Download - 2. Enveloped DNA Viruses
-
7/27/2019 2. Enveloped DNA Viruses
1/102
Enveloped DNA viruses
-
7/27/2019 2. Enveloped DNA Viruses
2/102
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
-
7/27/2019 2. Enveloped DNA Viruses
3/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
4/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
5/102
HERPESVIRIDAE
-
7/27/2019 2. Enveloped DNA Viruses
6/102
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 )
-
7/27/2019 2. Enveloped DNA Viruses
7/102
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
-
7/27/2019 2. Enveloped DNA Viruses
8/102
Prevalence of Herpes infections
-
7/27/2019 2. Enveloped DNA Viruses
9/102
Herpesvirus Virion
Virion has 4 basic structures
1. Envelope,
2. Tegument
3. Icosahedral capsid-162 capsomers
4. DNA-containing core.
-
7/27/2019 2. Enveloped DNA Viruses
10/102
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
-
7/27/2019 2. Enveloped DNA Viruses
11/102
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
-
7/27/2019 2. Enveloped DNA Viruses
12/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
13/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
14/102
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
-
7/27/2019 2. Enveloped DNA Viruses
15/102
Herpesvirus Particle
All herpesviruses - identicalmorphology
Cannot be distinguished from eachother under electron microscopy.
-
7/27/2019 2. Enveloped DNA Viruses
16/102
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
-
7/27/2019 2. Enveloped DNA Viruses
17/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
18/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
19/102
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).
-
7/27/2019 2. Enveloped DNA Viruses
20/102
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.]
-
7/27/2019 2. Enveloped DNA Viruses
21/102
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
-
7/27/2019 2. Enveloped DNA Viruses
22/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
23/102
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
-
7/27/2019 2. Enveloped DNA Viruses
24/102
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
-
7/27/2019 2. Enveloped DNA Viruses
25/102
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
-
7/27/2019 2. Enveloped DNA Viruses
26/102
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 .
-
7/27/2019 2. Enveloped DNA Viruses
27/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
28/102
A. Epidemiology and pathogenesis
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.
-
7/27/2019 2. Enveloped DNA Viruses
29/102
A. Epidemiology and pathogenesis
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
-
7/27/2019 2. Enveloped DNA Viruses
30/102
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
-
7/27/2019 2. Enveloped DNA Viruses
31/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
32/102
-
7/27/2019 2. Enveloped DNA Viruses
33/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
34/102
-
7/27/2019 2. Enveloped DNA Viruses
35/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
36/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
37/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
38/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
39/102
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
-
7/27/2019 2. Enveloped DNA Viruses
40/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
41/102
Herpes labialis
-
7/27/2019 2. Enveloped DNA Viruses
42/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
43/102
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 .
-
7/27/2019 2. Enveloped DNA Viruses
44/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
45/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
46/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
47/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
48/102
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
-
7/27/2019 2. Enveloped DNA Viruses
49/102
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
-
7/27/2019 2. Enveloped DNA Viruses
50/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
51/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
52/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
53/102
Clinical significance
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 .
-
7/27/2019 2. Enveloped DNA Viruses
54/102
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
-
7/27/2019 2. Enveloped DNA Viruses
55/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
56/102
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
-
7/27/2019 2. Enveloped DNA Viruses
57/102
Clinical significance
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
-
7/27/2019 2. Enveloped DNA Viruses
58/102
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
-
7/27/2019 2. Enveloped DNA Viruses
59/102
Herpes zoster
-
7/27/2019 2. Enveloped DNA Viruses
60/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
61/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
62/102
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
-
7/27/2019 2. Enveloped DNA Viruses
63/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
64/102
CMV ,EBV and HHV 8
-
7/27/2019 2. Enveloped DNA Viruses
65/102
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
-
7/27/2019 2. Enveloped DNA Viruses
66/102
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
-
7/27/2019 2. Enveloped DNA Viruses
67/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
68/102
Pathogenesis & Immunity
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.
-
7/27/2019 2. Enveloped DNA Viruses
69/102
Pathogenesis & Immunity
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.
-
7/27/2019 2. Enveloped DNA Viruses
70/102
Pathogenesis & Immunity
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.
-
7/27/2019 2. Enveloped DNA Viruses
71/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
72/102
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
-
7/27/2019 2. Enveloped DNA Viruses
73/102
Laboratory Diagnosis
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.
-
7/27/2019 2. Enveloped DNA Viruses
74/102
Laboratory Diagnosis
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.
-
7/27/2019 2. Enveloped DNA Viruses
75/102
(Virology Laboratory, New-Yale Haven Hospital)
-
7/27/2019 2. Enveloped DNA Viruses
76/102
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,
-
7/27/2019 2. Enveloped DNA Viruses
77/102
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.?
-
7/27/2019 2. Enveloped DNA Viruses
78/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
79/102
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..
-
7/27/2019 2. Enveloped DNA Viruses
80/102
Transmission & Epidemiology
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.
-
7/27/2019 2. Enveloped DNA Viruses
81/102
Transmission & Epidemiology
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
-
7/27/2019 2. Enveloped DNA Viruses
82/102
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
-
7/27/2019 2. Enveloped DNA Viruses
83/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
84/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
85/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
86/102
Hairy leukoplakia
-
7/27/2019 2. Enveloped DNA Viruses
87/102
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
-
7/27/2019 2. Enveloped DNA Viruses
88/102
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
-
7/27/2019 2. Enveloped DNA Viruses
89/102
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
-
7/27/2019 2. Enveloped DNA Viruses
90/102
Association with cancer
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 .
-
7/27/2019 2. Enveloped DNA Viruses
91/102
-
7/27/2019 2. Enveloped DNA Viruses
92/102
Association with cancer
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.
-
7/27/2019 2. Enveloped DNA Viruses
93/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
94/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
95/102
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
-
7/27/2019 2. Enveloped DNA Viruses
96/102
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
-
7/27/2019 2. Enveloped DNA Viruses
97/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
98/102
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
-
7/27/2019 2. Enveloped DNA Viruses
99/102
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
-
7/27/2019 2. Enveloped DNA Viruses
100/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
101/102
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.
-
7/27/2019 2. Enveloped DNA Viruses
102/102
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.