Is the function of the HBeAg really unknown?

Abstract

The immune response to the hepatitis B virus (HBV) vaccine in newborns of hepatitis B e antigen (HBeAg)-positive or HBeAg-negative mothers is the subject of Huang et al. The authors report no correlation between the HBeAg status of the mothers/cord blood and the newborns immune response to the vaccine, but, unfortunately, draw unfounded conclusions regarding the tolerogenic potential of in utero exposure to HBeAg. In this reply, I address the possible influence of in utero exposure to the HBeAg, and briefly review other characteristics of the HBeAg, that may promote HBV chronicity. I argue that the function of HBeAg should no longer be considered "unknown" and that immunotolerance/ immunomodulation represent the dominant functions of the HBeAg in viral-host interactions.

Specific determination of hepatitis B e antigen by antibodies targeting precore unique epitope facilitates clinical diagnosis and drug evaluation against hepatitis B virus infection

“…In the HBV life cycle, HBeAg is not essential for viral infection, replication and cccDNA formation. However, e antigen is a pan-orthohepadnavirus conserved product which is considered as an essential immune-modulator contributing to establish persistent viral infection [ 33 ]. Clinically, HBeAg is an important diagnostic marker for CHB clinical management.…”

Peculiarities in the designations of hepatitis B virus genes, their products, and their antigenic specificities: a potential source of misunderstandings

“…Opinions diverge upon the functional significance of HBeAg in the biology of HBV, but its main contribution is probably the induction of immune tolerance against HBeAg and HBcAg in newborns of HBV-infected mothers [40]. This function is obviously so central to the biology of HBV-like viruses that it is conserved in most Hepadnaviridae species [40], although recently several HBeAg-negative species were identified in shrews [41]. Nevertheless, HBeAg is the most important marker of reduced immune reactivity during the highly replicative phase of HBV infection, while HBcAg is the strongest T and B cell antigen expressed by HBV [42].…”

Is hepatitis B antigen in cord blood an immunotolerogen playing a critical role in the pathogenesis of chronic hepatitis B?

“…12 Dr. Milich agreed on Hsu et al's explanation that the unresponsiveness was resulted from immune tolerance to HBeAg/HBcAg at the T-cell level, because of HBeAg exposure in utero. 1 However, we think that this conclusion was somewhat far-fetched, because those healthy and HBeAgunexposed neonates also had no responsiveness to HBcAg. It was likely that the unresponsiveness in HBeAg-exposed neonates was associated with the cord blood T cells not primed by HBcAg in utero, as in utero HBV transmission very rarely occurs.…”

“…We appreciate Dr. Milich's comments on our article recently published in Human Vaccine & Immunotherapeutics, 1 in which we concluded that the transplacentally acquired maternal hepatitis B e antigen (HBeAg) in utero appears not inducing immunotolerance to hepatitis B virus (HBV) and may be not associated with the pathogenesis of chronic HBV infection after neonatal exposure to HBV, based on the findings of similar levels of antibody response to hepatitis B vaccination between infants with and without fetal exposure to maternal HBeAg and between infants with relatively high and low fetal HBeAg exposure respectively. 2 Dr. Milich considered that our conclusion is not supported by our findings, because we did not directly measure the immune tolerance to HBeAg in HBeAg-exposed and -unexposed infants and did not determine the chronic HBV infection rate in infants born to HBeAg-positive and -negative mothers in the absence of immunoprophylaxis.…”

“…2 Dr. Milich considered that our conclusion is not supported by our findings, because we did not directly measure the immune tolerance to HBeAg in HBeAg-exposed and -unexposed infants and did not determine the chronic HBV infection rate in infants born to HBeAg-positive and -negative mothers in the absence of immunoprophylaxis. 1 Indeed, we did not measure the T cell responses to HBV antigens, such as hepatitis B surface antigen (HBsAg), HBeAg, and hepatitis B core antigen (HBcAg) in our study, and we could not compare the specific T cell responses in HBeAg-exposed and -unexposed infants. However, previous studies demonstrated that production of antibody against HBsAg (anti-HBs) is dependent on the participation of T cells.…”