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Chapter 22

Hepatitis Viruses. Chapter 22. 肝炎病毒. pathogen of viral hepatitis. Introduction. 1. Human hepatitis viruses.  HAV (+ssRNA) , HBV (dsDNA) , HCV (+ssRNA) , HDV ( – ssRNA) and HEV (+ssRNA)  HGV (+ssRNA) and TTV ( –ssDNA). 2.Other viruses of causing viral hepatitis.

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Chapter 22

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  1. Hepatitis Viruses Chapter 22 肝炎病毒 pathogen of viral hepatitis

  2. Introduction 1. Human hepatitis viruses HAV(+ssRNA), HBV(dsDNA), HCV(+ssRNA) , HDV(–ssRNA)andHEV(+ssRNA) HGV(+ssRNA) and TTV(–ssDNA) 2.Other viruses of causing viral hepatitis (CMV,EBV,Rubella virus,VZV,Yellow fever virus,etc.)

  3. Hepatitis A virus 甲型肝炎病毒(HAV) *pathogen of hepatitis type A *classified as Hepatornaviridae (肝RNA病毒属)

  4. Ⅰ.Biological Properties 1. Shape and structure capsomere VP1-4 Naked virus •spherical particle(d=27nm) •icosahedral nucleocapsid Genome •ssRNA (positive stranded)•can code for polyprotein,RNA polymerase and proteinase ↓ Cleave 4 polypeptide (VP1 to VP4) ↓ capsomere→capsid

  5. Antigenicity ofcapsid protein:HAV-Ag (only one serotype) 2.Resistance stable to treatment with ether(乙醚), acid (PH3) and heat(60℃ for 1 hour) tolerate boiling for 5 minutes 3.Cultivation infective model(黑猩猩、狨猴、红面猴) cell culture (原代肝细胞或恒河猴胚肾传代细胞) (multiply slowly, non-CPE)

  6. Ⅱ.Pathogenicity and Immunity 1.Pathogenicity Source of infection by fecal-oral route (通过粪-口途径传播 ) Route of transmission Feature of HAV-infection •asymptomatic or only mildly ill •acute hepatitis of short incubation •fulminant hepatitis and favorable prognosis 很常见 罕见慢肝和携带者 罕见暴发性肝炎,预后良好

  7. 2.Pathogenesis Virus in feces Intestine and local lymphoid tissue by fecal-oral route (污染食物和水) (replication) blood liver 通过日常生活接触→散发性肝炎 通过污染食物和水→肝炎的暴发流行 Immunopathogenesis  Damage caused by HAV ?

  8. ---long-lasting immunity 3.Immunity virus in blood IgM anti-HAV+---recent infection antibody to HAV(IgG---lifetime persistence)

  9. Ⅲ.Laboratory Diagnosis 1.Detection of viral antibody  IgM anti-HAV （ELISA,早期诊断） IgG anti-HAV （ELISA，既往感染/流调） 2.Detection of virus particles in feces(IEM) 3.Detection of viral RNA Ⅳ.Specific Prevention 1.Artificial active immunity 2.Artificial passive immunity (vaccine---strain H2 ) (gamma globulin）

  10. Hepatitis B Virus 乙型肝炎病毒 Pathogen of hepatitis B

  11. Ⅰ.Biological Properties in the blood of patients with HB 1.Shape and structure Shape ---three viral particle in the blood of infected persons •largerspherical particle •small spherical particle •tubular particle/filaments virion of HBV, i.e. Dane particle 42 nm 1:1730:120

  12. Structure of virion ---Spherical particle with double-shelled capsid ⑴outer shell (contains HBsAg, Pre-S1 and Pre-S2 Ag) ⑵viral core---nucleocapsid HBcAg (d=27nm) HBsAg •surface---inner shell •core DNA polymerase dsDNA (contain HBcAg and HBeAg) core protein kinase *ds-DNA *DNA polymerase *Protein kinase 27nm d=42nm

  13. 2.Genome structure Circular ds-DNA(has a single-chain region) –DNA Pre-S2 Pre-S1 •long chain---complete•4 ORF (open reading frames) S P -DNA +DNA +DNA (short chain ---variable length) DR1 DR2 C 5‘ Sticky end & direct repeat (DR1,2) Pre-C X (DNA成环和病毒复制的关键序列)

  14. 3.Replication of HBV Unique mode of replication ---retrovirus-like pathway of replication Replicative cycle (p287 Figure 22-5) dsDNA DNA多聚酶 外衣壳蛋白 （HBsAg） 完整的环状ds-DNA 子代HBV 作为mRNA 转译 cccDNA 转录 2.1kbRNA RNAP dsDNA 转译 内衣壳蛋白 （HBcAg） 3.5kbRNA 与负链结合 与DNAP进入内衣壳 前基因组 -DNA +DNA 逆转录 复制

  15. 4.Compositions of antigen • Hepatitis B surface antigen(HBsAg) • Hepatitis B core antigen(HBcAg) • Hepatitis B e antigen(HBeAg) • Other antigen (Pre-S1, Pre-S2 antigen, HBxAg)

  16. HBsAg ⑴Exist in blood from infected person with HBV •outer shell of Dane particle • small spherical particle • tubular particle HBsAg

  17. ⑵ Subtypes of HBsAg •contains common epitope a , subtype epitope d/y and w/r • 4 major subtypes ---- adr , adw , ayr , ayw ⑶HBsAg+---marker of HBV infection ⑷Anti-HBs:neutralizing antibody •具有免疫保护作用 •抗-HBs+表示感染过/患病已恢复/接种过疫苗获得免疫力

  18. HBcAg (cann’t find in serum) ⑴Locate in surface of viral core ⑵Anti-HBc+---marker of viral infection and replication • IgM anti-HBc+ ---active replication of HBV •IgG anti-HBc+ ---past infection *marker of recent infection *high titers---marker of acute hepatitis B (non-neutralizing Ab)

  19. HBeAg ⑴Exist in HBsAg-positive serum ⑵Associated with presence of Dane particles and DNAP ⑶HBeAg+---marker of virus replication and high infectivity of serum ⑷Anti-HBe+ ----marker of lower infectivity

  20. 5.Animal model and cell culture 6.Resistance of HBV •stable to heat(60℃ for 4 hour) •disinfectant (常用0.5%过氧乙酸和5% 次氯酸钠)•高压灭菌法、100 ℃加热10分钟和环氧乙烷可灭活病毒

  21. Ⅱ.Pathogenicity and Immunity Source of infection 1.Pathogenicity •patients with hepatitis B •asymptomatic HBsAg carrier (无症状HBsAg携带者,ASC) Route of transmission •via infected blood or blood products •vertical transmission 杜绝医源性传播!

  22. Feature of HBV-infection •Diversity of clinical finding ---ASC, acute/chronic or fulminant hepatitis •Long incubation hepatitis •Liver damage is caused by the host immunologic response •prognosis *progress toward choronic (10%) *leading to hepatocirrhosis *often associated with primary hepatocellular carcinoma （肝硬化） （原发性肝细胞癌）

  23. Pathogenesis ---liver damage is caused by the host immunologic response ⑴immunopathogenic damage mediated by cellular immunity ⑵pathogenic damage caused by IC ⑶pathogenic damage caused by autoimmunity ⑷immune tolerance & chronic hepatitis ⑸viral variation & immune escape (CTL,CD4+T;CKs→→→急性、慢性、重症肝炎和肝硬化) （重症肝炎以及肝外症状） (LSP→慢迁肝和慢活肝)

  24. 2.Immunity ---neutralization of anti-HBs (清除血中的游离病毒) • Specific humoral immunity • Specific cellular immunity 抗-PreS1、抗Pre-S2 也有保护作用 ---double effects mediated by CTL •免疫保护作用---清除细胞内病毒 •免疫损伤作用---参与致病作用 3.HBV & primary hepatocellular carcinoma

  25. Ⅲ.Laboratory Diagnosis • Detection of viral antigens and • antibodys Including : HBsAg, anti-HBs , anti-HBc, HBeAg and anti-Hbe Methods :ELISA or RIA  Clinical analysis and signification (“二对半”的检测)

  26. p291 二对半检测结果的临床分析 HBsAg HBeAg anti-HBs anti-HBe anti-HBc 结果分析 + ––––HBV感染者或ASC ++ – – – 急性/慢性肝炎或 ASC (传染性强) ++– –+ 急性/慢性肝炎或 ASC (传染性强) +––++急性感染趋向恢复 ––+++既往感染恢复期 ––++–既往感染恢复期 ––––+ 既往感染/ 窗口期 ––+––对再感染有免疫力 (恢复期、既往感染或接种过疫苗) “大三阳” “小三阳”

  27. “二对半”的检测的实际应用 ⑴特异性诊断 ⑵筛选供血者 ⑶判断病人、ASC和孕妇的传染性 ⑷估计病人的转归和预后 ⑸流行病学调查与追踪传染源 ⑹确定母婴传播阻断对象 “大三阳”, IgM抗-HBc+ ; HBsAg单项阳性(ASC) 筛去HBsAg+,抗-HBc+ HBsAg+伴HBeAg+ •HBsAg+与HBeAg+在2 个月内阴转—好 •“大三阳”持续6个月以上---慢性转化 •慢活肝HBeAg一旦 消失示病情好转 (抗-HBs 和HBsAg及其亚型的检测) 2.Detection of HBV-DNA HBV-DNA+----病毒正在复制,其血清传染性强

  28. Ⅳ.Principle of prevention 1.General prevention 2.Specific prevention Artificial active immunity  Artificial passive immunity  Passive-active immunity vaccine (HBIg) (HBIg+vaccine)

  29. Hepatitis C virus 丙型肝炎病毒 1.General properties 30-60nm spherical particle, enveloped virus Genome structure ( p297) ---linear ss-RNA (positive strand) 2.Pathogenicity Souse of infection Route of transmission Cause hepatitis C 患者或慢性携带者 血源性传播为主 非经血传播→散发性丙肝 血源性传播→输血后丙肝

  30. Feature of HCV-infection •asymptomatic, acute hepatitis and chronic hepatitis • cause extrahepatic damage • prognosis (40% ~ 50%) 肾小球肾炎 *progress to hepatocirrhosis (20%) *often associated with primary cellular carcinoma 3.Diagnosis 4.Prevention --- detection of HCV-RNA and anti-HCV 抗-HCV+表示已感染HCV (不可献血) Stop iatrogenic transmission!!! 严格筛选供血者,使用灭活的血制品

  31. Hepatitis D virus 丁型肝炎病毒 1.Shape & structure Shape  structure RNA HBsAg HDAg •capsid:HBsAg •viral core *genome: circular –ssRNA *HDAg( P24,P27) 35-37 nm HDV--- defective virus (helper virus: HBV)

  32. 2.Pathogenicity Hematogenic transmission Cause acute hepatitis D •coinfection (联合感染或共同感染) •superinfection(重叠感染) 3.Diagnosis (detection of anti-HD, HD-Ag and HDV-RNA)

  33. Hepatitis E virus 戊型肝炎病毒 1.Shape & structure Shape •32-34nm spherical particle •naked virus with appearance of a calicine 形似杯状 Genome ---+ssRNA (p301 Figure 29-11)

  34. 2.Pathogenicity Route of transmission Cause acute hepatitis E (by fecal-oral route) 水源污染→暴发流行 流行及临床似甲肝 3.Diagnosis (detection of HEV-RNA and anti-HEV)

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