MYCOLOGY AND VIROLOGY (MIDTERM) - HERPESVIRIDAE MLS 3G DCM.CAC.NDI.

FSK

FAMILY HERPESVIRIDAE CLASSIFICATION OF HUMAN HERPESVIRIDAE

- Herpesviruses have the ability to establish lifelong persistent infections (table from book)
in their hosts and to undergo periodic reactivation
- The reactivation infection may have different signs and symptoms than
the primary infection REPLICATION OF HERPESVIRUSES
- Herpesviruses are large, spherical, enveloped, icosahedral viruses - Replication involve both the cytoplasm and nucleus of host cells
- Herpesviruses have double-stranded linear DNA for their genome - Replication is divided into:
a. Immediate-early phase
IMPORTANT PROPERTIES OF HERPESVIRUSES b. Early phase
c. Late phase
VIRION Spherical
150-200 nm in diameter A. IMMEDIATE-EARLY PHASE
Icosahedral - Viral envelope glycoproteins fuse with the cell surface
GENOME Double stranded DNA glycosaminoglycans (GAGs) especially Heparan Sulfate
Linear Cellular receptors of herpesvirus
125-240 kbp Has a similar structure with heparin which is a natural
Reiterated sequences anticoagulant but the heparin is more sulfated
PROTEIN More than 35 proteins in virion - Viral nucleocapsid in transported to the nuclear pore
ENVELOPE Contains viral glycoproteins - Uncoating releases linear DNA into the nucleus
Fc receptors - Linear DNA becomes circular DNA
REPLICATION Nucleus - Circular DNA is transcribed to form immediate-early mRNA
Bud from nuclear membrane - Immediate-early mRNA is transported to cytoplasm
OUTSTANDING Encode many enzymes - Immediate-early mRNA in the cytoplasm is translated to a-proteins
Establish latent infections
CHARACTERISTICS Persist indefinitely in infective hosts B. EARLY PHASE
Frequently reactivated in - a-proteins is the start of early phase
immunosuppressed hosts - a-proteins are transported back to the nucleus
Some cause cancer - a-proteins transcribe circular DNA in nucleus to form Early mRNA
- Early mRNA is transported to cytoplasm
- Early mrNA in the cytoplasm is translated to B-proteins

C. LATE PHASE
- B-proteins are transported back to the nucleus
- B-proteins transform circular DNA in nucleus to concatemeric DNA
Repeated sequences of nucleotides
- Concatemeric DNA is replicated and transcribed to form late mRNA
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- Late mRNA is transported to the cytoplasm - Establish latent infections in nerve cells
- Replicated concatemeric DNA is cleaved to form viral DNA Favorite hide out of HSV
- Some late mRNAs in the cytoplasm are translated to structural y- Dorsal root ganglia of spinal cord
proteins - Recurrences of HSV infections are common
- Structural y-protein are transported to nucleus - responsible for a spectrum of diseases
- Some late mRNAs in the cytoplasm are translated to viral glyocproteins Gingivostomatitis
- Viral glycoproteins attach to nuclear membrane Lesions in the gingiva or gums
- Viral nucleocapsids bud off from nuclear membrane with viral Singaw
glycoprotein to form enveloped progeny viruses Keratoconjunctivitis
- Enveloped progeny viruses pass through ER and Golgi apparatus Encephalitis
- Eveloped progeny viruses are released from Golgi apparatus to outside Genital Disease
the cell by exocytosis Infections of newborns

CYTOPATHIC EFFECTS OF HERPESVIR US REPLICATION PATHOGENESIS OF HSV INFECTIONS

- HSV in Hep-2 cells cause swollen, rounded cells - Cause cytolytic infections
- Varicella-Zoster virus in human kidney cells cause multinucleated giant Cell lysis
cells with acidophilic intranuclear inclusion - Pathologic changes due to necrosis of infected cells with inflammatory
- CMV (Cytomegalovirus) showing multinucleated giant cells with response
acidophilic intranuclear and cytoplasmic inclusions - Lesions induced by HSV-1 and HSV-2 resemble those of Varicella-Zoster
Different from adenovirus because CMV has 2 nuclei
CHARACTERISTIC HISTOPATHOLOGIC CHANG ES OF HSV
HERPES INFECTIONS IN HUMANS - Ballooning of infected cells
A. Herpes Simplex Virus - Production of Cowdry Type A intra-nuclear inclusions
B. Varicella-Zoster Virus - Margination of chromatin
C. Cytomegalovirus Chromatins are pushed at the sides of the nucleus because of
D. Epstein-Barr Virus the intra-nuclear inclusions
E. Human Herpesvirus 6 - Formation of multi-nucleated cells
F. Human Herpesvirus 7
G. Human Herpesvirus 8 PRIMARY HSV INFECTION
H. Herpesvirus B HSV is transmitted by entry of HSV into mucosal surfaces or broken
skin
HERPES SIMPLEX VIRUSES (HSV) HSV-1 infections are usually limited to the oropharynx
- Most popular HSV-1 is spread by respiratory droplets or direct contact with infected
- Belong to subfamily Alphaherpesvirinae saliva
- Belong to genus Simplexvirus HSV-2 is usually transmitted by genital routes
- Are human Herpesvirus Type 1 and 2 Primary HSV infections are usually mild and asymptomatic

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MYCOLOGY AND VIROLOGY (MIDTERM) - HERPESVIRIDAE MLS 3G DCM.CAC.NDI.FSK

But sometimes HSV-2 is seen in the mouth 3. GENITAL HERPES

o Indicates that the mouth has come in contact with the genitalia - Usually caused by HSV-2, sometimes by HSV-1
Genitalia lesions infected by HSV-1 Primary Genital Herpes Recurrent Genital Herpes
o Indicates that the genitalia has come in contact with the mouth Severe Milder
LATENT HSV INFECTIONS Vesiculoulcerative lesions Limited vesicles
Many HSV recurrences are asymptomatic of the penis, cervix, vulva, Some are asymptomatic
Symptomatic recurrent HSV-1 infections are usually manifested as cold vagina or perineum
sores (fever blisters) near the lip Lesions may be painful
HSV-1 usually involves the head area and may be associated
HSV-2 involves the lower region of the body with fever, malaise,
dysuria, inguinal
lymphadenopathy
1. OROPHARYNGEAL DISEASE
- Caused by HSV-1
4. SKIN INFECTIONS
- Appears on the fingers
Primary HSV-1 Recurrent HSV-1
- Caused by HSV-1 and HSV-2
Gingivostomatitis Labialis
- Intact skin is resistance to HSV
If only 1 lesion in the gums is seen, its probably no t herpes - Fingers of the dentists and hospital personnels are affected
Become herpetic whitlow
- Worsens with patients who has an eczema
2. KERATOCONJUNCTIVITIS
- Caused by HSV-1
Localized lesions may occur in:
Primary HSV-1 Eye Infection Recurrent HSV-1 - Abrasions contaminated by HSV (traumatic herpes)
Severe Dendritic keratitis - Fingers of dentists and hospital personnel (herpetic whitlow)
keratoconjunctivitis Corneal ulcers - Bodies of wrestlers (herpes gladiatorum, mat herpes)
Vesicles on the eyelids
May lead to permanent
Cutaneous HSV infections are severe in individuals with skin disorders
opacification and
blindness - Primary infection of HSV-1 in persons with chronic eczema (eczema
Recurrent HSV-1 herpeticum)
infections rank second - Eczema herpeticum may be fatal
to trauma as cause of
corneal blindness in USA a. ENCEPHALITIS
A severe form of encephalitis with high mortality caused by HSV
HSV goes to the CNS
Survivors have residual neurologic defects

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MYCOLOGY AND VIROLOGY (MIDTERM) - HERPESVIRIDAE MLS 3G DCM.CAC.NDI.FSK

HSV-1 is the most common cause of sporadic, fatal encephalitis in - Safe sexual practices
USA - Experimental vaccines are still being developed

b. NEONATAL HERPES
HSV-1 and HSV-2 infections of newborns usually from the mother VARICELLA-ZOSTER VIRUS
Three categories of disease in babies with neonatal herpes - VZVs belong to Subfamily Alphaherpesvirinae
- Lesions localized to the skin, eye, mouth - VZVs belong to Genus Varicellosvirus
- Encephalitis with or without localized skin involvement - VZVs are Human Herpesvirus Type 3
- Disseminated disease involving multiple organs including the CNS. - VZVs establish latent infections in nerve cells
Worst prognosis in newborns with disseminated disease is usually - VZVs are morphologically identical to HSVs
viral pneumonitis or intravascular coagulopathy - CPE of VZVs are more focal and spread much more slowly than those by
Many survivors are left with permanent neurologic impairment HSV
- VZVs have no animal reservoirs
LABORATORY DIAGNOSIS OF HSV A. VARICELLA

- Cytopathology by staining scrapings from base of vesicles to show Chickenpox

multinucleated giant cells
- HSV isolation from lesion and other body specimens (throat washings,
CSF stool) remains the definitive approach
- HSC identification by tissue culture, Nt test or immunofluorescence
staining
- PCR
- Serology
EPIDEMIOLOGY OF HSV
- HSV are worldwide in distribution
- HSV transmission is by contact with infected secretions
- HSV-1 is more constantly present in humans than any other virus
- HSV-2 is usually acquired as a STD
TREATMENT, PREVENTION AND CONTROL OF HSV
- Acyclovir, Valacyclovir and Vidarabine antiviral drugs that inhibit viral
DNA synthesis
- Protecting newborn patients with eczema and immunocompromised
patients from people with active herpetic lesions
Its lesion is similar to the lesion caused by the smallpox
A mild, highly contagious disease chiefly of children
Characterized by generalized vesicular eruption of the skin and
mucus membrane
Acute disease that follows primary contact with VZV
B. ZOSTER
Shingles
If you already had a chickenpox before and it recurs
Sporadic, incapacitating disease of adults or immunocompromised
patients
Characterized by a rash limited or distribution to the skin
innervated by a single sensory root ganglion
More painful
Response of partially immune host to reactivation of VZV
PATHOGENESIS OF VARICELLA
Route of infection
- Mucosa of the upper respiratory tract or conjunctiva
Incubation period with primary viremia
- 10 to 21 days

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- Subclinical Varicella is rare - Most common complication in elderly is Postherpetic Neuralgia (nerve
- Incubation of varicella is typically 10 to 21 days pain) that may continue for months
- Malaise and fever are the earliest symptoms followed by rashes
- Rashes usually appear first on the trunk, then on the face, limbs and LABORATORY DIAGNOSIS OF VZV
mouth
- Rashes last about 5 days - Multinucleated cells are seen in stained smears of scrapings or swabs of
- Complications are rare and mortality is very low the base vesicles (Tzanck smear)
- Complications include encephalitis and pneumonia - Rapid diagnostic procedures to detect VZV antigens or DNA
- If you are infected by varicella, it doesnt mean that youll get infected - VZV isolation and identification using cell cultures of human cells
by zoster - Electron microscopy can differentiate VZV from Poxviruses
1. Varicella-zoster virus is inhaled; infects mucosal cells in nose and - Serologic tests
throat
2. The virus infects nearby lymph nodes, replicates, and enters the EPIDEMIOLOGY OF VZV
bloodstream
- VZV occur worldwide
3. Infection of other body cells occurs with replication in liver, spleen, - Varicella occur more in children
resulting in secondary viremia
- Zoster occurs more in adults previously affected with varicella
4. The virus causes successive crops of skin lesion, which evolve into
blisters and crusts
Varicella is spread by:
5. Immune system eliminated the infection except for some virions that
a. Airborne droplets
establish latent infections inside the nerve cells
b. Direct contact
6. If immunity wanes with age or other reason, the virus persisting in
the nerve ganglia can infect the skin, causing herpes zoster
TREATMENT AND PREVENTION OF VZV
7. Transmission to others occurs from respiratory secretions and skin
- Varicella in normal children is mild and requires no treatment
PATHOGENESIS OF ZOSTER - High risk patients exposed to Varicella can be protected by
immunoglobulin before onset of varicella
- Skin lesions are histopathologically identical to Varicella - Acyclovir, Valacyclovir, Famicyclovir, and Foscarnet can be used as
- There is an acute inflammation of sensory nerves and ganglia antiviral drugs
- Distribution of lesions in the skin correspond to areas of innervation - Use of live attenuated Varicella vaccine to prevent chickenpox in
from individual dorsal root ganglion children
- It is believed that waning immunity triggers reactivation of latent VZV - Use of more potent Zoster vaccine to prevent shingles in adults
to cause shingles
- Shingles begin with severe pain in area of skin or mucosa supplied by CYTOMEGALOVIRUS (CMV)
one or more groups of sensory nerves and ganglia - Subfamily Betaherpesvirinae
- Trunk, head and neck are most commonly affected - Genus Cytomegalovirus
- Involvement of the ophthalmic division of the trigeminal nerve - Human Herpes Virus Type 5
manifest with Herpes Zoster Ophthalmicus - Establish latent infections in glands and kidneys
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MYCOLOGY AND VIROLOGY (MIDTERM) - HERPESVIRIDAE
- Cause massive enlargement of cells they infect
- Have largest content among the human Herpesviruses
CMV INFECTION IN NORMAL HOSTS
- Primary infection of older children and adults is usually asymptomatic
but occasionally causes spontaneous infectious Mononucleosis
Syndrome
- Causes 20-50% of heterophile-negative (non-EBV) mononucleosis
cases
- Heterophile tests are used to determine if Infectious Mononucleosis is
due to EBV or not
A blood test which detects the heterophile antibody
Response to EBV infection
If positive, it is caused by EBV
Negative, 20-50% it is caused by cytomegalovirus
CMV MONONUCLEOSIS
- Mild disease with rare complications
- Subclinical hepatitis is common
- Hepatosplenomegaly is frequently observed in children under 7 years
old
- CMV gas has been associated with restenosis (contaminated by
microorganisms especially CMV which causes thickening of the arterial
wall and reducing or narrowing of the blood vessel) in patients after
coronary angioplasty
CMV INFECTION IN IMMUNOCOMPROMISED HOSTS
- Morbidity and mortality are increased in primary and recurrent CMV
infections in immunocompromised hosts
- Pneumonia is the most common complication of CMV infection
OTHER MANIFESTATIONS OF CMV INFECTION IN
IMMUNOCOMPROMISED HOSTS
- Leukopenia in solid organ transplant
- Obliterative broncholiotis in lung transplant recipients
MLS 3G DCM.CAC.NDI.FSK
- Graft artherosclerosis in heart transplant recipients
- Allograft rejection in kidney transplant recipients
CMV OFTEN CAUSE DISSEMINATED DISEASE IN UNTREATED AIDS
PATIENTS
- Gastroenteritis
- Choriorentinitis that may lead to blindness
CMV CONGENITAL AND PERINATAL INFECTIONS
- Fetal and newborn infections with CMV may be severe
- Congenital CMV infection may cause death of fetus in utero
- Newborn CMV infection may involve CNS and RES
- CMV is the most common intrauterine infection associated with
congenital defects
CLINICAL FEATURES OF CMV CONGENITAL AND PERINATAL
INFECTIONS (book Table 33-12)
LABORATORY DIAGNOSIS
- CMV is endemic in all parts of the world throughout the year
- CMV epidemics are still unknown
- It is more prevalent in children and adults in developing nations and
lower socioeconomic groups
- Humans are the only known host
- CMVs are transmitted from person to person by close contact with
CMV-bearing material
TREATMENT AND CONTROL OF CMV
- Ganciclovir has been shown to be successful in treating serious life-
threatening CMV infections
- Foscarnet is used to treat CMV retinitis
- Ancyclovir and Valacyclovir have shown benefits in bone marrow and
renal transplant patients
- Isolation of infected individuals especially newborns
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MYCOLOGY AND VIROLOGY (MIDTERM) - HERPESVIRIDAE MLS 3G DCM.CAC.NDI.FSK

- Screening blood and transplant donors CANCERS ASSOCIATED WITH EBV

- Both live and recombinant CMV vaccines are still under development
a. Nasopharyngeal carcinoma
EPSTEIN-BARR VIRUS (EBV)
Cancer of epithelial cell and is common in males of Chinese
- Subfamily Gammaherpesvirinae
origin
- Genus Lymphocryptovirus
b. Burkitt Lymphoma
- Herpesvirus Type 4
A tumor of the jaw in African children and young adults which
- Establish latent infections in lymphoid tissue
is associated with Plasmodium falciparum infection
- Main causative agent of Acute Infectious Mononucleosis
(malaria)
- Major target in B-lymphocyte
Can spread to other sites
- To enter B-cells
Burkitt cells contain numerous intracytoplasmic lipid droplets
EBV glycoprotein gp350 (seen in EBV) binds to cellular receptor
c. Hodgkin Lymphoma
CD21 (also known as CR2)
Presence of Reed-Sternberg cell
d. Non-Hodgkin lymphomas
PATHOGENESIS Majority involve B cells; a few are of T-cell lineage
- It is commonly transmitted by infected saliva e. Gastric carcinoma
- It initiates infection in the oropharynx f. Other lymphoproliferative disorders and Oral Hairy Leukoplakia in
- Replication occurs in the epithelial cells or surface B-lymphocytes of immunodeficient individuals
the pharynx and salivary glands Oral Hairy Leukoplakia (white thickening of a certain area) is
- Primary infections in children are subclinical a wart-like growth that develops on the tongue
- Infections in young adults present with Infectious Mononucleosis
LABORATORY DIAGNOSIS
INFECTIOUS MONONUCLEOSIS - Nucleic acid hybridization is the most sensitive means of detecting EBV
- Incubation period of 30-50 days in patient materials
- Typical presentation includes: - It can be isolated from saliva, peripheral blood or lymphoid tissue
a. Headache - Common serologic procedures for detection of EBV antibodies include:
b. Fever a. ELISA
c. Malaise b. Immunoblot assays
d. Fatigue c. Indirect immunofluorescence tests
e. Sore throat
- Typical illness is self-limited and lasts for 2-4 weeks EPIDEMIOLOGY
- During disease, there is an increase in the number of circulating WBCs,
- It is common in all parts of the world
especially large, atypical T-lymphocytes
- 90% of adults are seropositive
- Large, irregular atypical lymphocytes in the peripheral blood
- It is transmitted primarily by contact with oropharyngeal secretions
- Indentation of the cytoplasm of the lymphocyte by the red blood cells
gives rise to the so-called Dutch skirt appearance to the border

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MYCOLOGY AND VIROLOGY (MIDTERM) - HERPESVIRIDAE MLS 3G DCM.CAC.NDI.FSK

- Infections occur early in life in developing countries with more than

90% of children infected by age of 6 infections occur later in life in
developed countries EXANTHEM SUBITUM
- Almost half of EBV infections manifest as Infectious Mononucleosis
- Also known as Roseola Infantumor Sixth Disease
PREVENTION, TREATMENT AND CONTROL - Mild common childhood disease characterized by high fever and skin
rash; no slapped-cheek
- No EBV vaccine - Associated with primary infection of HHV 6 or HHV 7
- Acyclovir reduces EBC shedding - HHV 6B variant seems to cause more of this disease
- Acyclovir has no proven benefit in reducing symptoms of Infectious
Mononucleosis or treating EBV-associated lymphomas in KAPOSI SARCOMA-ASSOCIATED HERPESVIRUS (KSHV)
immunocompromised patients - Subfamily Gammaherpesvirinae
- Genus Rhadinovirus
HUMAN HERPES VIRUS 6 (HHV 6) - Human Herpes Type 8
- Subfamily Betaherpesvirinae - Establishes latent infections in lymphoid tissues
- Genus Roseolovirus - A lymphotropic Herpesvirus first recognized in 1994 Kaposi Sarcoma
- Human Herpesvirus Type 6 specimens
- Establishes latent infections in lymphoid tissues - More closely related to EBV and Herpesvirus Saimiri
- Is a T-lymphotropic Herpesvirus first recognized in 1996 - Transmitted through oral secretions, sexually, by blood, organ
- Infections typically ccur in early childhood transplants and in breast milk
- Transmitted through oral secretions - Not as ubiquitous as other herpesviruses
- Reactivation tends to occur after hematopoietic stem cell transplant
and has been associated with delayed engraftment, CNS dysfunction KSHV is associated with:
and increased mortality a. Kaposi Sarcoma
Vascular tumor found on AIDS patients
HUMAN HERPESVIRUS 7 (HHV 7) b. Vascular tumors of mixed cellular composition
- Subfamily Betaherpesvirus c. Body cavity-based lymphomas occurring in AIDS patients
- Genus Reseolovirus d. Multi-centric Castleman disease
- Human Herpesvirus Type 7
- Establishes latent infections in lymphoid tissue KAPOSI SARCOMA
- A T-lymphotropic Herpesvirus recognized in 1990
- Shares 50% DNA homology with HHV 6, but is immunologically distinct - A vascular tumor that causes lesions in skin, mucous membranes of the
- Infections typically occur in early childhood but later than HHV 6 mouth, nose and throat, lymph nodes and other organs
infections - Lesions are usually purple and are made of cancer cells, new blood
- Transmitted through oral secretions vessels, red blood cells, and white blood cells
- May be seen in advanced HIV infection

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MYCOLOGY AND VIROLOGY (MIDTERM) - HERPESVIRIDAE MLS 3G DCM.CAC.NDI.FSK

HERPES B VIRUS
- Designated as cercopithecine (refers to an Old World Monkey)
Herpes Virus 1 replacing the older name Herpes Simiae
- Virus of Old World monkeys that is highly pathogenic and fatal in
humans
- Infections in humans usually result from monkey bite, respiratory
route, or ocular splash
- Disease in humans present with acute ascending encephalomyelitis
- No treatment or vaccine is available

SUMMARY OF HERPESVIRIDAE
- Are large viruses with a double-stranded DNA genome
- All herpesviruses establish lifelong latent infections
- HSV 1 is usually associated with oropharyngeal lesions and is the most
cause of sporadic, fatal encephalitis
- HSV 2 primarily causes genital infections
- VZV causes chickenpox on primary infection in children and Shingles
after reactivation in adults
- CMV are important causes of developmental defects and mental
retardation after congenital infections
- EBV establishes latent infection in B-lymphocytes, causes Infectious
Mononucleosis and is associated with several human cancers
- KSHV is not as ubiquitous as other herpesviruses and is the cause of
Kaposi Sarcoma, a vascular tumor

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