Herpesviruses

Herpes virus types that infect humans

'Herpein' - 'to creep' = chronic/latent/recurrent infections

Herpes simplex I & II: (cold sores, genital herpes)

Varicella zoster : (chicken pox, shingles) Cytomegalovirus (microcephaly, infectiousmononuclosis) Epstein-Barr virus (mononucleosis, Burkitts lymphoma) Human herpesvirus 6 & 7 (Roseola) Human herpesvirus 8 (Kaposis sarcoma)

Classification of Human Herpesviruses

Family Herpesviridae Sub family herpesvirinae Sub family Genus Official name Alpha simplex

Common HHV 1 Herpes simplex type 1 HHV 2 Herpes simplex type 2 ________________________________________ Varicello HHV 3 Varicella Zoster virus _________________________________________________________ Beta herpevi Cytomegalo HHV 5 Cytomegalovirus Roseolo HHV 6 HHV 6 HHV 7 HHV 7 ____________________________________________________________ Gamma her Lymhocrypto HHV 4 Epstein-Bar virus Rhadino HHV 8 Kapossis sarcoma associated herpes virus

Herpes virus
Capacity to persist in host indefinitely in nucleus of the cell Varicella zoster and herpes simplex viruses establish latent infections in neurons Reactivation Varicella zoster: herpes zoster (shingles) HSV 1: recurrent labial herpes HSV 2 : genital herpes CMV , EBV and HHV-6 : persist in lymphocytes

Herpesvirus Virion
1. 2. 3. 4. Virion has 4 basic structures Envelope Tegument Icosahedral capsid-162 capsomers DNA-containing core

Herpesvirus Virion
Spherical 150- 250 nm Icosahedral Enveloped ds DNA linear 124-235 kbp More than 35 proteins in virion Envelope:8nm spikes viral glycoproteins. Fc receptors.

Replication nuclear, bud from nuclear membrane

Infection: Lytic, latent and recurrent

Herpes virion -Properties

Size:150-200nm Envelope:Present;asossated glycoproteins-spikes. Tegument:Protein-filled region between capsid and envelope. Capsid:Icosahedral, 95-105nm diameter; 162 hexagonal capsomers. Core:Toroidal (DNA around protein), ~75nm diameter. Genome: Large, 130-230kbp and encode at least 100 different proteins and many virus-specific enzymes , Linear, d/s DNA,, G+C 31-75 % Replication:Nuclear. Assembly:Nuclear. Common Antigens:None!

Herpes Simplex Viruses

Extremely widespread in the human population. Broad host range, being able to replicate in many types of cells and to infect many different animals. They grow rapidly and are highly cytolytic. Responsible for a spectrum of diseases, ranging from gingivostomatitis to keratoconjunctivitis, encephalitis, genital disease, and infections of newborns. The herpes simplex viruses establish latent infections in nerve cells; recurrences are common

Properties of the Viruses

There are two distinct HSVs: type 1 and type 2 (HSV-1, HSV-2). Their genomes are similar in organization They can be distinguished by sequence analysis or by restriction enzyme analysis of viral DNA. The two viruses cross-react serologically, but some unique proteins exist for each type. They differ in their mode of transmission HSV-1 is spread by contact, usually involving infected saliva HSV-2 is transmitted sexually or from a maternal genital infection to a newborn.

Pathogenesis
Tropism-Herpes Virus can broadly be devided to to two subgroups based on the use of either neurone or leukocyte as latent site of infections Neural Leukocytic Alphaherpesvirus Beta & Gamma HSV1 CMV-monocytes HSV2 EBV-B cells VZV HHV6-leukocytes HHV7-leukocytes HHV8-leukocytes

Characteristics
HSV causes cytolytic infections Lesions induced in the skin and mucous membranes by HSV-1 and HSV-2 are the same and resemble those of varicellazoster virus. Changes induced by HSV are similar for primary and recurrent infections . Characteristic histopathologic changes include Production of Cowdry type A intranuclear inclusion bodies formation of multinucleated giant cells. Cell fusion provides an efficient method for cell-to-cell spread of HSV, even in the presence of neutralizing antibody.

Primary Infection
HSV is transmitted by contact of a susceptible person with an individual excreting virus. HSV-1 infections are usually limited to the oropharynx, and virus is spread by respiratory droplets or by direct contact with infected saliva. HSV-2 is usually transmitted by genital routes. Viral replication occurs first at the site of infection. Virus then invades local nerve endings and is transported by retrograde axonal flow to dorsal root ganglia, where, after further replication, latency is established. Oropharyngeal HSV-1 infections result in latent infections in the trigeminal ganglia genital HSV-2 infections lead to latently infected in sacral ganglia.

Primary Infection
Primary HSV infections are usually mild; in fact, most are asymptomatic. Only rarely does systemic disease develop. Widespread organ involvement can result when an immunocompromised host is not able to limit viral replication and viremia occurs.

HSV1 and HSV2 produce ulcerative lesions within mucosal regions

Clinical Findings
Oropharyngeal Disease Primary HSV-1 infections are usually asymptomatic. Symptomatic disease occurs most frequently in small children (15 years of age) and involves the buccal and gingival mucosa of the mouth The incubation period is short (about 35 days, with a range of 212 days), and clinical illness lasts 23 weeks. Symptoms include fever, sore throat, vesicular and ulcerative lesions, gingivostomatitis, and malaise. Gingivitis (swollen, tender gums) is the most striking and common lesion. Primary infections in adults commonly cause pharyngitis and tonsillitis. Localized lymphadenopathy may occur.

Clinical findings
Recurrent disease is characterized by a cluster of vesicles most commonly localized at the border of the lip Intense pain occurs at the outset but fades over 45 days. Lesions progress through the pustular and crusting stages, and

healing without scarring is usually complete in 810 days.

The lesions may recur, repeatedly and at various intervals, in the same location. The frequency of recurrences varies widely among individuals.

Alphaherpes Latent Infections 1. HSV 1 Site of latency- Terminal ganglia 2. HSV 2 Site of latency- Sacral ganglia 3. VZV Site of latency- Dorsal Root ganglia

Keratoconjunctivitis
HSV-1 infections may occur in the eye, producing severe keratoconjunctivitis. Recurrent lesions of the eye are common and appear as dendritic keratitis or corneal ulcers or as vesicles on the

eyelids.
With recurrent keratitis, there may be progressive

involvement of the corneal stroma, with permanent opacification and blindness. HSV-1 infections are second only to trauma as a cause

Genital Herpes
Genital disease is usually caused by HSV-2 Primary genital herpes infections can be severe, with illness lasting about 3 weeks. Genital herpes is characterized by vesiculoulcerative lesions of

the penis of the male or of the cervix, vulva, vagina, and

perineum of the female. The lesions are very painful and may be associated with fever, malaise, dysuria, and inguinal lymphadenopathy. Viral excretion persists for about 3 weeks.

Skin Infections
Intact skin is resistant to HSV, so cutaneous HSV infections are uncommon in healthy persons. Localized lesions caused by HSV-1 or HSV-2 may occur in abrasions that become contaminated with the virus

(traumatic herpes).
These lesions are seen on the fingers of dentists and hospital personnel (herpetic whitlow) and on the bodies of wrestlers (herpes gladiatorum).

Herpes whitlow (Herpes skin infection)

Encephalitis
A severe form of encephalitis may be produced by herpesvirus. HSV-1 infections are considered the most common cause of sporadic, fatal encephalitis in the United States.

The disease carries a high mortality rate, and those who

survive often have residual neurologic defects. About half of patients with HSV encephalitis appear to have primary infections, and the rest appear to have recurrent infection.

Neonatal Herpes
HSV infection of the newborn may be acquired in utero, during birth, or after birth. The mother is the most common source of infection in all cases. Neonatal herpes is estimated to occur in about one in 5000 deliveries per year. The newborn infant seems to be unable to limit the replication and spread of HSV and has a propensity to develop severe disease.

Laboratory diagnosis
Cytopathology A rapid cytologic method is to stain scrapings obtained from the base of a vesicle (eg, with Giemsa's stain)

the presence of multinucleated giant cells indicates that

herpesvirus (HSV-1, HSV-2, or varicella-zoster) is present

Isolation and identification of virus

Inoculation of tissue cultures is used for viral isolation. The agent is then identified by immunofluorescence staining with specific antiserum.

Typing of HSV isolates may be done using monoclonal

antibody or by restriction endonuclease analysis of viral DNA Polymerase Chain Reaction (PCR) PCR assays can be used to detect virus and are sensitive and specific.

Serology
Antibodies appear in 47 days after infection and reach a peak in 24 weeks. They persist with minor fluctuations for the life of the host. The diagnostic is limited by the multiple antigens shared by HSV-1 and HSV-2.

Treatment
Inhibit DNA synthesis-inhibit viral replication Acyclovir-drug of choice Famiclovir Valaciclovir better absorption Idoxyuridine Vidarbine

Varicella-Zoster virus

Varicella-Zoster virus
Two almost universal human diseases 1 Chickenpox (Varicella)-exanthema of childhood 2 Herpes zoster (Shingles) Disabling disease of Aged persons Immunocompromised patients

Varicella-Zoster
Varicella-Chicken pox Latency Zoster-Shingles VZ virus causes two distinct clinical entities Both diseases same virus Morphologically identical HSV No animal reservoir (except primates) Grow readily cell culture Intra-nuclear inclusions, balooning, swelling

Varicella-Zoster Virus
Normal individuals Primary infection (chickenpox) is one of the classical rash diseases of childhood. Following primary infection, the virus remains latent in the cranial-spinal ganglia. Reactivation leading to the appearance of shingles occurs in 10-20% of infected individuals and usually occurs after the fourth decade of life.

Immunocompromised individuals
Primary infection Severe in children -anti malignancy drugs- leukaemia and lymphoma. Life-threatening complications such as disseminated varicella, pneumonia, and encephalitis are much more likely to be seen. Reactivation Immunocompromised : herpes zoster, appear at an earlier age and more than one episode may occur. Severe, disseminated disease may occur but fatality is rare.

Varicella Zoster Virus Herpes zoster -Shingles

Properties of VZ virus
A ubiquitous and extremely contagious infection Morphologically identical HSV No animal reservoir

Intranuclear inclusions
Same virus chicken pox and zoster Only one serotype HSV

Varicella Highly contagious disease of children

Route URT / conjunctiva Circulates in blood Multiple cycles of replication Localizes in skin viral infection of capillary endothelial cells Neonatal / complicated Lung and Other organs ( severe disease )high mortality

Varicella or Chicken pox

Always acute disease IP 7-23 d-infectious 2 d before rash Rash-face, neck trunk, limbs, shoulder blades Maculae-papule-vesicle-crust- in crops Duration of disease-7 and 10 days, up to 2-4 wks Complications rare Mortality very low

Chicken pox-neonatal
Varicella from mother Virus different organs High mortality about 30 %

Congenital Varicella
Varicella in pregnancy rarely crosses placenta Congenital varicella syndrome

Chicken pox-adults (Primary)

Serious Pneumonia most common complication Mortality 10-40 %

ZOSTER or Shingles
Herpes zoster, a sporadic disease, is the consequence of reactivation of latent VZV from the dorsal root ganglia. No history of recent exposure

Incidence is highest among individuals in the sixth decade of

life and beyond. Recurrent herpes zoster is exceedingly rare except in immunocompromised hosts Unilateral vesicular eruption within a dermatome, often

associated with severe pain.

Zoster in AIDS patient

Zoster
Skin lesions similar to varicella Often only single ganglion involved Limited to skin of an individual dorsal root ganglion

Acute inflammation of sensory nerves and ganglia

Trigger of reactivation ?? Affected immunity

Clinical manifestations- Zoster

Very painful Virus : nerve to cell Area supplied by nerve-crop of vesicles Incapacitating disease Unilateral common- trunk, head, neck Any age Facial paralysis (trigeminal nerve)

Diagnosis
Clinical Cytology-multinucleated giant cells Intracellular viral antigen-IF

EM diff poxviruses
Molecular methods-PCR,EIA Serology-CF,cell culture

Immunity
Primary Varicella-life long immunity to Varicella Zoster can occur CMI important in recovery

Treatment and Prevention

Acyclovir -severe varicella or zoster infections. A live attenuated vaccine controversial in immunocompromised individuals.

VZIG can be used to prevent primary infection in

susceptible individuals.

Cytomegalovirus
The largest of the Herpesviruses

CMV infection are 'slow' - 7-14 days

CMV infection is common more than 50 % population experience infection by the age of 40 Most infections are asymptomatic occurs in people except with immune defects (T-cell defects) /pregnancy / newborns

(congenital)
CMV can be transmitted vertically or horizontally Latency is within Monocytes

 In developed countries with a high standard of hygiene, 40% of adolescents are infected and ultimately 70% of the population is infected. In developing countries, over 90% of people are ultimately infected. CMV can be transmitted vertically or horizontally usually with little effect on the host. Latency is within monocytes. Upon reactivation infectious virions appear in the urine and the saliva. Transmission may occur in utero, perinatally or postnatally.

Cytomegalovirus
Normal individuals Primary infection is usually asymptomatic, occasionally an infectious mononucleosis-like illness may be seen. Reactivations or re-infections are common throughout life and are usually asymptomatic.

Immunocompromised individuals
Both primary and recurrent infection may lead to symptomatic disease.
Primary CMV infection is usually more severe than recurrent infection, with the exception of bone marrow transplant recipients, where primary and recurrent infections are just as severe.

Clinical Manifestations
Fever Pneumonitis Hepatitis Gastrointestinal manifestations eg. colitis Encephalopathy Retinitis Poor graft function Pneumonitis is the most severe manifestation, and carries a mortality rate of 85% in the absence of treatment.

AIDS Patients
CMV disease is present in 7.4% to 30% of all AIDS patient. Sight-threatening retinitis, colitis, and encephalopathy are the most common manifestations of CMV disease in AIDS patients.

Pneumonitis is extremely rare.

Solid organ transplant recipients

Most common infection, leading cause of morbidity and mortality. Occurs 1 - 3 months following transplant. Primary infection more severe than recurrent infection. Patients may present with fever, pneumonitis, GI manifestations, hepatitis, and poor graft function. Does not appear to be associated with organ rejection.

Congenital CMV Infection

Mother infected in pregnancy : fetus at high risk Maternal infection usually asymptomatic Fetal infection asymptomatic to severe and disseminated Fetus damaged at any stage Severe developmental defects Mental retardation / deafness Defined with the isolation of CMV from the saliva or urine within 3 weeks of birth. Most common congenital viral infection, affects 0.3 -1% of all live births May be transmitted to the fetus during all stages of pregnancy.

 The second most common cause of mental handicap after Down's syndrome and is responsible for more cases of congenital damage than rubella. Transmission to the fetus may occur following primary or recurrent CMV infection. 40% chance of transmission to the fetus following a primary infection.

Perinatal CMV Infection

Infected birth canal / maternal milk or other secretions Protracted interstitial pneumonitis Poor weight gain, adenopathy, rash, Hepatitis and anemia persist for months to years Overall, 2 - 10% of infants are infected by the age of 6 months worldwide. Perinatal infection is thought to be 10 times more common than congenital infection

Laboratory Diagnosis (CMV)

Sample could be blood, urine or respiratory secretions
1. Cytology / histology : large cytomegalic 25-35 um intranuclear inclusions-owls eye 2 Culture -Gold standard(Human fibroblast cells) 4-6 weeks 3 Nucleic acid antigen detection IFA 4 Serology 5 PCR

Cytopathic Effect of CMV

Treatment (CMV)
Ganciclovir - is the drug of choice. However, it is associated with neutropenia and trombocytopenia. Forscarnet - can be used as the 2nd line drug. Again it is very toxic and is associated with renal toxicity. Cifofovir - approved for the treatment of CMV retinitis. It is also associated with renal toxicity. Fomivirsen - intravitreal fomivirsen is approved for the treatment of CMV retinitis.

CMV hyperimmune globulin - found to be effective against CMV pneumonitis.

Epstein-Barr Virus

Epstein-Barr Virus
Ubiquitous Acute infectious mononucleosis / nasopharyngeal carcinoma Burkitts Lymphoma and other lymphoproliferative disorders

Dual cell tropism for human B-lymphocytes (generally nonproductive infection). Highly host specific-No suitable animal host infection) and epithelial cells (productive

Epstein-Barr Virus
EBV DNA genome Two viral types: EBV1 and EBV2 Depending on: Variation in genome Structure Antigen expression Biologic properties

EBV-clinical manifestations
Primary infection-infected saliva

Icubation period 30-50 days Initiate infection in oropharynx Replication in B cells or epithelial cells Most asymptomatic/ subclinical in child In adults could be symptomatic
Sore throat, head ache Fever, malaise, fatigue Enlarged LN Few-hepatitis

Clinical Manifestations
Young adults: Infectious mononucleosis: Autoantibodies Self limiting lasts 2-4 weeks Symptoms like primary infection Nasopharyngeal Carcinoma Oral Hairy Leukoplakia: Wart like growth on tongue of some HIV persons and transplant patients. Burkitts lymphoma

Nasopharyngeal carcinoma (NPC)

A malignant tumor of the squamous epithelium of the nasopharynx. It is very prevalent in S. China, where it is the most common tumor in men and the second most common in women. Multiple copies of EBV genome and EBV EBNA-1 antigen can be found in cells of undifferentiated NPC. Other environmental and genetic co-factors besides EBV infection?

Hairyleukoplakia Often presents as white plaques or warts on the lateral surface of the tongue and is associated with EBV infection.

Burkitt's lymphoma
Tumor of jaw African children/ young adults Contain EBV DNA Most cases express EBNA 1 Genetic and environmental factors EBV DNA

Burkitts lymphoma

Diagnosis
1. Sign and symptom 2. Hematologic abnormalities 3. Serology Heterophile antibodies Viral specific antibody assays

HHV-6 and HHV-7

HHV-6 and HHV-7

HHV-6 is a very common virus and is acquired by respiratory secretions Infects T lymphocytes HHV-6 and HHV-7 Develop latency following primary infection Reactivated from time to time in immune suppressed individual HHV-6 infection is firmly associated with roseala infantum. It is associated with : Neurological manifestations (febrile convulsions, meningitis, and encephalitis) A variety of symptoms in transplant recipients such as fever, graft vs host disease, liver and CNS manifestations.

Roseala infantum
A benign disease, of infants and young children, in which
High fever (for 34 days) is followed by a Rubelliform rash on the trunk, spreading to the limbs and face

HHV-7
Is very common, with serological prevalence rates of 90% Most transmitted Via saliva and infects lymphocytes Causes about 5% of all cases of roseola Neurological involvement is rare

Human Herpes Virus 8 or Kaposi Sarcoma Herpes Virus (KSHV)

Transmitted via oral secretions Associated with Kaposis sarcoma HHV-8 DNA is found in almost 100% of cases of Kaposis sarcoma. It is found in latent cases in B cells Most patients with KS have antibodies against HHV-8 HHV-8 does not have a ubiquitous distribution Homosexuals Fosarnet, Ganiclovir, Cidofovir.

KSHV
KS lesions were indicative of HIV infection/ AIDS progression in the 80s Seroprevalence is low in general population Nearly a 100% association with KS Virus specifies many oncogenes, cellular regulation and growth factors AIDS related B-cell lymphoma

KSHV

Summary :Human Herpesviruses

Virus Subfamily
a

Disease
Orofacial lesions

Site of Latency
Sensory Nerve Ganglia

Herpes Simplex Virus I

Herpes Simplex Virus II

Varicella Zoster Virus

a
a

Genital lesions
Chicken Pox Recurs as Shingles Microcephaly/Mono Roseola Infantum Roseola Infantum

Sensory Nerve Ganglia

Sensory Nerve Ganglia

Cytomegalovirus Human Herpesvirus 6 Human Herpesvirus 7

b b b g g

Lymphocytes CD4 T cells CD4T cells

Epstein-Barr Virus Human Herpesvirus 8

Infectious Mono Kaposis Sarcoma

B lymphocytes, salivary Kaposis Sarcoma Tissue