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• W2034671034 abstract "Hepatitis B virus (HBV) is a noncytopathic, enveloped, double-stranded DNA virus that causes hepatitis B, a necroinflammatory liver disease of variable severity (1). Studies performed in animal models have shown that the hepatocyte number directly killed by the virus is relatively small, the injury mainly resulting from an inflammatory response initiated by cytotoxic T lymphocytes (CTL) (2). Hepatitis B virus is transmitted through different routes: sexually, parenterally, and vertically from mother to infant. The majority of perinatally infected infants develops chronic hepatitis B due to failure to mount an effective immune response against HBV. In contrast, 90% to 95% of adult patients are able to control the virus and to resolve HBV infection. In such patients, the efficient control of viral replication is carried out by polyclonal, multispecific humoral and cellular immune responses against viral proteins. On the contrary, patients destined to develop chronic hepatitis B infection, or who have already developed it, show no or minimal virus-specific immune reactivity; if present HBV is also narrowly oriented and directed against a restricted number of viral determinants (3). These findings suggest that the different outcomes of HBV infection depend on a complex interplay between viral and host factors, the varying balance of which may explain the wide spectrum of clinical manifestations associated to HBV infection. In acute, self-limited hepatitis, the majority of HBV virions are cleared during the incubation phase before symptoms become clinically manifest. This favourable outcome is underpinned by the production of antiviral cytokines, which reflects an efficient innate and early adaptive immune reactivity (3). The initial response is magnified by recruitment and activation of antigen–nonspecific bystanding cells that home into the liver. The resulting intrahepatic cellular infiltrate enacts the immune responses controlling viral replication. In most adult patients this inflammatory process coincides with the onset of clinical symptoms, laboratory signs of acute hepatitis B, and liver injury. Resolution of acute, self-limited hepatitis B is characterized by the clearance of hepatitis B antigens (HBeAg and HBsAg), the development of neutralizing antibodies (anti-HBe and anti-HBs), and the expansion and persistence of HBV-specific memory T cells. This expanded memory T cell antigen–specific population is kept on constant alert by minute amounts of persistent HBV DNA (4). The vigorous, polyclonal, and antigen multispecific CD4+ and CD8+ T cell reactivity characterizing successful viral control of acute infection becomes detectable in the peripheral blood within the first week following infection and reaches its apex just before liver damage, signalled by alanine transaminase elevation. The interaction of CTL with infected hepatocytes is of particular importance because it leads to several consequences. First, CTLs induce programmed death (apoptosis) of individual hepatocytes, which is triggered by direct interaction between the CTL Fas-ligand receptor and the hepatocyte Fas-receptor; although this is an effective mechanism for hepatocyte apoptosis because it narrows down the number of infected hepatocytes, it is not particularly efficient at eradicating cytoplasmic HBV nucleocapsides and replicative HBV DNA intermediates (5). Second, CTLs induce direct lysis of hepatocytes through the perforin/granzyme system, further decreasing the number of infected hepatocytes; however, it is relatively inefficient with respect to HBV eradication. Third, CTL can “cure” hepatocytes of HBV infection without killing them. This is the result of CTLs' releasing proinflammatory cytokines, such as tumour necrosis factor-α and interferon-γ (IFN-γ), and represents the most efficient mechanism for the clearance of HBV nucleocapside particles, replicative virus intermediates, transcriptional templates of the virus, and episomal covalently closed circular (ccc) DNA (6). CD4+ T cells also participate in this noncytolytic intracellular inactivation of the virus (7). As alluded to earlier, perinatally acquired HBV infection typically results in chronic hepatitis, in contrast to the infection acquired later on in life. The strong inverse correlation between age and rate of infection reflects the increasing competence of a maturing immune system to interact with the virus. The weak and narrowly oriented T cell responses of chronic hepatitis B, which a small number of kintetic studies have confirmed affect both CD4+ and CD8+ T cells (3), may be the result of a variety of converging factors. First, HBV-specific immune responses can be downregulated or even exhausted by high concentrations of HBeAg (8,9). Second, an initial overreactive immune response may paradoxically preclude the establishment of a strong long-term adaptive response by reducing the virus expressed by antigen-presenting cells to levels so low that they are inadequate at invoking T cell help. These antigen levels, insufficient for CD4 T cell activation, may be able to induce activation of cytotoxic T cells and their effector functions bypassing T cell help. These CTL responses, although unable to clear the virus, are sufficient to mediate liver injury. There are also viral factors that lead to an inadequate immune response. HBV can develop mutations within immunodominant epitopes and thus evade T cell control. The virus can infect extrahepatic cells, which are less accessible to T cell responses and create a difficult-to-control source of HBV replication. Finally, the virus can, through continuous engagement and stimulation of CTLs, induce their apoptosis (10). As mentioned earlier, the immaturity of the immune system is the key factor permitting the establishment of chronic infection in children with vertically acquired hepatitis B. In particular, the interaction of the immature immune system with HBeAg appears to be pivotal to viral persistence. HBeAg has been shown to be responsible for promoting immune tolerance in utero in perinatal infection (11) and to modulate immune responses to HBcAg (8). Whether these effects are due to the HBeAg unique structure, to its peculiar mechanism of replication, or to its existence in a nonparticulate form remains (12) to be established. One end product of HBeAg interacting with the immune system is the shifting of immune responses toward Th2 reactivity. This relative Th2 predominance favours the persistence of viral infection and characterizes the development of the prolonged phase of immune tolerance in HBV-infected neonates and infants (3,8,10–13). The immune system starts recognizing HBV and its antigens early in adolescence, with some 5%/year of patients in this age group undergoing HBeAg seroconversion. HBeAg seroconversion is linked to a significant reduction in HBV DNA load, transient increase in transaminase activity (flare), and development of a strong immune reactivity against core and envelope antigens. The transaminase levels then normalise and HBV DNA load decreases and remains low. In HBeAg negative/HBsAg positive patients, the immune system is incompletely successful at controlling viral replication. These are patients in whom the virus undergoes mutations within the precore region of the HBV core gene leading to the abrogation of HBeAg synthesis. This HBeAg negative status is characterized by inadequate HBV-specific T cell response, high levels of viral replication, and fluctuation of aminotransferase activity. Only a small proportion of HBV-infected patients who have HBeAg-anti-HBeAg seroconversion in the absence of precore region mutations is able to reduce spontaneously HBV DNA levels and to clear HBeAg; an even smaller fraction (0.2%–0.8%/year) is able to clear HBsAg and develop the neutralizing anti-HBs antibodies. In the latter case, a strong and multispecific T cell reactivity is detectable from before HBeAg clearance, during HBsAg seroconversion, and long-term thereafter (13,14). In this issue of the Journal, Fischler et al investigate HBV core antigen (HBcAg)–specific T cell responses in 3 subgroups of paediatric patients with chronic hepatitis B at different stages of the HBV infection natural history: HBeAg positive with normal aminotransferases-immunotolerant, HBeAg positive with elevated aminotransferases-immunoactive, and HBeAg-negative patients (15). Amongst the immunotolerant patients, 55% were able to mount an HBcAg-specific immune response. This is an unexpectedly high proportion because the consensus in the literature is that no or few immunotolerant patients are capable of mounting significant HBV-specific immune responses. The unique data of the present study need, therefore, to be revisited critically. From a technical standpoint it is notable that although T cell proliferative responses were studied against different concentrations of recombinant HBcAg, no data are given on the dose-dependent effect and on the choice of antigen concentration for the subsequent experiments. The authors also studied cytokine production following peripheral blood mononuclear cell stimulation with HBcAg, but did not provide correlations with T cell proliferative responses, which may have helped to explain their unusual findings. Another piece of information that would have been important is the genotype of HBcAg used in the proliferation assay. Taking into account the natural history of the disease, only 22% of the patients in the immunotolerant group had a confirmed vertical transmission. A total of 44% of the immunotolerant patients in the study who gave a proliferative response had in excess of 107 viral copies per milliliter, a load normally associated with a poor immune response (9). The difference with previous studies may be due in part to the limited period of time over which the patients have been investigated. A long-term follow-up of this group in terms of HBeAg and HBsAg seroconversion would be of great interest. In the immunoactive patients and in those who had lost HBeAg there was a frequency of reactivity (89%) higher than in immunotolerant patients, and this was an expected finding. When analysing data from this and other studies based on the investigation of peripheral blood mononuclear cells, it is important to remember that events are documented from a remote point of observation. How faithfully peripheral events reflect those occurring in the liver can be ascertained only by studying simultaneously peripheral and liver immune responses. Antiviral therapy with the immunomodulator IFN-α alone or in combination with nucleoside analogues leads to a decrease in both HBV DNA replication and number of hepatitis B viral particles, enabling the immune system to restore its reactivity toward HBV antigens. A few weeks (6–14,16–20) after initiating antiviral treatment with IFN-α alone or in combination with nucleoside analogues, both HBV-specific CD4+ and CD8+ T cell responses become detectable in the circulation of responders and remain detectable after cessation of treatment. When nucleoside analogues are used alone, HBV DNA is suppressed, and during long-term therapy (>52 weeks) a small proportion of patients is able to HBeAg seroconvert (0%–19%) at the end of therapy, but none is able to clear HBsAg and develop neutralising anti-HBs antibodies (16–22). Returning to the study by Fischler and coworkers, HBcAg-specific T cell responses increased during IFN-α treatment, especially in those patients who lost HBeAg, a finding in line with the literature. In contrast with the literature (2,3,9,23) was the finding that spontaneous HBeAg seroconversion was not associated with a vigorous HBV-specific T cell response. The authors had the unique opportunity to study the effect on the immune response of suboptimal and optimal therapeutic doses of IFN-α in 1 patient. Due to a misunderstanding, the therapy with conventional IFN-α was initially underdosed (only once per week for 12 weeks), whereas the correct IFN-α schedule (3 times per week) was used for the following 24 weeks. In the first phase of therapy, when IFN-α was underdosed, the viral load remained unchanged with a detectable HBcAg-specific interleukin-10 response, but absent proliferative and IFN-γ responses. When appropriate IFN-α dosing was begun, HBcAg-specific T cell proliferation and IFN-γ production became detectable, interleukin-10 production decreased, and the viral load decreased. These findings demonstrate how the balance between Th1/Th2 responses may have a major influence on the outcome of the infection. Studies investigating how antiviral therapy influences HBV-specific T cell reactivity and controls viral replication indicate that a complete inhibition of replication by antiviral drugs (IFN-α and nucleoside analogues) can, as mentioned, restore HBV-specific T cell immune responses in some cases, but does not necessarily induce the same level of immunity as in those who spontaneously recover from the infection. Thus, HBsAg seroconversion occurs only in a smaller proportion of patients after antiviral therapy with IFN-α than in those who clear the virus spontaneously, breaking tolerance to HBsAg (23). Although we have learnt a large amount about host–HBV interaction during the past few decades, there is still a great deal that we do not know. To push forward the frontiers of our knowledge we need to use a variety of methodological approaches, such as T cell proliferation, enzyme-linked immunosorbent assay, enzyme-linked immunosorbent spot, pentamer/tetramer staining, intracellular cytokine staining, and antigen-specific cytokine secretion, to evaluate the different, complementary aspects of the virus-specific response. Similarly, more detailed information on the virus is needed, ranging from its structure to its behaviour under “stress” (ie, during antiviral therapy or immune-selective pressure) to obtain important clues about how to tailor therapeutic strategies for the control of viral replication." @default.
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• W2034671034 title "The Role of Viral-specific Immune Responses on the Outcome of Chronic Hepatitis B (HBV) Infection in Children: New Insights Into Immunopathology" @default.
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