1. Prof. Dr. Asem Shehabi Faculty of Medicine University of Jordan
Herpes Viruses
Prof. Dr. Asem Shehabi
Faculty of Medicine
University of Jordan

2. Classification-1
Herpesviruses : All composed of large ds-linear DNA, amorphous protein layers(Tequment) attached to Capsid (162 capsomeres) & Lipid Envelope (11 Glycoproteins) spikes/peplomeres.
8 Herpes groups: All Herpes viruses have ability to infect various types of host cells & replicate in them.
All are replicated in a similar multi-step process.. First Virus genome enter cellular cytoplasm.. transported to the cell nucleus..Tegument proteins activate genes & viral structural proteins are expressed in nucleus.. Progeny virus released from membranes of both nucleus & cell membrane by budding .. accompanied mostly by cell lysis /death. Replication Herpesviruses is not always efficient with a high ratio of non-infectious viral particles.

4. Herpesviruse Groups
Latency: A unique characteristic of all Herpes viruses is their ability to establish latent infection. Each virus type has the potential to establish latency in specific host cells.
latent viral genome may be either extra-chromosomal DNA as Episome or direct integrated into DNA host cells.. Later any time can be reactivated & causing disease.
Alpha-herpesviruses: Herpes simplex virus (HSV-1, HSV-2). both are closely related with nearly 70 % genomic DNA homology..only human infection.
Both types are characterized by an extremely short reproductive cycle (8-16 hours), prompt destruction of the infected cell.. Ability to replicate in a wide variety of host tissues.. Causing nuclear inclusion bodies, multinucleate giant cells & mostly death of cells.

5. Herpes1,2 & Cytomegalovirus Multinucleate & Ballooning cells

6. Herpes simplex virus (1,2)
Primary HSV-1: Mostly infect oral mucosa..Rarely genital mucosa..Transmitted by direct contact .. kissing , saliva ,fingers.. 90% infects mouth & lips during early childhood.. May spread to Nose, Eye, Skin face, rarely reach blood & CNS of infants.
Vesicles eruption usually develop between 1-3 days.. contain fluid , multinucleate cells, inclusion bodies .. Developing lesion/ulcer ..often associated with mild fever and cervical lymphadenopathy..Herpes ulcer on skin ended with developing crusts after one week.
Oral lesions usually heal within 2 weeks.
Recurrence lesions remains mostly localized to the first site of inoculation..mild -severe erythema, one or more vesicles/ulcers may occurs every few months or after years..Long Live latent infection.

7. Latency HSV-1
Latent HSV-1 DNA persists as free circular episomal form integrated into nucleus of the Orofacial trigeminal ganglia .. few genes expressed in latent stage & cause again infection on the same body site/ mostly oral mucosa
State of latency may persist for many months to years before reactivation.. 5% of infected Children.
Virus particles travel down the axon to infect nerve cell ending which supply skin or mucous membrane.. causing vesicles, ulcerations.
Virus Reactivation may be provoked by a number of stimuli: including sunlight, stress, febrile illnesses, trauma, menstruation, immunosuppression, Reactivation may be clinically asymptomatic/ symptomatic including rarely meningitis or Encephalitis.

8. HSV1 and HSV2 can establish latent infection in the sensory ganglia cells: Orofacial trigeminal ganglia or Genital sacral ganglia (1% neuron cells carry viral DNA) that supply the site of the primary infection. During Reactivation Virus travel via axon to infect nerve ending.

9. Common HSV-1 Diseases-1
Mucocutaneous: junction of lips are the most common clinical manifestations of 99% primarily HSV-1 infection rarely HSV-2.
Gingivostomatitis: Cold sores/ Fever blisters.. followed by the development of vesicular & ulcerative lesions on the oral-pharyngeal mucosa , Tongue.. characterized by fever, sore throat/ erythematic lesion.. caused mostly by HSV-1 .. in children less than five years.
Herpetic stomatitis occurs in older children, young adults.. rarely may disseminate to blood & internal organs.
Recurrent HSV-1 infections mostly appear on the lips. .. Intraoral lesions/ Oropharynx are uncommon in the normal host found frequently with immunodeficiency

10. Cold Sores on Lips & Skin

11. Follow/2
Herpes keratitis is usually caused by HSV-1 accompanied by keratoconjunctivitis ..corneal ulceration /scarring in many cases.. may result in vision loss without treatment.. Occurs mostly in old persons.
Skin manifestations: HSV-1 infections can manifest at any skin body site.. Common among health care workers.. lesions on skin of the Index finger & Thumb.. herpetic whitlow.. painful..heals slowly within one month or more.
Eczema herpeticum can be severe.. mostly children.
Herpes encephalitis : mostly caused by HSV-1 ..characterized by hemorrhagic necrosis of temporal lobe in Brain.. Rare cases.. Highly fatal .

12. Immunity to Herpes-1,2
During first viral infection.. Natural Killer cells, cytotoxic T cells & helper T lymphocytes.. play a significant role to stop the virus multiplication..
Specific antibodies & induced delayed hypersensitivity. .Both important in recovery.
Level of specific Antibodies (IgG) reduce the severity of infection.
Newborn baby normally protected against HSV-1 infection during first 6 months by maternal antibodies
Infection with HSV-2 protects against infection with HSV-1, but HSV-1 can only slightly prevent HSV-2 infection.
HSV-1& 2 infection may disseminate to blood, other organs causing serious diseases.. Aseptic meningitis & Encephalitis. in immunocompromised persons.

13. Genital Herpes
Genital herpes is caused mostly by HSV-2 .. Recent years increasing number of cases caused by HSV-1 or both at same time.. About 50% of genital infections are asymptomatic..not recognized..increased risk transmission with other Sexually transmitted diseases.
Primary infection in women usually involves mucosa vulva, vagina, and cervix .. painful ulceration.. frequently associated with dysuria, urethritis, fever, vaginal discharge, regional lymphadenopathy.
In men, initial infection is mostly associated with lesions on glans male organ & surrounding skin.. associated with fever, malaise, urethritis, regional lymphadenopathy
Recurrent genital Herpes: Varies significantly ..Two-third cases have approximately 3 recurrences or more each year..second attacks milder & shorter.

14. Neonatal Herpes Virus Infection
Neonatal herpes: Most cases caused by HSV-2 . through infected mother.. contact of the fetus with maternal genital secretions/ genital ulceration at the time of delivery.
Neonatal HSV-1 infection mostly acquired by contact with infected person in hospital or family.
Manifestations of both neonatal herpes infection are divided into three categories:
1- Common conjunctivitis, mouth & skin lesions
2- Rarely systemic infection.. Pneumonia, fever, poor feeding, jaundice & skin lesions.. Meningitis / Encephalitis .. high mortality.
Cesarean delivery is recommended in case mother has herpes

15. Diagnosis & Treatment of HSV-1,2
Tissue culture used in research & to detect resistant Herpesvirus strains..
Rapid direct detection DNA HSV particles in vesicle fluid, blood, CSF, vaginal swabs by PCR.
Serology: Specific antibodies (IgG) are not always very useful because there is a high prevalence of herpes antibodies in the normal population.
A high antibodies titer for HSV-1/2 indicates acute infection by Enzyme immunoassay.
Treatment: Aciclovir /Valaciclovir should be given in early acute infection .. Inhibits viral DNA.. Topical, Oral, Intravenous drugs..according the clinical case..
Viral latency can’t be eradicated by treatment.. No Vaccine.

16. Varicella-Zoster virus
Classifided as Gamma Herpesvirus (HSV-3) has the most limited host cells infection.. replicate in lymphoid cells causing lytic effects in certain targeted cells.
Varicella-Zoster virus: Causing 2 clinical diseases:
1-Chickenpox is primary acute infection occurs mostly young children 5-10 years.. Spread by Respiratory droplets or skin contact ..infect mucosa Resp. Tract / conjunctive or both at the same time.
Varicella-zoster virus spread mostly through airborne droplet from RT..Rarely through skin contact . Virus multiples first lymph tissues RT.. spread to blood & reticulo-endothelial system.. Following viraemia.. develop a characteristic vesicular skin rash, oral mucosal lesions, Mild fever.. Incubation 1-2 weeks.

17. 2 /
Skin rash begins on the face, head, trunk and spreads to all body sites. The lesions are initially small vesicles, become pustular, crusting & healing within 10 days .
Serious complications are rarely seen in children.. More in young adult & compromised host..
Secondary bacterial & viral infection.. Pneumonia, Myocarditis, Arthritis. Rarely affects CNS.
Neonatal/ Congential varicella .. Acute encephalitis may occur before or after delivery..New borne babies of new infected mothers should be protected by Passive Immunization with immunoglobulin.
Latent virus infection can be demonstrated in human.

18. 3/
Immunity: Lack enough of cell-mediated immunity, Cytotoxic T cells & specific antibodies affect rapid skin healing and more associated with complications.
Generally most children & young adult who infected naturally develop enough antibodies against Varicella-zoster virus.
All primary infection, varicella-zoster virus establish latency in nerve cell bodies, mostly dorsal root ganglia .. less in cranial nerve & lymphoid tissue
2- Herpes zoster/shingles: This clinical feature is a reactivation of latent virus.. Virus travel along the spinal axon nerve.. affect one dermatome & skin area served by that nerve..most skin vesicles appears as clusters on chest.
1-2% Persons over 50 year develop zoster

19. Zoster Clinical Infection
Zoster Clinical Infection ..Virus reach the sensory ganglion from periphery by traveling up nerve axons.. Virus reactivation allow virus to return back to one thoracic or upper lumbar dermatome

20. Herpes Zoster

21. 4/
Typically Zoster manifests as a localized vesicular rash limited to thoracic or upper lumbar regions.. associated with erythema & burning sensation, itching followed development of clear vesicles & healing
Acute herpes zoster neuritis & postherpetic neuralgia very painful disease..may be persist few weeks-months , complications may involve internal organs, lung & brain in immunocompromised.
Ocular zoster affects ophthalmic trigeminal nerve..associated with 25% Zoster cases..corneal ulceration, keratitis , scarring & blindness.
The average time to healing for shingles ranges from 2-4 weeks.. depending upon the age and immune status of the person.. Total specific antibodies.. Early oral or intravenous Aciclovir reduce the severity of infection.. Available vaccine protects to some extent.

22. Epstein-Barr Virus
HSV 4 (EBV): Infect & replicate in two major cell types: the outer oropharyngeal epithelial cells of the salivary gland & B lymphocytes (B-cells)..Human host.
EBV produces about 100 different large glycoproteins during the active phase of the viral replication, Infection develops first in the salivary gland.. Large amounts of the virus released in the saliva for Few weeks.. Highly infectious for close contact.
latent infection persist in memorial B lymphocytes, Most people become infected during their childhood. Infants become susceptible to EBV as soon as maternal antibody protection disappears.
Most EBV infection in children are usually asymptomatic or with symptomatic with Mild Respt. tract illnesses..sore throat, fever, enlargement of regional lymph nodes for few days.

23. 2/
Asymptomatic infection increased with immuno-suppresion. .Infection of B-cells causes them to proliferate as atypical Lymphocytes .. Can be detected in blood.. Lack of immune response of both humoral & cellular represents a high risk of developing a form of cancer.
Latent infection may develop autoimmune disease.. Rheumatoid arthritis, multiple sclerosis.
Infectious mononucleosis/ glandular fever is most common clinical disease associated with EBV.
Occurs commonly in Young Adults.. Mild to sever forms.. Most symptoms are fever, sore throat, and swollen lymph glands.. Less a swollen spleen or liver.
Common clinical features: myalgia, pharyngitis, cervical adenopathy, atypical lymphocytosis, oral Hairy Leucoplakia.. white lesions on cheek mucosa & sides of tongue..Common in AIDS patients

24. 3/ Other Diseases of EBV
T cell lymphoma, Immunoplastic lymphoma.. infected B lymphocytes.. Hodgkin’s disease is second common EB disease.. Develop mostly in highly immunodeficient individuals.. affects heart & bone marrow / common in organ transplant patients.
Burkitt’s Lymphoma..Tumor of Jaw.. develop African Children & Adults.
Nasopharyngeal Carcinoma.. Long Latent EBV infection associated with undifferentiated nasopharyngeal epithelium.. Affects mostly males of Chinese Origin.. Rare in other countries.
Lab Diagnosis: Saliva/throat washing/ blood , presence atypical B-lymphocytes, heterophile antibodies. Detection Type-specific antibodies (IgA, IgG, IgM) or nuclear /capsid antigens by PCR.. Aciclovir treatment.. No vaccine

25. Human Cytomegalovirus
Beta-herpesviruses: HSV-5 / CMV many genotypes Has a large genome..slow growth in infected tissues (4-8 weeks).
HSV-5 replicate in epithelial cells Respiratory Tract, salivary glands, Kidney causing Endothial multinucleate giant cells.
CMV endemic throughout the world.. Generally Infection occurs in most children.. More common in developing countries with lower hygiene & socioeconomic conditions .
CMV ..Spread orally by close contact with body fluids.. urine, saliva, breast milk, blood, tears, semen, and vaginal fluids..

26. 2/CMV
During acute & latent CMV infection.. Virus shed mainly in saliva & urine.. For weeks-years.
CMV remains stable for few days outside the body.. persist life-long in host mononuclear cells.. At the same time in various tissues (kidney, liver, lung)..
Latent infection stage is often associated with kidney tissues more than other body organs
Recurrence may follow reactivation of latent virus or due to infection with new strain.
Congenital CMV .. Primary intrauterine infection.. Mostly asymptomatic.. Few may develop serious.. symptomatic disease.. Cytomegalic Inclusion body disease.. Associate with Brain defects.. Mental retardation Down syndrome, Hearing & Vision loss, Gastrointestinal disorder.

27. 3/
New born babies acquired CMV infection.. developing permanent disabilities..Each year about 100,000 cases worldwide.
In healthy persons primary infection persist 4-6 weeks often asymptomatic.
Immunity: Host response associated with develop IgM, IgG, T cell..cell mediated immunity.. important to control CMV infection.
Lack of sufficient immunoresponse can cause serious illness in immuno-compromised patients.. Retinitis, Pneumonitis,Colitis, Hepatitis,Encephalitis, Pancreatitis.
CMV infection can cause secondary increases microbial opportunistic infections immunosuppressed.

28. 4/
Primary CMV infection in patients may weakened immune systems can lead to serious disease.. including organ transplant recipients, hemodiaylsis, immunosuppressive drugs, Cancer patients.
CMV is the most common viral opportunistic infection after bone marrow / organ transplantation.. Mortality rate may reach 90% if it is left untreated.
CMV infection in infant / children/young adults.. begins with signs and symptoms of fever, malaise, leukopenia ..rarely mononucleosis.
Invasive disease .. Blood sepsis.. spread into many organs.. CMV has mutagenic effects.. A possible role in oncogenesis.
Sexual transmission..is common & asymptomatic in healthy persons.

29. 5/ Diagnosis: A newborn has congenital CMV infection
if the virus is found in urine, saliva, or blood during the first 3 weeks after birth.  
Antigen Detection by TORCH Test: Examination blood & urine for Toxoplasma, Rubella, CMV, HSV-2..
IgM antibodies indicate recent Infection.. IgG antibodies old infection.
Virus DNA can be detected by PCR
Ganciclovir treatment.. Suppress DNA virus multiplication.. Early treatment may prevent hearing loss in infants born with congenital CMV..
Available vaccine protective up to 90% .

30. Human Herpesvirus 6 and 7
Human herpesvirus 6 and 7 classified as a gamma herpesvirus infect CD4 T cells.. Can be found in blood of patients with Lymphoma.. Both are related genetically to CMV .. Infect Human, animals
HSV-6, more than -7 cause Rosella Infants disease/ Roseola infantum.. Common among 6 months- 3 years children.. illness is characterized by days of fever, respiratory illness, cervical lymphadenopathy, macular rash mostly on face..Rare neurological complications or hepatitis.
Early children infection starts in family through close contact with oropharyngeal secretions & Saliva.. mostly asymptomatic
HSV -6 may cause infection adult patients.. Hepatitis, central nervous system.. Results in rejection of transplanted kidneys. . No viral treatmentt, No vaccine

31. 2/
Herpesvirus-8 : Causes Kaposi's Sarcoma.. KS Virus is partially homologous to the DNA of EBV..affects endothelial cells of vascular and lymph origin..transmitted by sexual route..less blood.
Sarcoma is a cancer that develops in connective tissues.. fibrous tissues below the skin surface, mucous membranes of the mouth, nose, anus.. Common in AIDS patients & Homosexual persons.. Highly mortality
Sarcoma cutaneous lesions spread at multiple body sites.. with or without internal organ involvement.. oral cavity, gastrointestinal tract, lymph nodes.
HV8 has been found in patients with B cell Lymphoma with AIDS.. Most KS cases developed in association with (HIV) infection .. Surgical treatment, Cryotherapy, Radiotherapy, Topical immunotherapy, Ganciclovir

32. Skin & Oral Kaposi