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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

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