1. 疱疹病毒 Herpesviruses Dongli Pan Herpes来源于希腊词语“herpein”（意为爬行、蠕动）why？
Department of Medical Microbiology and Parasitology
Zhejiang University School of Medicine

2. Classification Herpesviridae Alphaherpesvirinae HSV-1 HSV-2 VZV
..…. (animal viruses)
Betaherpesvirinae
HCMV
HHV-6
HHV-7
…...(animal viruses)
Gammaherpesvirinae
EBV
KSHV
There are 8 currently known human herpesviruses

3. Common features 包膜糖蛋白 包膜 线性dsDNA 皮层 衣壳
1.Shape and structure：spherical, nm in diameter, dsDNA genome ( kb，encoding proteins） is linear in the viral particle but become circularized in infected cells；Capsids have icosahedral （20面体）symmetry. There is a tegument （皮层） and an envelope (包膜）。
包膜糖蛋白 包膜
线性dsDNA 皮层 衣壳

4. 2. Viral replication: Replication and assembly of viral capsids occurs in the nucleus. Many viral enzymes are involved in the process.
3.Immunity: The viruses encode multiple proteins to evade and manipulate host immunity. Host immunity can control productive infection, but cannot prevent establishment of latency, nor can eliminate latent virus.
4. Types of infection
All herpesviruses
a. Primary infection: viral replication and cytolysis
b. Latent infection: No viral replication, DNA genome remains in the life time of host
c. Recurrent infection: viral replication after reactivation
Some herpesviruses
d.Congenital infection：HSV-1, HSV-2, VZV, HCMV
e.Integrated infection：HHV-6, occasionally in EBV
原发感染
潜伏感染
复发感染
先天感染
整合感染

5. Biological Cycle of Herpesviruses
先天感染
(Including congenital infection)
Primary Infection
原发感染
建立潜伏
潜伏感染
增殖性感染（裂解感染）
Productive (lytic) infection
Latent infection 激活
Reactivation
建立潜伏
Recurrent Infection
复发感染

6. Human herpesviruses 卡波西肉瘤 Subfamily Virus Species Primary Target Cell
Site of Latency
Means of Spread
Diseases α
herpesvirinae
HSV-1
(HHV-1)
Mucoepithelial cells
Neuron
Close contact
Cold sores, gingivostomatitis
Herpetic keratitis, Encephalitis
HSV-2
(HHV-2)
Close contact ( sexual transmission)
Genital herpes
VZV
(HHV-3)
Respiratory and close contact
Chicken pox, Shingles β
HCMV
(HHV-5)
Monocyte, lymphocyte, and epithelial cells
Monocyte, lymphocyte, and ?
Close contact transfusions, tissue transplant, congenital
Infectious mononucleosis, Retinitis,
Diseases for newborn and immunocompromised
HHV-6
T cells and ?
Roseola, Others?
HHV-7 ? γ
EBV
(HHV-4)
B cell and epithelial cell
B cell
Saliva ( Kissing disease )
Infectious mononucleosis, nasopharyngeal carcinoma,
Burkitt’s lymphoma
malignant lymphoma
KSHV
(HHV-8)
Lymohocyte and other cell
Close contact (sexual), saliva?
Kaposi’s sarcoma
口唇疱疹
龈口炎
疱疹性角膜炎 脑炎
生殖器疱疹 水痘
带状疱疹
单核细胞增多症
视网膜炎
新生儿和免疫低下者感染 红疹
鼻咽癌
卡波西肉瘤

7. Herpesviridae Herpes Simplex Virus (HSV) • HSV-1 (HHV-1)

8. Biological properties
Spherical, nm, 150 kb dsDNA
HSV-1 and HSV-2 are 50% homologous
Can be easily propagated in many cell lines (most commonly Vero cells)
Form visible plaques, multinucleated giant cells and Cowdry type 1 inclusion bodies (acidophilic nuclear inclusion bodies)
Animal models: mouse, rabbit, Guinea pig.
multinucleate cell with dark
staining inclusions
Plaque

9. Diseases caused by HSV HSV-1 HSV-2 Cold sores 生殖器疱疹 口唇疱疹
Herpetic gingivostomatitis
Herpetic keratitis
Herpes simplex encephalitis (70% fatality rate)
Neonatal herpes
生殖器疱疹
口唇疱疹
Genital herpes, can be caused by HSV-1 too)
Herpetic meningitis
Neonatal herpes
齿龈炎
脑膜炎
角膜炎
疱疹病毒性脑炎
新生儿疱疹 9

10. Pathogenesis • Primary infection Neonatal infection
– Transmission by direct touch or sex (HSV-2 mostly by sex)
– cytolysis
– Blisters in the skin
Neonatal infection
Mother to baby transmission through placenta 水疱 胎盘

11. Reactivation and recurrent infection
• Latent infection
– latently infected ganglia in a non-replicating state
– HSV-1, trigeminal ganglia(三叉神经节);
– HSV-2, sacral ganglia(骶神经节)
Reactivation and recurrent infection
Triggers: fever, emotional stress, fatigue, menstruation, immunosuppression, etc.
The virus starts to replicate and travels back to peripheral tissues, resulting in recurrent infection.
Latency/reactivation cycles are with you LIFE TIME.

12. Diagnosis Approach Test/Comment
Tzanck test: Direct microscopic examination of cells from base of lesion
Multinucleated giant cells and cowdry type A inclusion bodies.
Cell culture (gold standard)
Inoculate Vero, BHK-21 cells, etc. HSV replicates and cause identifiable cytopathic effect: see plaques.
Assay of tissue biopsy, smear, cerebrospinal fluid, or vesicular fluid for HSV antigen or genome
ELISA, immunofluorescent stain, in situ hybridization and PCR
Serology
Specific IgM indicates recent infection

13. Treatment and prevention
阿昔洛韦
Acyclovir (or similar nucleoside analogs and their derivatives)
Patients with genital herpes should avoid intercourse when they have the prodromal itching symptoms or an active lesion.
No vaccine yet. HSV-2 vaccine is under-development N HN
H2N
CH2 O
HO-CH2
Acyclovir, a nucleoside analog,
inhibits viral DNA polymerase

14. Herpesviridae
Varicella-Zoster Virus (HHV-3)
水痘-带状疱疹病毒
一毒两疾病！
皆因可潜伏！

15. Biological properties
Similar to HSV
Has only 1 serotype
Replicates in fibroblast or epithelial cells
Form multinucleated giant cells and Cowdry type 1 inclusion bodies, like HSV
But no working animal model

16. Chicken pox Droplets, direct contact
主要通过飞沫传播
Enter through respiratory system, conjunctiva or skin, etc
Skins of whole body
Second Viremia
Proliferate in local lymph node
Proliferate in mononuclear macrophage
First Viremia
病毒血症

17. Shingles 俗称为:金蛇缠腰或缠腰龙 Chicken pox as a child
Virus establishes latency in dorsal root ganglia or trigeminal ganglia
背根神经节
三叉神经节
Replicate in skin
After adulthood, when stimulated
Reactivated
Travel along Axons of sensory neuron to skin
Host immunity cannot prevent reactivation

18. Congenital Varicella syndrome
(先天性水痘综合征)
• Caused by infection in utero
during the first trimester
• Leads to scarring of the skin of
the limbs, damage to the lens,
retina and brain

19. Diagnosis and intervention
Symptoms are typical. Usually no need of lab tests.
Tzanck test: Staining of samples scraped from the base of a vesical and look for multinucleated giant cells, Cowdry type A inclusion bodies, etc.
Treatment
Acyclovir
Vaccine
Live attenuated vaccine virus
VZV-Ig for emergency prevention (like for immunocompromised patients)
VZV特异性免疫球蛋白

20. Herpesviridae
Human cytomegalovirus (HCMV, HHV-5)

21. Biological properties
Spherical, nm.
HCMV only infects human cells. Fibroblast cells are used for propagation. It replicates slowly.
Infected cells become enlarged and form owl’s eye inclusion bodies (big acidophilic nuclear inclusions with the appearance of an “owl’s eyes”)
Resistance is weak. Long term storage requires liquid nitrogen.
成纤维细胞
猫头鹰眼状内涵体
嗜酸性核内内涵体
H&E stain of lung section showing owl’s eye inclusions

22. Modes of transmission
Direct contact: Sexual transmission, mouth to mouth, hand to mouth
Vertical transmission: transplacental, intrauterine infection, cervical secretions, milk, saliva, etc
Medical devices: Blood transfusion, organ graft 胎盘
子宫内
宫颈分泌物
60-90% of adults are seropositive

23. Outcomes of HCMV infections
Infection of healthy children and adults
Usually a lifelong and subclinical infection
Primary infection can lead to infectious mononucleosis
Congenital infection
HCMV infection is the leading cause of infectious congenital disease
Infection of CNS can cause neurological abnormalities and death)
Neonatal infection
Virus reactivated during delivery
Usually protected by mothers’ antibodies
Infection of immunosuppressed individuals
Transplant recipients and AIDS patients
Severe complications including retinitis,
Meningitis, pneumonia, colonitis
90% in North America
视网膜炎
脑膜炎 肺炎
结肠炎
HCMV retinitis

24. Diagnosis and intervention
Laboratory diagnosis
Cell culture
qPCR
Tests of pp65 antigen in peripheral blood leukocytes
Serology: ELISA for CMV-specific IgM indicates active infection, but may give false-positives
Treatment and prevention
Ganciclovir （更昔洛韦）
Foscarnet（膦钾酸）
No vaccine, but under development

25. Herpesviridae
Epstein- Barr Virus (HHV-4)

26. Biological properties
Typical herpesvirus morphology and structure.
Cannot be grown in normal cell culture.
Lytic infection of EBV usually occurs during primary infection of oropharyngeal epithelial cells or during reactivation from latency in B cells.
Important lytic antigens include: early antigen (EA), viral capsid antigen (VCA) and membrane antigen (MA)
Latent infection mostly occurs in B cells. During latent infection limited viral antigens are expressed. They include EB nuclear antigen (EBNA) and latent membrane protein (LMP)
Latent infection by EBV can transform and immortalized B cells, and occasionally results in malignancies. EBNA-2, EBNA-3C and LMP-1 antigens are essential for transformation. 口咽

27. Pathogenesis Transmitted mainly by saliva
Replication in oropharyngeal epithelial cells
Infects B cells in the local lymphatic system
Spread throughout the body in B cells
Latent infection of B cells (lifetime)
B cells are transformed resulting in malignancies.

28. Diseases related to EBV infection
感染性单核细胞增多症
Infectious mononucleosis (mostly caused by primary infection, fever, sore throat, enlarged lymph nodes in the neck, and feeling tired)
Nasopharyngeal carcinoma (Guangdong, China; areas in southeast Asia)
Burkitt's lymphoma (Africa)
Malignant lymphoma
鼻咽癌
Burkitt淋巴瘤
恶性淋巴瘤
A conjunctival hemorrhage of the right eye
of this patient with infectious mononucleosis.
Burkit’s lymphoma.

29. Diagnosis and intervention
嗜异性（有交叉反应性的）
Heterophile antibody test: rapid test for antibodies induced by EBV infection. It’s diagnostic for infectious mononucleosis.
EBV-specific antibody test
PCR test for viral DNA
No drugs or vaccines are available for Epstein-Barr virus.

30. Pathogens of vertically transmitted infections