BETA HERPES VIRUS:

CYTOMEGALOVIRUS,
HHV 6 & HHV 7

PALOMO
RICO
SALOMA
 Definition
Characterised by:
- Restricted host range
- Long reproductive cycle

Latency is establish in lymphocytes, secretory

glands, and cell of kidneys and other cell types

Numbers suggest the sequence of virus discovery

 History
Cytomegalovirus (CMV) first found
by Ribbert in 1881 but only in 1921
was it suggested to be a viral agent
HHV-6 was isolated in 1986
HHV-7 was isolated in 1990
PROPERTIES
OF THE

VIRUS
Classification
Etymology
Greek
herpein
To
creep Greek
herpes
Shingles
Latin
herpes
A spreading
 Family
Herpesvirales

Herpesvirida
e
Betaherpesviri
nae

Proboscivir Cytomegalo Muromegalovir Roseoloviru

us virus us s
Types
Morpho-anatomy
Spherical to pleomorphic
Symmetry: T = 16
150nm 200nm in diameter
Capsid:
o Enveloped
o Icosahedral symmetry
o 162 capsomeres
o Surrounded by amorphous tegument
o Gylcoprotein complexes embedded in the lipid
envelope
 Genome
Double stranded DNA of 140
240 kb
Linear
Segmentation = monopartite
Has terminal and internal
reiterated sequences
 Replication
1. Attachment and Entry
~ viral glycoproteins attaches to the
host receptors then goes through
endocytosis
~ Capsid is transported to the
nuclear pore where the viral DNA is
released into the nucleus
2. Transcription of immediate early
genes
~ promote transcription of early
genes & protect virus against host
immunity
3. Transcription of early viral mRNA by
host polymerase II
~ encodes proteins for the
replication of viral DNA
4. Bidirectional replication
1st round of circular genome amplification
5. Rolling circle
synthesis of linear concatamer copies of viral
DNA
6. Transcription of late mRNAs by
host polymerase II
encodes structural proteins
8. Assembly
@ nuclear viral factories
9. Release
budding through the inner lamella of the
nuclear membrane
Epidemiology
HHV-6 & HHV-7 are highly
ubiquitous
CMV infection and
seroprevalance
1. Age
2. geographic location
3. socioeconomic status
- in developed countries, 20-40%
of adults in mid to upper class
SES are CMV seropositive
compared to more than 80%
among those in lower SES. In
developing countries, more than
80% of children are
Clinical and
Pathological
Aspects
Clinical Features
For Infants
Yellow skin and eyes (jaundice)
Purple skin splotches or a rash or both
Small size at birth (or low birth
weight)
Enlarged spleen
Enlarged and poorly functioning liver
Pneumonia
Seizures
 For the
immunocompromised
Fever
Pneumonia
Diarrhea
Ulcers in the digestive tract, possible causing bleeding
Hepatitis
Inflammation of the brain (encephalitis)
Behavioral changes
Seizures
Coma
Visual impairment and blindness
Characteristic Features

HEARING LOSS
VISUAL
IMPAIRMENT
Pathology and
Pathogenesis
 Lungs
NUCLEAR & CYTOPLASMIC
INCLUSIONS SHOWING
CYTOMEGALY IN CELLS

Epithelial cells of the

airways and alveoli ;
fibroblasts ;
macrophages ;
endothelial cells
Gastrointestinal tract
Gastrointestinal lesions are erosive-ulcerous or ulceronecrotic.
Infection and viral replication, mostly occurs in ulcerative disease
of intestine. Example: Crohns disease, Ulcerative colitis.
Inclusions are seen in endothelial & mucosal cells.

PATHOGENETIC CHAIN:
Vasculitis -> microcirculatory disorders -> segmental ischemia ->
necrosis with inflammatory infiltration and CMV transformation of
the cells-> fibrosing -> cicatricial transformation of the organ wall.
Some authors have suggested that developing sclerosis due to
cytomegalovirus involvement of the intestine may promote cancer.
 Skin
Dermal Erythropoiesis
Immune Response
Primary infection with cytomegalovirus (CMV)
in immunocompetent hosts is accompanied
with activation and differentiation of naive
CD8+ T cells to effector/memory cells
secreting interferon- (IFN-). Alteration of
these responses during the perinatal period
is suggested by a higher rate of CMV
diseases in congenital infection. Cellular
immune responses can be detected as soon
as the 22nd week of gestation where infected
fetus' T-cells secrete more IFN-y than normal.
Laboratory Diagnosis
1. Demonstration of CMV
2. Antiviral antibody
3. PCR- detection of viral genome
 Treatment,
Prevention &
Control
 Wash your hands often. Use soap and water for 15 to 20 seconds,
especially if you have contact with young children or their diapers, drool
or other oral secretions. This is especially important if the children
attend child care.
Avoid contact with tears and saliva when you kiss a child.
Instead of kissing a child on the lips, for instance, kiss on the forehead.
This is especially important if you're pregnant.
Avoid sharing food or drinking out of the same glass as others.
Sharing glasses and kitchen utensils can spread the CMV virus.
Be careful with disposable items. When disposing of diapers,
tissues and other items that have been contaminated with bodily fluids,
be careful not to touch your hands to your face until after thoroughly
washing your hands.
Clean toys and countertops. Clean any surfaces that come into
contact with children's urine or saliva.
Practice safe sex. Wear a condom during sexual contact to prevent
spreading the CMV virus through semen and vaginal fluids.
Intrauterine-
Perinatal
Saliva
Breast Milk
Sexual Transmission
Blood Transfusion
Organ Transplantation
CDC Compares Causes of Birth
Defects
Pathogenesis

Routes of
Transmission
Transplacental Transmission
Intrapartum Transmission
 Transplacental Transmission
CMV is transmitted from mother to fetus
in approximately 35% of pregnancies in
which a maternal primary infection occurs
Transplacental transmission rates are
lower, approximately 20%, with infection
in the first trimester, and increase with
advancing gestational age to
approximately 75% with third trimester
infection
 Maternal CMV-specific IgG have a protective effect
against fetal infection
Transmission depends on the pre-conceptional
serological status of the mother
Transmission rate is 1.2 % for seropositive
and 12.9 % for seronegative women
Maternal CMV infections are usually clinically
unrecognized; studies that used screening for
CMV antibody to detect primary infections were
instrumental in improving our knowledge of
them.
Congenital CMV infection due to first trimester
maternal primary infection is more likely than
later gestational infection to cause fetal disease
that is apparent in the newborn as signs of
congenital infection and results in disability due
to central nervous system damage, hearing
 CMV can also be transmitted from mother to fetus
if the mother had CMV infection in the past and was
immune at the time of conception (recurrent
infection)
Little is known about the biology of these infections
or why maternal immunity from previous infection
is unable to prevent all congenital infections.
CMV infection is chronic; the human host never
eliminates the virus, and persistent infection or
reactivation of latent virus is possibly invo
There is evidence that reinfection with a CMV
strain with slightly different envelope
glycoprotein epitopes from the initial strain
results in maternal reinfections that can lead to
congenital infectionlved.
 Intrapartum Transmission
CMV MTCT also occurs during birth and is
due to presence of virus in the cervix or
vagina.
Cervicovaginal shedding of virus is common
in women who are CMV antibody positive.
Active CMV infection with cervicovaginal
shedding of virus is more common in
women infected with HIV, especially those
with poor control of HIV infection and low
CD4T cell counts, and CMV infection rates
are high in their babies.
Specific Infections
Temporary Symptoms Permanent Symptoms
Liver problems or Disabilities
Spleen problems Hearing loss
Jaundice (yellow skin Vision loss
and eyes) Mental disability
Purple skin splotches Small head
Lung problems Lack of coordination
Small size at birth Seizures
Seizures Death
Diagnosis of Infection in
Pregnant Women
Serologic tests for CMV specific IgG
and IgM antibody from
maternal or fetal sera using
ELISA, ABBOT IM or IMMULITE
CMV DNA tests by PCR (B-CMV-
DNA) from , maternal/fetal blood,
sera, amniotic fluid,
neonate`s urine
 Prenatal Diagnosis of
Congenital CMV
Infection
A reliable prenatal diagnosis of congenital CMV
infection is based on PCR from amniocentesis samples
Best sensitivity and 100% specificity by PCR from
amniotic fluid is after 21 gestational weeks
Mean interval between the diagnosis of maternal
infection and antenatal procedure is 7 weeks
CMV- specific IgM antibody detection from cord blood
samples has a sensitivity of 60%
Ultrasound has limited sensitivity in detection of
fetal infection
Pregnancies with evidence of vertical
transmission and definite ultrasound findings
indicating suspected fetal damage are at
significant risk of abnormal sequelae
 Management
Postnatal therapy with ganciclovir transiently
reduces virus shedding and may lessen the
audiologic consequences of CMV in some infected
infants, however, additional strategies are
needed to prevent congenital CMV disease and to
improve the neurodevelopmental prognosis of
infants infected with CMV in uterus.
Termination of pregnancy, in some countries, can
be offered to women whose infants have evidence
of intrauterine CMV infection and sonographic
signs of central nervous system damage.
 Results of small studies in the United
States and in France suggest that providing
CMV antibody negative pregnant women
with information about CMV risk and
methods of prevention could reduce the
rate of maternal infection
The Centers for Disease Control and Prevention
(CDC) in the United States has made specific
recommendations for steps for pregnant women to
take to prevent acquisition of CMV infection; these
recommendations focus on avoidance of contact
with body fluids from children, and the importance
of hand washing and cleaning surfaces after child
care activities associated with body fluids exposure
 Reduce Chances of
Contracting CMV
Wash hands often with soap and water for 15-20
seconds, especially after wiping runny noses, changing
diapers, picking up toys, etc. If soap and water are not
available, use alcohol-based hand gel.
Use soap and water or a disinfectant to clean hard
surfaces that have been contaminated by secretions (the
virus lasts approximately 30 minutes on surfaces)
Dont share food, drinks, or eating utensils with young
children
Dont kiss young children on the lipsgive them a big
hug and a kiss on top of the head.
Defective
Immunity
 The characteristic lifelong persistence of herpesviruses
reflects the delicate balance these viruses establish with the
host's immune system. Following primary infection,
abundant virus-specific T-cell responses are induced that
control viral replication and reduce virus-related pathology.
Nevertheless, the virus persists, mostly in a latent state with
limited viral gene expression. In this way, herpesviruses
restrict the amount of antigens available for immune
detection.
Additionally, herpesvirus persistence is facilitated by
dedicated viral immune evasion mechanisms that evolved
during millions of years of coevolution of these viruses and
their host. Various herpesvirus immune evasion molecules
have been discovered now; a significant amount of them
 Cytomegalovirus
Infection with HCMV is followed both humoral and cellular
immune responses. Antibody-mediated complement lysis is an
important mechanism for elimination of virus-infected cells.
Human cytomegalovirus (HCMV) have evolved mechanisms
limiting complement activity and it is able to inactivate the
complement cascade, increasing virus replication and survival
Humoral immunity is established early and immunoglobulin G
(IgG) antibody remains the standard assay for determining
infection history but the protection value of this response is
unclear
The crucial role of cell-mediated immunity against HCMV
demonstrates the fact that severe and prolonged HCMV
infections occur in individuals with congenital, iatrogenic, or
acquired immune deficiencies.
Infection in most individuals with primary B cell disorders
usually is not severe
 The primary manifestation of the immunodeficiences is
undue susceptibility to infection. It means too many, too
severe, prolonged, complicated and unusual infections.
HCMV infections of immunocompetent hosts are
characterized by a dynamic, life-long interaction in which
host immune response, particularly of T cells, restrain
viral replication and prevent disease but do not eliminate
the virus or preclude transmission.
HCMV infection may be severe in the
immunocompromised host, particularly in the face of T
cell deficiency such as due to primary immunogenetic
defects or acquired immunoficiency states. HCMV is
poorly adapted to survive within an immunosuppressed
host, and, in this situation, there is often uncontrolled
viral replication with subsequent viral reactivation
 Common variable immunodeficiency (CVID) is the most common
primary antibody deficiency caused by a variety of inherited
genetic defects. Many of CVID patients have a T cell lymphopenia,
which is often, associated with poor T cell proliferation to
mitogens in vitro what appears to be a significant defect in
cellular immunity.
As result of transplacental transmission, CMV constitutes the
most commonly acquired congenital viral infection, causing major
prenatal neurological damage (sensorineural hearing loss and
other CNS abnormalities), which is particularly severe when
primary maternal infection occurs during the first 16 weeks of
pregnancy, when organs are developing and neuronal migration
is occurring
The reduced immune responsiveness, the characteristic neonatal
bias towards a Th2 response (unable to fight intracellular
pathogens), the lack of the typical CMV Th1 signature, and the
sustained IL-8 levels (which can directly augment CMV
replication) are among the factors that prevent the generation of
a protective immune response, leading to uncontrolled viremia
and severe clinical damage in congenitally infected newborns
 CMV mononucleosis
Intestinal complications
Liver complications
Nervous system complications
Lung complications

Complications arising from newborn CMV infection

Eye abnormalities, including central vision loss, scarring of the
retina, an inflammation of the light-sensing layer of the eye
(retinitis), and swelling and irritation of the eye (uveitis)
Mental disability
Lack of coordination
Small head
Seizures
Death
 Treatment
There's no cure for CMV, and treatment for the virus
generally isn't necessary or recommended for healthy
children and adults.
Newborns and people with compromised immune
systems, however, need treatment when they're having
symptoms of CMV infection, such as pneumonia. The kind
of treatment depends on the symptoms and their
severity.
If treatment is needed, it's most often in the form of
antiviral drugs. Antiviral drugs slow the virus
reproduction, but can't cure it. Researchers are studying
new medications and vaccines to treat and prevent CMV.
Although vaccinesfor CMV are still in the research and
developmental stages, there are some treatment
options. One study revealed that hyperimmune globulin,
when given to pregnant women with CMV, may help
prevent the fetus from contracting the infection.
 HHV 6
~ utilizes a number of strategies to down-regulate the host immune
response,
including molecular mimicry by production of a functional chemokine
and chemokine receptors.
Immunosuppression is enhanced by depletion of CD4 T lymphocytes via
direct infection of intrathymic progenitors and by apoptosis induction.
Infection is widespread in infants between 6 months and 2 years of age.
A minority of infants develop roseola infantum, but undifferentiated
febrile illness is more common.
Reactivation from latency occurs in immunocompromised hosts. Organ-
specific clinical syndromes occasionally result, but indirect effects
including interactions with other viruses such as human
immunodeficiency virus type 1 and human cytomegalovirus or graft
dysfunction in transplant recipients may be more significant
complications in this population.
Recent advances in quantitative PCR are providing additional insights
into the natural history of infection in paediatric populations and
immunocompromised hosts.
 Treatment
Three drugs initially developed to target HCMV infection
have been shown to be efficient against HHV-6 infection
bothin vitroandin vivo: ganciclovir, foscarnet, and
cidofovir.
Acyclovir, the emblematic antiviral drug against herpes
simplex virus and varicella-zoster virus infections, is active
against HHV-6in vitro, but only at very high concentrations.
These concentrations cannot readily be obtained in body
fluidsin vivo, which explains why HHV-6 has to be
considered naturally resistant to this agent. The three
efficient anti-HHV-6 compounds exhibit the same inhibition
activity against both HHV-6A and HHV-6Bin vitro. The
mechanisms of this antiviral activity are similar for both
HCMV and HHV-6: the viral DNA polymerase is specifically
inhibited by the triphosphorylated form of ganciclovir, the
diphosphorylated form of cidofovir, and foscarnet, in the
latter case without any chemical modification.
 HHV 7
HHV-7 resides mostly inCD4+ T cells,albeit only in certain
strains of them. To enter CD4+ T cells, HHV-7, unlike HHV-6,
uses CD4 and possibly some cell-surfaceglycoproteinsto enter
CD4+ T cells. About a week after HHV-7 has infected a cell, it
begins todown regulateCD4 transcription, which interferes
withHIV-1 infection but may reactivate HHV-6 infection. It is
however unclear exactly what effect HHV-7 has on HIV infection
Primary HHV-7 infections can also cause roseola, albeit less
frequently. Roseoloviruses can affect the central nervous
system
HHV-7 infects almost all children by the age of three years and
persists lifelong, with the shedding of infectious virus in saliva.
It is similar to (HHV-6 in its genetic content and many of its
biological properties, including the ability to cause at least
some cases of roseola infantum
 Treatment

A process known asloop-mediated isothermal

amplification(LAMP) has recently been developed to speed
up detection of HHV-7, although a larger sample size of
patients must be tested first to see if the test will still
work across a broad range of subjects.
No reliableserologicaltest has been developed yet for
HHV-7 alone, but multiple are in the process of being
developed. The use of PCR assays to test for HHV-7 is also
being explored.
No treatment for HHV-7 infection exists, but no clinical
situation where such treatment would be useful has yet
been discovered
Thank You!