cause this situation above. 4, e antigen-negative variants in addition to the above immune selection possibilities, certain pre-C site or BCP variants may have viral replication advantage. In patients with HBV genotypes B, C, D, and E, a change from G to A at locus 1896 not only creates an abort codon, but also results in the appearance of new base pairs on the ε-encapsulation signal of the pre-genomic RNA of HBV, thereby increasing the stability of the ε-signal, and also improving the efficiency of viral replication in these mutants compared to wild strains. A similar phenomenon can be caused by BCP mutations in genotype A patients, which reduce HBeAg expression at the transcriptional level and may simultaneously increase viral replication efficiency. However, such studies are currently controversial, as some studies have shown increased replication in this mutant strain while others have concluded the opposite, and some recent studies have found that mutations at additional sites of the virus alter the replication capacity of the virus, and further study of all e-antigen-negative genes may help to clarify the significance of the changes at other sites of the viral genes. A unique feature of HBV is the production of a secreted, non-viral component of the nucleoprotein, HBeAg. The nucleocapsid, or HBcAg, is an intracellularly expressed protein that self-aggregates to form particles that encapsulate the viral genes and polymerase, which are necessary for viral maturation. In contrast, the role of secreted HBeAg in the viral life cycle is unclear, as the presence of this protein is not required for either infection or replication of the virus. Some scholars have speculated that HBeAg may have an immunomodulatory function thereby promoting continued viral infection. For example, in HBeAg-expressing transgenic mice it was demonstrated that HBeAg crosses the placenta into the non-transgenic offspring resulting in Th cell tolerance to both HBeAg and HBcAg due to the cross-reactivity of Th cells to the two antigens. The mechanism by which this occurs may contribute to the occurrence of high rates of chronic infection (>90%) in the offspring of HBeAg-positive mothers. Indeed, mother-to-child transmission of HBeAg-negative variant HBV often results in acute rather than chronic infection. Similar findings have been reported in a groundhog model of chronic infection. Thus, maintaining secretion of HBeAg may be a strategy of the virus to ensure persistent infection after mother-to-child transmission, a source that accounts for a major portion of chronic infection in endemic areas. However, HBeAg secretion is also present in ornithophilic hepatotropic viruses, in which case there is no relationship between it and immune tolerance. Moreover, infection of adults with HBeAg-negative variant HBV often causes outbreaks of infection rather than the relatively benign acute course of infection with wild strains in most adults. In addition, the presence of HBeAg-negative variants in chronic active HBV infection often causes increased liver injury and poor prognosis. These phenomena suggest that HBeAg has a function in modulating the immune response in chronic HBV infection in adults, in addition to immune tolerance in neonates.