Volume 120, Issue 4, Pages 1000-1008 (March 2001) Molecular anatomy and pathophysiologic implications of drug resistance in hepatitis B virus infection  Edward Doo, T.Jake Liang  Gastroenterology  Volume 120, Issue 4, Pages 1000-1008 (March 2001) DOI: 10.1053/gast.2001.22454 Copyright © 2001 American Gastroenterological Association Terms and Conditions

Fig. 1 (A) The replication cycle of HBV. Details are explained under HBV Replication. (B) Mechanism of HBV replication within the nucleocapsids. (1) The pol binds to the 5' epsilon on the pgRNA denoted by the dashed line and synthesizes a short oligodeoxynucleotide. The boxes on the pgRNA represent direct repeat sequences. (2) The pol-oligonucleotide complex translocates to the complementary 3' direct repeat and synthesizes the negative DNA strand. (3) As the negative DNA strand is synthesized, the pgRNA is degraded. (4) At the completion of the negative DNA strand synthesis, the residual 5' 15–18 oligoribonucleotides of the pgRNA remain. (5) The residual oligoribonucleotide translocates and complements the direct repeat at the 5' end of the negative DNA strand and serves as the primer for the positive DNA strand. (6) A template exchange occurs that allows the positive DNA strand to continue synthesis and permit circularization of the genome. Modified and reprinted with permission.9 Gastroenterology 2001 120, 1000-1008DOI: (10.1053/gast.2001.22454) Copyright © 2001 American Gastroenterological Association Terms and Conditions

Fig. 2 Three-dimensional models of HBV nucleocapsids by cryoelectron microscopy. (A) Exterior view of assembled HBV core particles illustrating the spikes. (B) Pores are better illustrated by the inner surface view. Reprinted with permission.16 Gastroenterology 2001 120, 1000-1008DOI: (10.1053/gast.2001.22454) Copyright © 2001 American Gastroenterological Association Terms and Conditions

Fig. 3 (A) Structural modeling of lamivudine-resistant reverse transcriptase. Lamivudine is shifted in the dNTP binding site of the M184V mutant HIV reverse transcriptase. The introduction of valine with its β-branched side chain for methionine at position 184 results in steric hindrance with the oxathiolane ring of lamivudine (blue), resulting in an altered binding position (magenta). The shift causes an increased distance between the 3'OH of the primer and the α-phosphate group of lamivudine, thus precluding chain termination. Reprinted with permission.19 (B) Space filling models of lamivudine (top) and adefovir (bottom) in the dNTP binding site of the wild-type and the M552V variant HBV reverse transcriptase. In the wild-type reverse transcriptase, the space occupied by the lamivudine oxathiolane ring (orange) is in close proximity to the methionine. In the M552V mutant, steric conflict between valine and the oxathiolane ring occurs as shown by the protrusion of the sulfur atom into the space occupied by the valine side group. Adefovir encounters no steric hindrance when modeled into either the wild-type or the M552V variant. Courtesy of Craig Gibbs. Gastroenterology 2001 120, 1000-1008DOI: (10.1053/gast.2001.22454) Copyright © 2001 American Gastroenterological Association Terms and Conditions

Fig. 4 The multiple pathways of immunopathogenesis of HBV infection. After infection of hepatocytes, HBV is released into the circulation and acquired by antigen-presenting cells. Through major histocompatibility complex class II molecules, the viral antigens are presented to CD4 T helper cells, which in turn activate the B cells to produce neutralizing antibodies. The CD4 T cells provide help to the maturation of CD8 cytotoxic T lymphocytes, which is activated by the antigen-presenting cells through major histocompatibility complex class I molecules. Activation of both CD4 and CD8 cells requires involvement of costimulatory molecules. The HBV-specific cytotoxic T lymphocytes recognize HBV-infected hepatocytes in the context of class I molecules and directly kill the cells through induction of apoptosis. The activated lymphocytes produce inflammatory cytokines that exert predominantly a noncytopathic mechanism to suppress viral replication. In addition, the cytokines also recruit nonantigen-specific inflammatory cells including macrophages and other lymphocytes to the liver, which serve as a rich source of additional cytokines. The nonantigen-specific inflammatory cells and cytokines are primarily responsible for the systemic manifestations of hepatitis. Before induction of the acquired immunity described above, the resident native immunity including Kupffer cells, natural killer cells (NK), and natural killer T cells (NKT) is probably involved in the early phase of antiviral immune response, either through production of antiviral cytokines or direct cytotoxicity. These same immune responses are also the mediators of hepatocellular injury. During the course of HBV infection, these multiple pathways are operational and the consequences of these complex interactions result in the various manifestations of HBV infection in response to various natural or exogenous selection pressures. Modified and reprinted with permission.50 Gastroenterology 2001 120, 1000-1008DOI: (10.1053/gast.2001.22454) Copyright © 2001 American Gastroenterological Association Terms and Conditions