Hepatitis B Infection: Molecular Mechanisms and Pathogenesis

Hepatitis B virus (HBV) infection is one of the leading causes of liver diseases, including inflammation, cirrhosis, and hepatocellular carcinoma (HCC). A key feature of HBV is that it can evade the immune response in some patients and establish a persistent infection in hepatocytes. However, the underlying mechanisms of viral persistence and the role of the immune system remain to be elucidated. Toll-like receptors (TLRs) serve as pathogen recognition receptors and play critical roles in viral recognition and induction of appropriate immune responses. Thus, it has been proposed that TLRs might be involved in inducing appropriate or inappropriate immune responses against HBV. In the current issue of Viral Immunology, Zare-Bidaki et al. review the role of one particular TLR—TLR4—on HBV infection. The authors present recent data on the status and important roles of TLR4 in HBV recognition and its regulation of the immune response. They also touch on the role of TLR4 in the pathogenesis of cirrhosis and HCC as complications of prolonged HBV infections. The main conclusion of the review is that future therapies should focus on treatments with agonists and antagonists of TLR4 to promote or regulate immune responses against HBV.

Three papers in this issue address specific challenges in vaccine design and efficacy. A key challenge for vaccinologists is that maternal immunity can interfere with the vaccination of neonates. For example, influenza vaccine-associated enhanced respiratory disease (VAERD) can be induced in pigs during a subsequent influenza virus exposure. (This is similar to the enhanced disease seen in humans that were vaccinated with a formaldehyde-inactivated respiratory syncytial virus [RSV] vaccination followed by wild-type RSV infection during a clinical trial in the 1960s.) Furthermore, VAERD is particularly prominent if the initial vaccination occurred in the presence of matched maternal-derived immunity. While VAERD is directly linked to maternal immunity, it is unclear whether maternal cellular or humoral immunity is at fault. Loving et al. investigate this issue by cross-fostering piglets to control the transfer of cellular immunity and show that maternal-derived antibody, but not cellular immunity, contributed to the mispriming of piglet immunity to influenza vaccine. These data have major implications for influenza vaccinations in both pigs and humans. A second paper in this issue also addresses pig vaccination. Wu et al. note that although porcine reproductive and respiratory syndrome virus (PRRSV) envelope glycoprotein 5 (GP5) is a key target for neutralizing antibodies, native GP5 is poorly immunogenic and not able to induce robust protection. To get around this problem, the authors have developed two Fc tagged GP5 proteins (GP5-Fc, containing a truncated GP5 with the deletion of its signal peptide and transmembrane regions, and GP5N-Fc, containing only the ectodomain of GP5). Immunization studies showed that both GP5-Fc and GP5N-Fc elicited strong serum responses to the native GP5 in the absence of adjuvant. GP5-Fc also induced neutralizing antibodies specific to PRRSV, establishing modified GP5 glycoproteins as candidates for new vaccines against PRRSV infection. A third paper focusses on the problem that recombinant virus vaccines are often less effective due to immunodominant responses against endogenous vector antigens. Bell et al. have addressed this problem by modulating responses to endogenous viral proteins by manipulating the host CD8+ T-cell repertoire prior to infection or through the use of mutations introduced into the virus genome. Both of these approaches enhance responses to vaccine antigens introduced into the picornavirus. The authors demonstrate that modification of the consensus MHC class I anchor residue within the virus genome can promote enhanced immunity to foreign antigens. These findings have important implications for future vaccine development.

A further three papers in this issue address viral pathogenesis, specifically with regard to the role of cytokines. Cervical intraepithelial neoplasias (CINs) are a major public health problem with up to one million American women diagnosed annually. The prevalence of CINs is higher in women with the human immunodeficiency virus (HIV), suggesting that there may be differences in the immune responses in the cervical stroma of HIV-infected and -uninfected women. Guimaraes et al. investigate this question by analyzing cytokine expression and local immune responses in patients with CIN. Their data suggest that there is an immunoregulatory environment in some CIN lesions, but concede future studies are needed to understand this response better, especially in HIV-infected women. Another study addresses postinfection fatigue in patients with a history of West Nile Virus (WNV) infection. An analysis of antiviral and proinflammatory cytokines by Garcia et al. indicates that prolonged fatigue post-WNV infection is associated with elevated antiviral and proinflammatory cytokines. The authors suggest that clinicians consider history of WNV infection as a possible factor when evaluating causes of prolonged fatigue following a febrile viral illness in their patients. Finally, Machado et al. investigated the relationship between disseminated Kaposi's sarcoma and immuno-dysregulation characterized by the abnormal production of inflammatory cytokines and chemokines. The authors quantified serum levels of several cytokines from patients with KS-AIDS, classic KS, and HIV positive without KS and demonstrate that IL-10 levels are higher in those individuals with disseminated disease than those with only localized lesions. The results are the first to establish a stratification of patients with KS-AIDS according to lesion topography and IL-10 levels

I would like to thank all of the authors for their excellent contributions to the journal.