The new england journal of medicine
n engl j med 350;jm march 11, 2004
1118 mechanisms of dia
Hepatitis B Virus Infection — Natural History
and Clinical Conquences
Don Ganem, M.D., and Alfred M. Prince, M.D.
From the Departments of Microbiology
and I mmunology and Medicine and the
Howard Hughes Medical Institute, Univer-
sity of California, San Francisco (D.G.); and
the Laboratory of Virology, Lindsley F. Kim-
ball Rearch I nstitute, New York Blood
Center, and the Department of Pathology,
New York University School of Medicine
— both in New York (A.M.P.). Address re-
print requests to Dr. Prince at the Laborato-
ry of Virology, Lindsley F. Kimball Rearch
Institute, New York Blood Center, 310 E. 67th
St., New York, NY 10021, or at aprince@
<
N Engl J Med 2004;350:1118-29.
Copyright © 2004 Massachutts Medical Society. n the past 10 years, remarkable strides have been made in the understanding of the natural history and pathogenesis of hepatitis B virus (HBV)infection. In this article we will review the advances, with particular reference
hepatitis in the decades after World War II. The groundbreaking studies of Krugman
and colleagues in 1967 firmly established the existence of at least two types of hepa-titis, 1 one of which (then called rum hepatitis, and now called hepatitis B) was parenter-ally transmitted. Links to the virus responsible for this form of hepatitis were derived by rologic studies conducted independently by Prince and colleagues 2-4 and by
Blumberg and colleagues. 5 Blumberg and colleagues, arching for rum protein poly-
morphisms linked to dias, identified an antigen (termed Au) in rum from pa-理疗床价格
tients with leukemia, leprosy, and hepatitis, though the relationship of this antigen to
hepatitis was initially unclear. By systematically studying patients with transfusion-
associated hepatitis, Prince and coworkers independently identified an antigen, termed
SH, that appeared in the blood of the patients during the incubation period of the
dia, and further work established that Au and SH were identical. 6,7 The antigen
reprented the hepatitis B surface antigen (HBsAg). 8,9 The minal studies made
possible the rologic diagnosis of hepatitis B and opened up the field to rigorous epi-
Hepatitis B virus (HBV) is the prototype member of the Hepadnaviridae (hepatotropic
DNA virus) family. Hepadnavirus have a strong preference for infecting liver cells, but
small amounts of hepadnaviral DNA can be found in kidney, pancreas, and mononu-
clear cells. However, infection at the sites is not linked to extrahepatic dia. 10-13
HBV virions are double-shelled particles, 40 to 42 nm in diameter (Fig. 1A), 14 with
an outer lipoprotein envelope that contains three related envelope glycoproteins (or
surface antigens). 15 Within the envelope is the viral nucleocapsid, or core. 16 The core
contains the viral genome, a relaxed-circular, partially duplex DNA of 3.2 kb, and a po-
lymera that is responsible for the synthesis of viral DNA in infected cells. 17 DNA -
quencing of many isolates of HBV has confirmed the existence of multiple viral geno-帅哥图库
types, each with a characteristic geographic distribution. 18
In addition to virions, HBV-infected cells produce two distinct subviral lipopro-
tein particles: 20-nm spheres (Fig. 1B) and filamentous forms of similar diameter
i The New England Journal of Medicine as published by New England Journal of Medicine.
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mechanisms of dia
(Fig. 1A).16 The HBsAg particles contain only en-A
B
Figure 1. Structure of HBsAg-Associated Particles
老男孩原唱(Phosphotungstic Acid–Negative Stain).
Panel A shows HBV virions (Dane particles) and fila-
ments. Panel B shows 20-nm HBsAg particles.
n engl j med 350;jm
march 11 , 2004 The new england journal of medicine
1120 identity of which remains unknown. After mem-
brane fusion, cores are prented to the cytosol and
transported to the nucleus. There, their DNA ge-
nomes are converted to a covalently clod circular
(ccc) form, 26 which rves as the transcriptional
template for host RNA polymera II. This enzyme
generates a ries of genomic and subgenomic
transcripts. 27
All viral RNA is transported to the cytoplasm,where its translation yields the viral envelope, core,and polymera proteins, as well as the X and preC polypeptides. Next, nucleocapsids are asmbled in the cytosol, and during this process a single mol-ecule of genomic RNA is incorporated into the as-mbling viral core. 28 Once the viral RNA is en-capsidated, rever transcription begins. 28 The
Entry of HBV
into cell Vesicular transport
to cell membrane
Budding into
endoplasmic
reticulum
Core asmbly and
RNA packaging Core particle废黜百家
Core particle plus
strand synthesis
Core particle minus strand synthesis
HBV
Translation
Transcription
Nucleus
Cytoplasm
cccDNA
Repair
Recycling
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mechanisms of dia
synthesis of the two viral DNA strands is quential. The first DNA strand is made from the encapsi-dated RNA template; during or after the synthesis of this strand, the RNA template is degraded and t
he synthesis of the cond DNA strand proceeds, with the u of the newly made first DNA strand as a template.25,27,29 Some cores bearing the mature genome are transported back to the nucleus, where their newly minted DNA genomes can be convert-ed to cccDNA to maintain a stable intranuclear pool of transcriptional templates.26 Most cores, how-ever, bud into regions of intracellular membranes bearing the viral envelope proteins. In so doing, they acquire lipoprotein envelopes containing the viral L, M, and S surface antigens and are then exported from the cell.
pathogenesis of hepatitis b
The HBV replication cycle is not directly cytotoxic to cells. This fact accords well with the obrvation that many HBV carriers are asymptomatic and have minimal liver injury, despite extensive and ongo-ing intrahepatic replication of the virus.30 It is now thought that host immune respons to viral anti-gens displayed on infected hepatocytes are the prin-cipal determinants of hepatocellular injury. This no-tion is consistent with the clinical obrvation that patients with immune defects who are infected with HBV often have mild acute liver injury but high rates of chronic carriage.31
The immune respons to HBV and their role in the pathogenesis of hepatitis B are incompletely understood. Correlative clinical studies show that in acute, lf-limited hepatitis B, strong T-cell re-sp
ons to many HBV antigens are readily demon-strable in the peripheral blood.32 The respons involve both major-histocompatibility-complex (MHC) class II–restricted, CD4+ helper T cells and MHC class I–restricted, CD8+ cytotoxic T lympho-cytes. The antiviral cytotoxic T-lymphocyte respon is directed against multiple epitopes within the HBV core, polymera, and envelope proteins; strong helper T-cell respons to C and P proteins have also been demonstrated in acute infection. By contrast, in chronic carriers of HBV, such virus-specific T-cell respons are greatly attenuated, at least as assayed in cells from the peripheral blood. However, anti-body respons are vigorous and sustained in both situations (although free antibodies against HBsAg [anti-HBs antibodies] are not detectable in carriers becau of the excess of circulating HBsAg). This pattern strongly suggests that T-cell respons, es-pecially the respons of cytotoxic T lymphocytes, play a central role in viral clearance. Figure 3 sum-marizes the major types of cellular immune re-spon to HBV.
The mechanisms by which cytotoxic T lympho-cytes kill liver cells and cau viral clearance have been incisively investigated in transgenic mice that express viral antigens or contain replication-com-petent viral genomes in the liver.32,33 Becau the mice harbor HBV genes in their germ-line DNA, they are largely tolerant to HBV proteins, and according-ly, clinically significant liver injury does
分数相乘怎么算not devel-op. However, if antiviral cytotoxic T lymphocytes of syngeneic animals are transferred into such mice, acute liver injury with many of the features of clini-cal hepatitis B develops.34 It is striking that, in this model, the number of hepatocytes killed by direct engagement between cytotoxic T lymphocytes and their targets is very small and clearly insufficient to account for most of the liver damage. This sug-gests that much of the injury is due to condary antigen-nonspecific inflammatory respons that are t in motion by the respon of the cytotoxic T lymphocytes. Presumably, much of the damage occurring in this context is due to cytotoxic by-prod-ucts of the inflammatory respon, such as tumor necrosis factor (TNF), free radicals, and proteas-es. Other immune-cell populations, notably natu-ral killer T cells,35 probably also contribute to liver injury.
Recent experiments suggest that some of the inflammatory by-products, notably interferon-g (IFN-g) and TNF-a, can have antiviral effects that do not involve killing the target cells. When cytotoxic T lymphocytes are transferred to mice that bear rep-licating HBV, viral DNA and RNA throughout the liver rapidly disappear, even from viable, uninjured hepatocytes — an effect that can be blocked by the administration of antibodies to TNF-a and IFN-g.34 Such noncytocidal antiviral effects may be impor-tant for viral clearance in natural infection. In fact, cytokine relea triggered by unrelated hepatic in-fections in HBV-transgenic mice can have the same effect.36 This phenomenon may expl
ain the sup-pression and occasional clearance of chronic HBV infection in patients with superimpod acute hep-atitis caud by unrelated virus.
natural history
Primary HBV infection in susceptible (nonimmune) hosts can be either symptomatic or asymptomatic. The latter is more common than the former, espe-
n engl j med 350;jm march 11 , 2004
The new england journal of medicine
1122 cially in young children. Most primary infections in
adults, whether symptomatic or not, are lf-lim-
ited, with clearance of virus from blood and liver
我的朋友600字优秀作文and the development of lasting immunity to rein-
fection. 37,38 However, some primary infections in
healthy adults (generally less than 5 percent) do not
resolve but develop into persistent infections. In
such cas, viral replication continues in the liver
and there is continual viremia, although the titers
of virus in the liver and blood are variable. Persis-
tent HBV infection may be symptomatic or asymp-
tomatic. People with subclinical persistent infec-
tion, normal rum aminotransfera levels, and
normal or nearly normal findings on liver biopsy
are termed asymptomatic chronic H BV carriers;
tho with abnormal liver function and histologic
features are classified as having chronic hepatitis B.
Cirrhosis, a condition in which regenerative nod-
ules and fibrosis coexist with vere liver injury,
develops in about 20 percent of people with chron-
ic hepatitis B. The resulting hepatic insufficiency and portal hypertension make this process one of the most feared conquences of chronic HBV in-fection. Primary Infection In primary infection, HBsAg becomes detectable in the blood after an incubation period of 4 to 10weeks, followed shortly by antibodies against the HBV core antigen (anti-HBc antibodies), which ear-ly in infection are mainly of the IgM isotype. 38 Vire-mia is well established by the time HBsAg is detect-ed, and titers of virus in acute infection are very high — frequently 10 9 to 10 10 virions per milliliter. 39 Cir-culating HBeAg becomes detectable in most cas,and studies of chimpanzees and other animals with primary hepadnaviral infection show that 75 to 100percent of hepatocytes are infected when this anti-gen is evident. 40 Thus, it is not surprising that epi-demiologic studies consistently show high rates of
MHC class I补气血吃什么药
MHC
class I Antigen-prenting cell
MHC
class II Infected hepatocyte CD4+
年味手抄报T cell
CD8+
T cell CD8+
T cell
HBV
peptides
HBV
peptides
HBV cores
HBV
antigens HBV DNA
HBV RNA Down-regulation of viral replication TNF-a
Interferon-g HBV
HBsAg
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