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(6) Enveloped DNA viruses 1

STUDY
PLAY
What 3 general groups of bacteria are enveloped DNA viruses?
- Herpes viruses
- Pox viruses
- Hepatitis B and D viruses
How many species of herpesviridae viruses are there?
8 known
TRUE or FALSE:
Only some of the herpesviridae species can enter a latent state.
***
FALSE
All herpesviridae species can enter a latent state
Describe the structure of the herpes virus in terms of
- shape of capsid
- type of envelope
Icosahedral capsid enclosed in lipid envelope
What lies between the envelope and capsid?
***
What does it contain?
- Proteinaceous material (TEGUMENT)

- Contains virus coded enzymes and transcription factors
Describe the genome of the herpes virus
- Single molecule of LINEAR dsDNA
- Codes for 70-200 proteins
What are the 3 classifications of herpesviruses?
- Alphaherpesvirinae
(herpes simplex virus group)
- Betaherpesvirinae
(cytomegalovirus group)
- Gammaherpesvirinae
(lymphoproliferative group)
What are the members of the Alphaherpesvirinae group?
Herpes simplex group:
- HSV1
- HSV2
- Varicella-Zoster Virus (VZV)
Describe the alphaherpesvirus growth cycle (rate/effect)
- Rapid
- Cytocidal
Where do alphaherpesvirus establish latency?
In the nerve ganglia
What is similar between the members of the alphaherpesvirus group?
Share significant nucleotide homology, therefore:
- Have similar replication
- Have similar pathogenesis
Which of the alphaherpesviruses has the smallest genome?
VSV
Describe the betaherpesvirus growth cycle (rate/effect)
***
- Slow replication cycle
- Allows formation of MULTINUCLEATED GIANT HOST CELLS
Where do betaherpesvirus establish latency?
- Non-neural tissues, for example:
- Glandular cells
- Lymphoreticular cells
What are the members of the betaherpesvirinae group?
- Human Cytomegalovirus (HCMV)
- Human Herpesvirus 6 and 7 (HHV6, HHV7)
Where do gammaherpesvirus replicate?
In the mucosal epithelium
Where do gammaherpesvirus establish latency?
In mucosal tissue
What do gammaherpesvirus induce?
Cell proliferation in lymphoblastoid cells
What are the members of the gammaherpesvirus group?
- Epstein-Barr Virus (EBV)
- Human Herpes Virus 8 (HHV 8)
Where in the cell do the herpesviruses replicate?

What mechanism do they use?
- Replicate in the nucleus
- Use standard mechanism for DNA viruses
What is the term used for transcription of herpesviruses?

What is it?
Cascade control
(expression of a first set of genes is necessary for a second set, which is needed for the expression of a third set of genes)
How does the virus get into the host cell?
1) Adsorbs to the host cell
2) Viral envelope glycoprotein allows fusion of the envelope with the cell's plasma membrane
What happens to the host cell when a herpesvirus enters?
1) Tegument protein gets the host cell's RNase to degrade mRNA
2) Host cell protein synthesis is halted
How do herpesviruses replicate?
1) Nucleocapsid transported to nuclear pore
2) Viral DNA released into nucleus
3) Tegument protein activates cellular RNA polymerase
4) Transcription of viral IMMEDIATE EARLY GENES
5) Expression of DELAYED EARLY GENES
6) Expression of LATE GENES
What are immediate early genes needed for?
Coding of a variety of regulatory functions
What do delayed early genes code for?
Enzymes needed for replication of viral DNA
- DNA polymerase
- Helicase
- Thymidine kinase
What do late genes code for?
Structural proteins of the virion
How do herpesvirus acquire the viral envelope?
***
- Virus buds through the nuclear membrane
- Newly formed envelope proteins accumulate on the nuclear membrane
Fill in the blank:
The latent virus hides in a ___________ than the type it infects.
The latent virus hides in a DIFFERENT TYPE OF CELL than the type it infects
How are HSV1 and HSV2 transmitted?
By direct contact with MUCOSAL or CUTANEOUS surfaces infected with virus
Where is HSV1 present?
In saliva
Because HSV1 is present in the saliva, in which region do infections occur?
Oropharyngeal region
Where is HSV2 present?
In genital secretions
Because HSV2 is present in the genital secretions, how is HSV2 transmitted?
- Sexual intercourse
- Newborn leaving birth canal
Where do HSV1 and 2 multiply?
In the epithelial tissue
Because HSV1 and 2 replicate in the epithelial tissue, what do they cause?
Shallow ulcers containing the virus
What other types of cells can HSV1 and 2 infect?
- Macrophages
- Lymphocytes
Who is vulnerable to HSV1 and 2?
Anyone coming into contact with bodily secretions
TRUE or FALSE:
Shedding may occur in the absence of visible lesions.
***
TRUE
What host cell kills cells infected with HSV1 and 2 to contain the infection?
Cytotoxic T cells
What is an HSV disease that occursi n healthcare workers?

Which HSV cause it?
- Herpetic whitlow
- Caused by either HSV1 or HSV2
What are the signs and symptoms of herpetic whitlow?
Lesions on the fingers or wrist
How long do HSV1 and HSV2 infections last?
Lifelong
Can HSV1 and HSV2 infected patients infect others when the virus reactivates after a latent stage?
Yes
What conditions can BOTH HSV1 and HSV2 cause?
- Gingivostomatitis tonsilitis labialis
- Pharyngitis
- Genital herpes
- Herpes whitlow
What conditions can ONLY HSV1 cause?
- Encephalitis
- Conjunctivitis
- Esophagitis
- Herpes gladiatorum
- Tracheobronchitis
What conditions can ONLY HSV2 cause?
- Meningitis
- Perianal herpes
What is the most common condition HSV1 causes?

How often does it occur?
- Herpes labialis (cold sorse)
-Can occur several times a year
Describe the formation and healing of a cold sore

What is the phrase used to describe its appearance?
- Clear vesicle formed containing infectious virus with a red lesion at the base
- Pus-containing ulcers develop
- Ulcer heals without scarring in 8-10 days

Referred to as "dewdrop on a rose petal"
What can cause reactivation of HSV1?
- Cold
- Trauma
- Stress
Who has HSV1?
Almost everyone
Describe HSV2 genital infection reactivation
- frequency
- symptoms
- result / infectiousness
- healing
- May occur monthly
- With no symptoms OR
- With genital herpes sores
- Results in viral shedding
- Increases risk of infecting a sexual partner
- Sores heal within 2-3 weeks
What are other symptoms of HSV2 reactivation?
- Flu-like symptoms
- Fever
- Swollen glands
Who more commonly get HSV2 infections?
Women
What do primary VSV infections cause?
Chickenpox
What do latent VSV infections cause?
Shingles
How is VSV transmitted?
***
Respiratory droplets
Describe the steps of multiplication and distribution of VSV
1) Infection begins in respiratory mucosa
2) Spreads to regional lymph nodes
3) Multiplies
4) Progeny virus enter bloodstream
5) Second round of multiplication occurs in liver/spleen
6) Second progeny distributed in body by MONONUCLEAR LEUKOCYTES
What cells infected by VSV cause the trademark symptoms?
- Endothelial cells of capillaries
- Skin epithelial cells
When do virus-containing vesicles of chickenpox appear after exposure?
Within 14-21 days after exposure
When is an individual with VSV contagious?
1-2 days before the rash appears
TRUE or FALSE:
Contact with the fluid inside vesicles of chickenpox is a common mode of transmission
***
FALSE
Contact with the fluid inside vesicles of chickenpox do NOT seem to be a common mode of transmission
Describe the normal course of a VSV primary infection in a normal healthy child

What other symptoms aside from the rash may appear?
1) First appearance is a rash on scalp, face, or trunk
2) Rash involves into a virus-containing vesicle that crusts over in 48 hours
3) Itching most severe during early stages

Other (later) symptoms include
- Fever
- Headache
- Malaise
- Abdominal pain
3)
Do VSV primary infections leave a scar?
Not usually
Where do the VSV lesions appear in primary infections in older adults and immune-compromised aptients?
On mucous membranes
What are the potential complications of VSV primary infections in adults and the immune-compromised?
- Varicella pneumonia
- Hepatic failure
- Encephalitis
What is the most serious complication of VSV primary infection?
Varicella pneumonia
What is the name of the syndrome that occurs as a result of treatment of VSV or influenza with ASA?

******
( do NOT use ASA for fever in kids)
Reye Syndrome
What results from Reye Syndrome?
- Acute encephalopathy
- Fatty liver
What is the concern of primary VSV infection in pregnant women?
- Can cause more severe infection
- May infect fetus or neonate
When during pregnancy does VSV primary infection usually infect the fetus?

What may result from early fetal infection?
- More common near term
- Typical VSV at birth or soon after

- Early fetal infection uncommon but may result in multiple developmental abnormalities
What is "herpes zoster"?
****
- Shingles
- Recurrent infection from latent VSV
Where does VSV establish latency?

Where in specific most commonly?
In MULTIPLE SENSORY GANGLIA

Trigeminal and dorsal root ganglia most common
What does herpes zoster result from?
Reactivation of latent virus
(NOT new exogenous exposure)
How often does herpes zoster occur?
occurs in 15% infected individuals
Describe the lesions and pain of herpes zoster
- Dermatomal lesons along skin supplied by cutaneous branches supplies by a SINGLE SPINAL NERVE
- Painful, unilateral vesicular rash
- Burning, throbbing, stabbing pain
How is VSV diagnosed in normal individuals?
Clinical presentation (no labs)
Why is it important to distinguish between VSV and other xanthems in immunocompromised individuals?
Because therapy is warranted
How is VSV diagnosed?
- Tissue culture
- In situ hybridization (more rapid)
- Specific antibody staining of samples from vesicles (more rapid)
How is VSV prevented?
Live attenuated vaccine for children and non-immune adults at risk of exposure to contagious individuals
What member of the betaherpesvirinae subfamily is the most common cause of intrauterine infections and congenital abnormalities?
******
Human Cytomegalovirus (HCMV)
What population is HCMV a serious threat to?
Immunosuppressed patients
What are the 4 modes of transmission of HCMV?
- Viral shedding in tears, urine, saliva of children
- Sexual contact through semen and vaginal secretions
- Organ transplants
- Blood transfusions
When does th initial infection of HCMV usually occur?
During childhood
What percentage of adults have Ab against HCMV?
35-90%
What symptoms do children have when infected with HCMV?
None
Can HCMV infect a fetus?
Yes - can cross the placenta
Where does HCMV replicate initially?
In the epithelial cells that line the respiratory and GI tracts
Where does HCMV likely establish latency?
- Monocytes
- Macrophages
- Kidney cells
What does HCMV cause?
8% of infectious mononucleosis
What are the signs and symptoms of infectious mononucleosis?
- Fever
- Muscle pain
- Lymphadenopathy
- Elevated lymphocytes
- Elevated liver enzymes
Fill in the blank:
Congenital HCMV infections are the most common _________________ viral infection.
Congenital HCMV infections are the most common INTRAUTERINE viral infection.
Name an important virus reservoir for HCMV
Infants (may shed virus for years)
Why are immunosuppressed patients (especially transplant patients) targets of HCMV?
Because the virus may be in transplanted tissue
HCMV is a concern for blood transfusions.
- In what blood cell may HCMV be carried?
- How can this be prevented?
- Carried in leukocytes
- Prevented by using washed RBC
What is a common pathologic result of HCMV in transplant recipients?
Destruction of
- GI tract tissue
- Hepatitis
- Pneumonia
What are the most common organs affected by HCMV in immunodeficient individuals?
- Lung
- Eye
What histologic clue might indicate HCMV?
Owl-eye inclusions in lung section
When do most HHV6 infections occur?
In first 3 years of life
(90% population have Abs by age 3)
Where does HHV6 replicate?
Salivary glands
How is HHV6 transmitted?
Oral secretions
What cells do HHV6 infect?
Peripheral blood lypmhocytes
What do HHV6 induce the synthesis of?
- CD4 glycoprotein
- INF alpha
- TNA alpha
- IL1 beta
What term is used to describe HHV6's effect on T-cells?

What T-cell in particular does HHV6 have a high affinity for?
- T-cell lymphotrophic
- High affinity for CD4 lymphocytes
In what populations are HHV6 infections most common?
- Infants
- Immunocompromised
What are the symptoms of primary HHV6 infections?
- High fever for 3-5 days
- Seizures
- Roseola infantum
What is roseola infantum?
- Rash that appears on the neck and trunk of 1/3-1/2 of infants primarily infected with HHV6
- Resolves after several days
In what population do recurrent infections of HHV6 occur?
- immune suppressed
- immune compromised
What complications can arise from recurrent infections of HHV6 in immunodeficient persons?
- Hepatitis
- Idiopathic pneumonitis
- Bone marrow suppression
- Encephalitis
- Fever
TRUE or FALSE:
Infantile HHV6 and HHV7 (alone or together) can present as an acute febrile illness with no rash present.
*******
TRUE:
Absence of rash does not rule out HHV6
What is a concern of HHV6 and HHV7 in HIV+ patients?
Co-infection may accelerate HIV pathogenesis
- more CD4 cells and transcriptional activation of HIV
- Disseminated infection of HHV6 frequent in terminal AIDS
Fill in the blanks:
_____, ______, or _____ accounts for 20% of ER visits for infant febrile illnesses and 1/3 of febrile seizures
HHV6, HHV7, or COINFECTION accounts for 20% of ER visits for infant febrile illnesses and 1/3 of febrile seizures
What 2 statistics indicate that most of the population has been exposed to HHV7?
- HHV7 can be isolated from the saliva of 75% of healthy adults
- Antibodies to HHV7 can be detected in the serum of 90% of the normal population
TRUE or FALSE:
Like HHV6 and HHV7, HHV8 is very common in the general population.
FASLE:
HHV8 is not very common in the general population
What is the concern of HHV8 infection in AIDS patients?
Karposi sarcoma
What has helped to improve the incidence of Karposi sarcoma from HHV8?
Availability of better antiretroviral drugs
(seldom seen now)
What is the #1 cause of infectious mononucleosis in young adults?
Epstein Barr Virus (EBV)
What types of diseases is EBV associated with?
Several human neoplastic diseases
How is EBV transmitted?
Intimate contact with saliva that contains the virus

(hence the name "kissing disease")
Where is the initial site of EBV viral replication?
Oropharyngeal epithelium
What blood cell an be abortively infected by EBV?

How does it do this?
Abortively infects B lymphocytes through:
- Induction of B-cell growth factors
- Induction of polyclonal B-cell proliferation (cell immortalization)
What B-cells increase as a result of EBV?
IgM
IgG
IgA
How is EBV diagnosed?
*******
Paul-Bunell Test
What is the basis of the Paul Bunell test?
****
IgM class are "heterophile antiobodies" that agglutinate sheep and horse RBC
What is the incubation period of infectious mononucleosis?
4-7 weeks
What signs and symptoms appear after the incubation period?
- Fever
- Pharyngitis
- Lymphadenopathy
- Increased liver enzymes
How long do mono symptoms last?
- Most symptoms last 2-3 weeks
- Fatigue and complete recovery can take much longer
What is a concern of EBV carrriers?
Healthy carriers can have asymptomatic shedding
What malignancies can EBV cause?
- T-cell malignancies
- B-cell malignancies
- Epithelial cell malignancies
What is Burkitt Lymphoma (BL)?
- Fast growing disease that originates in the B-cells (result of EBV)
- Results in malignancies of the jaw
Where is BL unusually frequent?
In children and young adults in equatorial Africa
What are symptoms of BL?
Painless enlargement of lymph nodes in the neck, underarms, groin
Where does BL spread to after the lymph nodes?
- Bone marrow
- Blood
- CNS
What is the main concern of BL?
Death
What genetic feature is BL associated with?
3 characteristic chromosome translocations
(c-myc proto-oncogene constitutively activated)
What are 2 risk factors for BL development?
- Malaria
- HIV infection
What disease caused by EBV is common in Asia, Africa, and the Inuit population in the USA?
EBV-associated Nasopharyngeal Carcinoma (NPC)
Is NPC associated with any characteristic chromosome alterations like BL?
No
What cells are involved in NPC?
Epithelial cells
What is the term used for the non-malignant lesions on the tongue of AIDs patients infected with EBV?
Hairy leukoplakia
What is contained in all the cells of the tumors of NPC?
Cytoplasmic viral DNA molecules
What is EBV's role in BL and NPC?

What is this in contrast to?
- In BL and NPC, EBV is just one step in the process
- EBV is sufficient to induce B-cell lymphomas in immunocompromised patients
In summary, what are the 5 viruses responsible for herpesvirus infections?
1) Herpes simplex virus 1 (HSV1)
2) Herpes simplex virus 2 (HSV2)
3) Varicella-zoster virus (VSV)
4) Cytomegalovirus (CMV)
5) Epstein-Barr virus (EBV)
In summary, what herpesviruses are in the alpha subfamily?
- HSV1
- HSV2
- VSV
In summary, what herpesviruses are in the beta subfamily?
- HCMV
- HHV6
- HHV7
In summary, what herpesviruses are in the gamma subfamily?
- EBV
- HHV8
In summary, what are the classic clinical manifestations of primary infection of HSV1?

What is its site of initial infection?
CLINICAL MANIFESTATION
- Keratoconjunctivitis
- Gingivostomatitis
- Pharyngitis
- Tonsilitis

SITE OF INFECTION
Mucoepithelial
In summary, what are the classic clinical manifestations of recurrent infection of HSV1?
CLINICAL MANIFESTATION
- Herpes labialis (cold sores)


SITE OF LATENCY
- Trigeminal sensory ganglia
In summary, what are the classic clinical manifestations of primary infection of HSV2?
CLINICAL MANIFESTATION
- Genital herpes
- Perinatal disseminated disease

SITE OF INFECTION
Mucoepithelial
In summary, what are the classic clinical manifestations of recurrent infection of HSV2?
CLINICAL MANIFESTATION
- Genital herpes

SITE OF LATENCY
Lumbar or sacral sensory ganglia
In summary, what are the classic clinical manifestations of primary infection of VSV?
CLINICAL MANIFESTATION
- Varicella (chickenpox)

SITE OF INFECTION
- Mucoepithelial
In summary, what are the classic clinical manifestations of recurrent infection of VSV?
CLINICAL MANIFESTATION
- Herpes Zoster (shingles)

SITE OF LATENCY
- Dorsal root ganglia
In summary, what are the classic clinical manifestations of primary infection of HCMV?
CLINICAL MANIFESTATION
- Congenital infection (in utero)
- Mononucleosis-like syndrome

SITE OF INFECTION
- Monocytes
- Lymphocytes
- Epithelial cells
In summary, what are the classic clinical manifestations of recurrent infection of HCMV?
CLINICAL MANIFESTATION
- Asymptomatic shedding of virus

SITE OF LATENCY
- Monocytes- Lymphocytes
In summary, what are the classic clinical manifestations of primary infection of EBV?
CLINICAL MANIFESTATION
- Infectious mononucloesis
- Burkitt lymphoma (BL)

SITE OF INFECTION
- Mucosal epithelium
- B lymphocytes
In summary, what are the classic clinical manifestations of recurrent infection of EBV?
CLINICAL MANIFESTATION
- Asymptomatic shedding of virus

SITE OF LATENCY
- B lymphocytes