2. Enveloped DNA Viruses

7/27/2019 2. Enveloped DNA Viruses

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Enveloped DNA viruses


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Overview

Two of the three enveloped DNA virus families- the Herpesviridae and the

Poxviridae will be discussed

[Note: Hepadnaviridae, the third enveloped DNA virus family, will be

discussed later]

The Herpesviridae and the Poxviridae are both structurally and genetically

more complex than other DNA viruses

For example,

there is less dependence on host cell-supplied functions with a correspondingly greater number of virus-coded functions

involved in viral replication


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Overview

This latter fact contributes to the greater success in

developing antiviral drugs against these viruses (more

virus-specific enzymes that can serve as targets for

inhibitors, in contrast to viruses that are more host cell

function-dependent).

Replication of herpesviruses and poxviruses is also

independent of the host cell cycle.


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Overview

The one highly virulent member of the poxvirus family,

variola (the cause of smallpox), is the only human

pathogen that has been successfully eradicated.

This success serves as a model for attempts to control

and potentially eradicate other infectious diseases.


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HERPESVIRIDAE


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HERPES VIRUS TYPES THAT INFECTHUMANS

Herpes simplex virus Type 1 (HSV-1)

Herpes simplex virus Type 2 (HSV-2)

Epstein Barr virus (EBV)

Cytomegalovirus (CMV)

Varicella Zoster Virus (VZV)

Human herpes virus 6 (exanthum subitum or roseola infantum)

Human herpes virus 8 (Kaposi's sarcoma-associate herpes virus )


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HERPESVIRUSES

Capacity to persist in host indefinitely in nucleus of the cell

Every vertebrate species has at least one host specific herpes virus

Varicella zoster and herpes simplex viruses establish latent infectionsin neurons

reactivation

Varicella zosterherpes zoster (shingles)

HSV 1recurrent labial herpes

HSV 2 Genital herpes

CMV , EBV and HHV-6 persist in lymphocytes


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Prevalence of Herpes infections


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Herpesvirus Virion

Virion has 4 basic structures

1. Envelope,

2. Tegument

3. Icosahedral capsid-162 capsomers

4. DNA-containing core.


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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


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Herpesviruses

Set up latent infection following primary infection.

Persist indefinitely in infected host

Reactivation are more likely to take place during periods of

immunosuppression.

Both primary infection and reactivation are likely to be more

serious in immunocompromised patients.

Some are cancer causing


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Herpesviridae: Structure and Replication

Eight human herpesvirus species are known.

All have the ability to enter a latent state following primary

infection of their natural host and be reactivated at a later

time.

However, the exact molecular nature of the latency and

the frequency and manifestation of reactivation vary with

the species of herpesvirus.


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A. Structure of herpesviruses

Herpesvirus virions consist of an icosahedral capsid enclosed in a

lipoprotein envelope.

Between the envelope and the capsid lies an amorphous proteinaceous

material (tegument)

the tegument contains virus-coded enzymes and transcription factors

essential for initiation of the infectious cycle , although none of these is a

polymerase.

Although all members of the family have some genes with homologous

functions, there is little antigenic relatedness between species.


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Classification of herpesviruses

Herpesviridae cannot readily be differentiated by

morphology in the electron microscope- they all have

similar appearances.

However, Herpesviridae have been divided into three

subfamilies, based primarily on biologic characteristics


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Herpesvirus Particle

All herpesviruses - identicalmorphology

Cannot be distinguished from eachother under electron microscopy.


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Classification of HumanHerpesviruses

Family HerpesviridaeSub family herpesvirinaeSub family Genus Official name CommonAlpha simplex 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 6HHV 7 HHV 7

____________________________________________________________ Gamma her Lymhocrypto HHV 4 Epstein-Bar virus

Rhadino HHV 8 Kapossis sarcoma associatedherpes virus


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Alphaherpesvirinae (herpes simplex virusgroup):

These viruses have a relatively rapid, cytocidal growth cycle and

establish latency in nerve ganglia .

Herpes simplex virus types 1 and 2 ( HSV-1 and HSV-2 ) and

varicella-zoster virus ( VZV ) belong to this group.

HSV-1 and HSV-2 share significant nucleotide homology and,

therefore, share many common features in replication and

pathogenesis.VZV has a smaller genome than HSV, but the two viruses have many

genes that are homologous.


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Betaherpesvirinae (cytomegalovirus group):

These viruses have a relatively slow replication cycle that results in

the formation of characteristic, multinucleated, giant host cells .

Latency is established in non-neural tissues, primarily

lymphoreticular cells and glandular tissues.

Human cytomegalovirus ( HCMV ) and human herpesviruses types 6

and 7 ( HHV-6 and HHV-7 ) are in this group.


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Gammaherpesvirinae (lymphoproliferativegroup):

These viruses replicate in mucosal epithelium , where they also establish

latent infections.

They induce cell proliferation in lymphoblastoid cells.

Epstein-Barr virus (EBV) was previously the only well-characterized

human gammaherpesvirus.

However, genome analysis of a virus recovered from cells of Kaposi

sarcoma revealed it to also be a human member of gammaherpesvirinae.

It has been designated human herpesvirus type 8 (HHV-8).


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C. Replication of the Herpesviruses

Herpesviruses replicate in the nucleus, following the basic pattern of DNA

virus replication .

Regulation of herpesvirus transcription is referred to as cascade control ,in that expression of a first set of genes is required for expression of a

second set, which in turn is required for expression of a third set of genes.

[Note: A similar pattern is found in some other DNA virus families in

which the genes are referred to as immediate early, delayed early, and

late.]


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1. Virus adsorption and penetration

Herpesviruses adsorb to host cell receptors that can differ

according to the virus species and the tissue type being infected.

Viral envelope glycoproteins promote fusion of the envelopewith the cell's plasma membrane, depositing the nucleocapsid

and tegument proteins in the cytosol.

One of the tegument proteins induces a host cell RNase that

degrades cellular mRNA , effectively shutting off host cell

protein synthesis


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2.Viral DNA replication and nucleocapsidassembly

The nucleocapsid is transported to a nuclear pore, through

which viral DNA is released into the nucleus.

Another tegument protein is an activator of cellular RNApolymerase that causes the enzyme to initiate transcription

of the set of viral immediate early genes,

which code for a variety of regulatory functions, includinginitiation of further gene transcription.


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2.Viral DNA replication and nucleocapsidassembly

Next, delayed early genes are expressed.

They code primarily for enzymes that are required for

replication of viral DNA, such as viral DNA polymerase,

helicase, and thymidine kinase.

As is the case with other DNA viruses, late genes code for

structural proteins of the virion and proteins involved in

assembly and maturation of viral progeny


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3. Acquisition of the viral envelope:

Newly synthesized envelope proteins accumulate in patches on the nuclear

membrane, and nucleocapsids that have been assembled in the nucleus

acquire their envelopes by budding through these patches.

The completed virus is transported by a vacuole to the surface of the cell.

Additional copies of the envelope glycoproteins are also transported to the

plasma membrane, which acquires herpesvirus antigenic determinants.

These glycoproteins may also cause fusion of neighboring cells , in somecases producing characteristic multinucleated giant cells.

The end result of this productive cycle is death of the cell resulting from

most cellular synthetic pathways being turned off


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Latency

All herpesviruses can undergo an alternative infection cycle, entering a

quiescent state (latency) from which they subsequently can be reactivated.

The cell type in which this occurs is usually not the same cell type inwhich productive, cytocidal infection occurs.

Because 1)the mechanism of latency, 2)the cells in which it is established,

3)the frequency of reactivation, 4) and the nature of the recurrent disease

are characteristic for each of the herpesviruses, the topic of latency is

discussed in the context of the individual virus species


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Herpes simplex virus, types 1 and 2

HSV-1 and HSV-2 are the only human herpesviruses that

have a significant degree of nucleotide homology (about

fifty percent).

They therefore share many common features in replication,

disease production, and latency .


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A. Epidemiology and pathogenesis

Transmission of both HSV types is by direct contact with

virus-containing secretions or with lesions on mucosal or

cutaneous surfaces.

Primary or recurrent infections in the oropharyngeal region,

caused primarily by HSV-1, are accompanied by virus release

into salivaTherefore kissing or saliva-contaminated fingers are major

modes of transmission.


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In genital tract infections, caused primarily by HSV-2, virus is

present in genital tract secretions.

Consequently, sexual intercourse and infections of newborns

during passage through the birth canal are major modes of

transmission.

Both HSV-1 and HSV-2 multiply in epithelial cells of the mucosal surface

onto which they have been inoculated, resulting in production of vesicles or

shallow ulcers containing infectious virus.


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In immunocompetent individuals, epithelial infection

remains localized

because cytotoxic T lymphocytes recognize the HSV-specific antigens on the surface of infected cells and kill

these cells before progeny virus has been produced.

A lifelong latent infection is usually established in the

regional ganglia as a result of entry of infectious virions

into sensory neurons


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B. Clinical significance

A useful generality is that HSV-1 is most commonly found

in lesions of the upper body, and HSV-2 is more

commonly the cause of genital tract lesions.

Either can, however, infect and cause similar lesions at the

opposite site


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Primary infections of the upper body:

Many primary HSV infections are subclinical, but the most

common symptomatic infections of the upper body are

gingivostomatitis in young children and pharyngitis or

tonsillitis in adults.

The lesions typically consist of vesicles and shallow

ulcers, which are often accompanied by systemic

symptoms such as fever, malaise, and myalgia.


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Primary infections of the upper body:

Another clinically important site of infection is the eye, in

which keratoconjunctivitis can lead to corneal scarring

and eventual blindness.If HSV infection spreads to the central nervous system

(CNS) it can cause encephalitis, which, if untreated, has a

mortality rate estimated to be 70 percent.Survivors are usually left with neurologic deficits.


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Primary infections of the genital tract

Primary genital tract lesions are similar to those of the

oropharynx

however, based on the frequency of antibody in the population,

the majority of these infections are asymptomatic.

When symptomatic (genital herpes), local symptoms include

painful vesiculoulcerative lesions on the vulva, cervix, and

vagina, or penis .

Systemic symptoms of fever, malaise, and myalgia may also be more

severe than those that accompany primary oral cavity infections.


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Primary infections of the genital tract In pregnant women with a primary genital HSV infection, the risk of

infecting the newborn during birth is estimated to be thirty to forty

percent (neonatal herpes).

Because such infants have no protective maternal antibody, a disseminated

infection, often involving the CNS, results.

There is a high mortality rate if untreated, and survivors are likely to have

permanent neurologic sequelae.

A newborn is also at risk of acquiring infection from an infected mother

by transfer on contaminated fingers or in saliva.

However, infection in utero appears to occur only rarely.


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Latency

In latently infected cells of the ganglia HSV-1 in

trigeminal ganglia and HSV-2 in sacral or lumbar ganglia

From one to thousands of copies of the viral genome are present as nonintegrated, circular molecules of DNA in the

nuclei.

Expression of HSV genes is shut off in latently infectedcells.


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Reactivation:

Several factors, such as hormonal changes, fever, stress and

Immunosuppression , are known to induce reactivation and

replication of the latent virusThe newly synthesized virions are transported down the axon to

the nerve endings from which the virus is released, infecting the

adjoining epithelial cells.

Characteristic lesions are thus produced in the same general

area as the primary lesions.


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Reactivation:

The presence of circulating antibody does not prevent this recurrence,

but does limit the spread of virus to surrounding tissue.

Sensory nerve symptoms, such as pain and tingling, often precede and

accompany the appearance of lesions.

In general, the severity of any systemic symptoms is considerably less

than that of a primary infection

and many recurrences, in fact, are characterized by shedding of infectious virus in the absence of visible lesions


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Reactivation:

HSV-1:

The frequency of oropharyngeal symptomatic

recurrences is variable, ranging from none to several ayear.

The lesions occur as clusters of vesicles at the border of

the lips (herpes labialis or cold sore fever blisters) andheal without scarring in eight to ten days.


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Herpes labialis


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Reactivation: HSV-2:

Reactivation of HSV-2 genital infections can occur withconsiderably greater frequency (for example, monthly)and is often asymptomatic, but still results in viral

shedding. Consequently, sexual partners or newborn infants may be at increased risk of becoming infected resulting fromlack of precautions against transmission.

The risk of transmission to the newborn is much lessthan in a primary infection because considerably less virus is shed and there is maternal

anti-HSV antibody in the baby.

This antibody also lessens the severity of the disease if infection does occur.


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Immunity

New born-passive immunity up to 6 months

6 mo-2 yr-highly susceptible

Transplacental antibodies infection

Primary infection antibodies +virus

latency

Recurrent antibodies change/modify subsequent disease

Both antibody-mediated and cell-mediated reactions are clinically

important .


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Diagnosis

Light microscopy-intranuclear inclusions

infected cell ballooning & fusion

Electron microscopy ?

Antigen detection

Virus culture-HSV 1, HSV 2 easiest to culture typical CPE

Serology Antibodies-4-7 d after infection CFT/ IHA/ELISA/RIA

Restriction endonuclease analysis of viral DNA or DNA sequencingcan be used to distinguish between the two types and among strains of

each subtype.


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Treatment

The guanine analog, acycloguanosine (acyclovir), is selectively

effective against HSV because it becomes an active inhibitor of

DNA synthesis only after initially being phosphorylated by the

HSV thymidine kinase .

The drug of choice for any primary HSV infection, it is

especially important in treating herpes encephalitis, neonatal

herpes, and disseminated infections in immunocompromised

patients.


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Treatment

Other drugs effective in treating herpes simplex infection include

famciclovir and topical penciclovir .

Famciclovir is a prodrug that is metabolized to the active penciclovir.

It provides more convenient dosing and greater bioavailability than

oral acyclovir.

Penciclovir is active against HSV-1 and HSV-2, and against VZV.

None of these drugs can cure a latent infection, but they can

minimize asymptomatic viral shedding, and recurrences of

symptoms.


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Prevention

Prevention of HSV transmission is enhanced by avoidance

of contact with potential virus-shedding lesions and by safe

sexual practice.

Prevention of neonatal HSV infections is of great

importance; however, genital infection of the mother isdifficult to detect because it is often asymptomatic.


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Prevention

When overt genital tract lesions are detected at the time of delivery,

cesarean section is usually warranted.

Prophylactic therapy of the mother and the newborn with acyclovir

can be employed if the presence of HSV is detected

just before or at the time of birth;

measures to prevent physical transmission following birth are also

important.

A vaccine is not currently available


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Varicella-Zoster Virus

VZV has biologic and genetic similarities to HSV, and is

classified with HSVs in the Alphaherpesvirinae subfamily.

Biologic similarities between VZV and HSV include the fact

that latency is established in sensory ganglia and infections

are rapidly cytocidal .

Primary infections with VZV cause varicella (chickenpox),

whereas reactivation of the latent virus causes herpes zoster


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Epidemiology and pathogenesis

Transmission of VZV is usually via respiratory droplets

which results in initial infection of the respiratory mucosa

followed by spread to regional lymph nodes .

Progeny virus enter the bloodstream, undergo a second

round of multiplication in cells of the liver and spleen,

and are disseminated throughout the body by infected

mononuclear leukocytes.


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Epidemiology and pathogenesis

Endothelial cells of the capillaries and, ultimately, skin

epithelial cells become infected, resulting in the characteristic,

virus-containing vesicles of chickenpox that appear from 14 to

21 days after exposure.

From one to two days before the appearance of the exanthem the

infected individual become contagious .

Contact with vesicular fluid is not a common mode of

transmission.


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Clinical significance

In contrast to HSV infections, the primary and recurrent

diseases (varicella and zoster) due to VZV are quite

distinct.

Neither is usually life-threatening in the normal, healthy

individual

Both can have severe complications in

immunocompromised patients.


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Primary infection (varicella, or chickenpox):

In a normal, healthy child, the incubation period is most commonly

from 14 to 16 days.

The first appearance of exanthem is often preceded by one or two days

of a prodrome of fever, malaise, headache, and abdominal pain.

The exanthem begins on the scalp, face, or trunk as erythematous macules , which evolve into virus-containing vesicles that begin to

crust over after about 48 hours .


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Primary infection (varicella, orchickenpox):

Itching is most severe during the early stage of vesicle

development.

While the first crop of lesions is evolving, new crops appear on

the trunk and extremities. .

Varicella is a more serious disease in healthy adults and

immunocompromised patients.

Varicella pneumonia is the most common of the serious

complications


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Primary infection (varicella, or chickenpox):

Fulminant hepatic failure and varicella encephalitis

may also occur .

Primary infection of a pregnant woman may cause her to

contract the more severe adult form of varicella , and may

affect the fetus or neonate as well.

More commonly, a fetus infected near the time of delivery

may exhibit typical varicella at birth or shortly thereafter.


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Primary infection (varicella, orchickenpox):

The severity of the disease depends on whether the mother has

begun to produce anti-VZV IgG by the time of delivery.

In older adults and the immunocompromised, lesions may also

appear on mucous membranes, such as in the oropharynx,

conjunctivae, and vagina.

Healing occurs without scarring


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Recurrent infection (herpes zoster, or shingles):

Due to the disseminated nature of the primary infection, latency

is established in multiple sensory ganglia, the most common

ones are trigeminal and dorsal root ganglia .

Unlike most of the herpesviruses, asymptomatic virus shedding

is rare.

Herpes zoster results from reactivation of the latent virus, not

from new, exogenous exposure.

i f i (h


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Recurrent infection (herpes zoster, orshingles):

Reactivation occurs in approximately fifteen percent of infected individuals.

The most striking feature of herpes zoster is that distribution of the clustered vesicular lesions is dermatoma l (affecting thearea of skin supplied by cutaneous branches from a singlespinal nerve ).

Acute inflammation of sensory nerves and gangliaIt is very painful lesionUnilateral (one side of the body) vesicular lesion is commonHealing occurs with scarring


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Herpes zoster


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Laboratory identification

Laboratory diagnosis of uncomplicated varicella or

zoster is generally not necessary

and not usually done because of the typical clinical

appearance and distribution of lesions.

However, in the immunocompromised patient in whom

therapy is warranted, it is important to distinguish VZV

infection from other similar exanthems.


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Laboratory identification

Cell tissue cultures inoculated with a sample of vesicle fluid show

gross cytopathic changes in several days;

A rise in specific antibody titer can be detected in the patient's serum

by various tests, including fluorescent antibody and ELISA

individual infected cells can be detected within 24 hours by use of

immunofluorescence staining with antibodies against viral early

proteins.

More rapid diagnosis can be made by reacting epithelial cells scraped

from the base of vesicles with the stains described above, or by doing

in situ hybridization with VZV-specific DNA probes.


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Treatment

Acyclovir- is the drug of choice

Oral acyclovir reduces the time course and acute pain of

zoster, but has little or no effect on the subsequent

postherpetic neuralgia .

Famciclovir and valacyclovir- as alternative


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Prevention

Susceptible individuals for example, neonates ,

nonimmune healthy adults , and immunocompromised

children who have been exposed to chickenpox or tozoster lesion fluid) can be protected by administration of

varicella-zoster immunoglobulin ( VZIg) .

Administration of VZIg has no effect on the occurrence of

zoster.


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CMV ,EBV and HHV 8


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Cytomegalovirus (CMV)

CMV is structurally and morphologically identical to other herpesviruses but is antigenically different.

It has a single serotype.

Humans are the natural hosts

Animal CMV strains do not infect humans.

Giant cells are formed, hence the name Cytomegalo


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Transmission & Epidemiology

CMV is transmitted by a variety of modes.

Early in life it is transmitted across the placenta, within the birth canal,

and quite commonly in breast milk.

In young children, its most common mode of transmission is via

saliva.

Later in life it is transmitted sexually; it is present in both semen and

cervical secretions.It can also be transmitted during blood transfusions and organ

transplants.

CMV infection occurs worldwide, and more than 80% of adults have

antibody against this virus.

P th g i & I it


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Pathogenesis & Immunity

Infection of the fetus can cause cytomegalic inclusion

disease

characterized by multinucleated giant cells with prominent

intranuclear inclusions.

Many organs are affected, and widespread congenitalabnormalities result infection of the fetus occurs mainly

when a primary infection occurs in the pregnant woman.


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i.e. When she has no antibodies that will neutralize the virus before it

can infect the fetus.

The fetus usually will not be infected if the pregnant women hasantibodies against the virus.

Congenital abnormalities are more common when a fetus is infected

during the first trimester than later ingestation

Because, the first trimester is when development of organs occurs and

the death of any precursor cells can result in congenital defects.


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Infections of children and adults are usually asymptomatic,

except in immunocompromised individuals.

CMV enters a latent state in leukocytes and can be reactivated

when cell-mediated immunity is decreased.

CMV can also persist in kidneys for years.

Reactivation of CMV from the latent state in cervical cells can

result in infection of the newborn during passages through the birth canal.


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CMV infection causes an immunosuppressive effect by

inhibiting T cells.

Host defenses against CMV infection include both

circulating antibody and cell-mediated immunity.

Cellular immunity is more important, because its

suppression can lead to systemic disease.


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Clinical Findings

Approximately 20% of infants with CMV during gestation show clinically

apparent manifestations of cytomegalic inclusion disease such as:

microcephaly, seizures,deafness,jaundice, and purpura.

Hepatosplenomegaly is very common.

Cytomegalic inclusion disease is one of the leading causes of mental

retardation in the United States.

Infected infants can continue to excrete CMV, especially in the urine, for

several years.


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Clinical Findings

In immunocompetent adults, CMV can cause heterophil-negative

mononucleosis, which is characterized by fever, lethargy and the presence of

abnormal lymphoctyes in peripheral blood smears.

Systemic CMV infections, especially pneumonites and hepatitis, occur in a

high proportion of immunouppressed patients,e g. those with renal and

bone marrow transplants.

In AIDS patients,CMV commonly infects the intestinal tract and cause

interactable diarrhea.

CMV also cause retinitis in AIDS patients, which can lead to blindness .

Laboratory Diagnosis


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The preferred approache involves culturing in special tubes

called shell vials coupled with the use of immunoflurescent

antibody , which can make a diagnosis in 72 hours.

If available, PCR -based assays that detect viral nucleic acids

are also useful.

Other diagnostic methods include fluorescent-antibody andhistologic staining of inclusion bodies in giant cells in urine

and in tissue.


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The inclusion bodies are intranuclear and have an

oval owls -eye shape.

A 4-fold or greater rise in antibody titer is also

diagnostic.

PCR-based assays for CMV DNA or RNA in

tissue or body fluids, such as spinal fluid are also

very useful.


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(Virology Laboratory, New-Yale Haven Hospital)


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Treatment

Granciclovior is moderately effective in the treatment of

CMV retinitis and pneumonitis in patients with AIDS.

Foscarnet is also effective but cause more side effects.

Unlike HSV and VZV, CMV is largely resistant to

acyclovir .

Cidofovir is also useful in the treatment of CMV retinitis,


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Prevention

There is no vaccine.

Ganciclovir can suppress progressive retinitis in AIDSpatients.

Infants with cytomegalic inclusion disease who are shedding

virus in their urine should be kept isolated from other infants.

Blood for transfusion to newborns should be CMV antibody-

negative.

If possible only organs from CMV antibody-negative donors

should be transplanted to antibody-negative recipients.?


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Epstein-Barr Virus (EBV)

EBV is structurally and morphologically identical to other

herpesviruses but is antigenically different.

The most important antigen is the viral capsid antigen(VCA ). Because it is used most often in diagnostic tests .

The early antigen ( EA ), which are produced prior to viral

DNA synthesis, and nuclear antigen ( EBNA ), which islocated in the nucleus bound to chromosomes, are

sometimes diagnostically helpful as well.


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EBV

Two other antigens, lymphocyte-determined membrane antigen

and viral membrane antigen, have been detected

Neutralizing activity is directed against the viral membrane

antigen .

Humans are the natural hosts.

EBV infects mainly lymphoid cells, primarily B lymphocytes .

In latently infected cells, multiple copies of EBV DNA are found in

the cytoplasm of infected B lymphocytes..


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EBV is transmitted primarily by the exchange of saliva, eg.

During kissing.

The saliva of people with a reactivation of a latent infection as

well as people with an active infection can serve as a source of

the virus.

In contrast to CMV, blood transmission of EBV is very rare.

EBV infection is one of the most common infections

worldwide;

More than 90% of adults in the United states have antibody.


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Infection in the first few years of life is usually

asympromatic.

Early infection tends to occur in individuals in lower socioeconomic groups.

The frequency of clinically apparent infectious

mononucleosis, however, is highest in those who are

exposed to the virus later in life. Eg, college students

P h i & i i


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Pathogenesis & immunity

The infection first occurs in the oropharynx (?epithelium,

?lymphoid tissue) and then spreads to the blood, where it

infects B lymphocytes.

Cytotoxic T lymphocytes react against the infected B cells.

The T cells are the atypical lymphs seen in the blood smear.

EBV remains latent within B lymphocytes.A few copies of EBV DNA are integrated into the cell

genome;

Many copies of circular EBV DNA are found in the


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Pathogenesis & immunity

The immune response to EBV infection consists first of IgM

antibody to the VCA.

IgG antibody to the VCA follows and persists for life.

The IgM response is therefore useful for diagnosing acute

infection,

whereas the IgG response is best for revealing prior infection

Lifetime immunity against second episodes of infectious

mononucleosis is based on antibodies to the viral membrane

antigen.


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Clinical Findings

Infection mononucleosis is characterized primarily by

fever,sore throat, lymphadenopathy, and splenomegaly .

Anorexia and lethargy are prominent.

Hepatitis is frequent;

encephalitis occurs in some patients.

Splenic rupture, associated with contact sports such as

football, is a feared but rare complication of the

splenomegaly.


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Clinical Findings

In addition to infectious mononucleosis, EBV causes two other diseases.

1. severe, often fatal, progressive form of infectious mononucleosis that

occurs in children with an inherited immunodeficiency called x-linked

immunoproliferative syndrome.

The mortality rate is 75% by age 10.

Bone marrow transplants may cure the underlying immunodeficiency.

2. Oral Hairy leukoplakia- a whitish lesion on the tongue of AIDSPatients.


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Hairy leukoplakia


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Laboratory

Isolation and Identification of Virus Nucleic acid hybridization is the most sensitive means of detecting EBV in

patient materials.

EBER RNAs are abundantly expressed in both latently infected andlytically infected cells and provide a useful diagnostic target for detection

of EBV-infected cells by hybridization.

Viral antigens can be demonstrated directly in lymphoid tissues and in

nasopharyngeal carcinomas

EBV can be isolated from saliva, peripheral blood, or lymphoid tissue


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Laboratory

SerologyCommon serologic procedures for detection of EBV antibodies include -

ELISA tests, immunoblot assays, and indirect immunofluorescence tests

Early in acute disease, a transient rise in IgM antibodies to viral capsid

antigen occurs,

Then replaced within weeks by IgG antibodies to this antigen, which

persist for life.

Slightly later, antibodies to the early antigen develop that persist for severalmonths.

Several weeks after acute infection, antibodies to EBNA and the membrane

antigen arise and persist throughout life

Treatment


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Treatment

No antiviral therapy is necessary for uncomplicated

infectious mononucleosis.

Acyclovir has little activity against EBV, butadministration of high does may be useful in life-

threatening EBV infections.

Prevention

There is no EBV vaccine

Association with cancer


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EBV infection is associated with cancers of lymphoid origin:

Burkitts lymphoma in Africa children.

Other B-cell lymphomas: nasopharyngeal carcinoma in the

Chinese population, and thymic carcinoma in the united

states.

The initial evidence of an association of EBV infection withBurkitts lymphoma was the production of EBV by the

lymphoma cells in culture.

In fact, this was how EBV was discovered by Epstein and Barr in 1964 .


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Additional evidence includes the finding of EBV DNA and

EBNA in the tumor cells.

EBV DNA and antigens are found in nasopharyngeal andthymic carcinoma cells also.

EBV can induce malignant transformation in B

lymphocytes in vitro.


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HHV-6 and HHV-7

Like other herpesviruses, HHV-6 and HHV-7 become latent

following primary infection and are reactivated from time to

time, especially during periods of immunosuppression.

HHV-6 infection is firmly associated with roseola infantum.

It had also been associated with neurological manifestations

such as febrile convulsions, meningitis, and encephalitis.


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HHV-6 and HHV-7

It had also been associated with a variety of symptoms in

transplant recipients such as fever, graft vs host disease, liver

and CNS manifestations

However such associations are very difficult to prove since

CMV is almost always concomitantly reactivated.

Likewise the role of HHV-6 reactivation in HIV infection

remains unclear.

HHV-7 is not associated conclusively with any human disease.


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HHV-6 and HHV-7

HHV-6 and HHV-7 become latent following primaryinfection Reactivation T- lymphotropic human viruses

HHV 6 - discovered in 1986,grows well in CD4Other cells like B cells too support growthOropharynx saliva -transmission

HHV-6-Early life-roseola infantum sixth disease persists for life reactivation in pregnancy-encephalitis?neurological manifestations


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Human Herpes Virus-7

HHV7 -discovered in 1990-Circulating T cells

Immunologically distinct from HHV-6

Ubiquitous

Infections in childhood(later than HHV-6)

Persistent infection in salivary glands


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HHV 8

A new herpesvirus, designated human herpesvirus 8

and also called Kaposi's sarcoma-associated

herpesvirus (KSHV)It was first detected in 1994 in Kaposi's sarcoma

specimens.

KSHV is lymphotropic and is more closely related to

EBV than to other known herpesviruses.


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HHV 8

The KSHV genome (about 165 kbp) contains numerous

genes related to cellular regulatory genes involved in cell

proliferation, apoptosis, and host responses (cytokines,chemokine receptor) that presumably contribute to viral

pathogenesis

KSHV is the cause of Kaposi's sarcomas, vascular tumorsof mixed cellular composition


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HHV 8

KSHV is not as ubiquitous as other herpesviruses;

About 5% of the general population in the United States

and northern Europe have serologic evidence of KSHVinfection.

It appears to be sexually transmitted among men who have

sex with men, who have a higher seroprevalence (30 60%).

Infections are common in Africa (> 50%), with infections

acquired early in life by nonsexual routes , possibly


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HHV 8

KSHV is shed in saliva independent of the subject's

immune status.

Viral DNA has also been detected in breast-milk samplesin Africa.

The virus can be transmitted through organ transplants

and places the recipients at risk of KSHV-related diseases.


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HHV 8

Viral DNA can be detected in patient specimens using

PCR assays.

Direct virus culture is difficult and impractical.

Serologic assays are available to measure persistent

antibody to KSHV, using indirect

immunofluorescence, Western blot, and ELISA

formats.


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HHV 8

Foscarnet, ganciclovir, and cidofovir have activity against

KSHV replication.

The rate of new Kaposi's sarcomas is markedly reduced inHIV-positive patients on effective antiretroviral therapy,

probably reflecting reconstituted immune surveillance

against KSHV-infected cells.

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2. Enveloped DNA Viruses

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