herpes viruses

Question 1

Define the shared properties of all herpesviruses

Answer 1

same morphology, large linear dsDNA genomes, lytic and latent phases of replication, labile and easy to kill in environment, viral genome is delivered to host nucleus where it forms an episome.

Question 2

Structure of herpes viruses

Answer 2

spherical, enveloped dsDNA viruses with icosahedral capsid surrounded by tegument

Question 3

define tegument

Answer 3

viral proteins with some RNAs and cellular proteins used to reprogram newly infected host cell

Question 4

morphology of lytic phase

Answer 4

Nuclear and cytoplasmic inclusions. Cytomegalic cells and syncytia formation. Lytic phase kills cells and release infectious particles.

Question 5

Genes of lytic infection

Answer 5

immediate early (IE) genes-set up environment conducive for viral replication and needed for expression of E and L genes.Early (E) genes-encode replication enzymes and nonstructural viral proteins. Late (L) genes- encode viral structural proteins needed for packaging a new virion and egress from infected cell

Question 6

How do herpes viruses replicate

Answer 6

Herpesvirus DNA replication occurs in the nucleus using viral-encoded DNA polymerase and accessory viral proteins. Encapsidation of genome occurs in the nucleus. Thus, intranuclear inclusions (accumulated viral capsid proteins) are often diagnostic on histopathology for herpesvirus infection.

Question 7

List the alpha herpes viruses, growth rate and location of latency

Answer 7

HSV1, HSV2 and VZV. Grow rapidly and lyse infected cells (12-24hrs). Establish latent infection in neurons of peripheral nervous system, primarily sensory nerve ganglia

Question 8

List the beta herpes viruses, growth rate and location of latency

Answer 8

cytomegalovirus, human herpes virus-6, HHV-7. Grow slowly (80-120hrs) and infect wide variety of cells. Establish latent infections in cells of myeloid lineage (neutrophils, basophils, eosinophils,) and endothelial cells. Replication in glandular epithelial cells allows for viral secretion in saliva, urine, breast milk.

Question 9

List the gamma herpes viruses, growth rate and location of latency

Answer 9

EBV, kaposis sarcoma associated herpesvirus. Grow slowly (80-120hrs) and infect wide variety of cells. Replicate in lymphoid cells and undergo lytic replication in epithelial cells, endothelial cells and fibroblasts. Latency in B cells, and endothelial cells. Capable of transforming these cells

Question 10

HSV-1 and HSV-2 mechanisms of spread

Answer 10

Localized oral and genital epithelial lesions and spread only into sensory neurons that innervate the site of epithelial replication. Both are transmitted via mucosal shedding of virus in oral cavity or genital secretions.

Question 11

VZV mechanism of spread

Answer 11

Initially infects upper respiratory epithelium and spreads to lymph noes and reticuloendothelial system (Liver/spleen). Dendritic cells and Tcells are largely the vehicles for dissemination that causes vesicular rash (chickenpox) and spread from local skin sites up sensory neuron axons to the dorsal root ganglia. Primary VZV is transmitted by respiratory droplets.

Question 12

CMV mechanism of spread

Answer 12

Infects various mucosal epithelial cell surfaces (oral or genital). Local replication results in dissemination by peripheral blood monocytes & dendritic cells. Spread via all body fluids and can be transmitted placentally.

Question 13

EBV mechanism of spread

Answer 13

Infects oral mucosal epithelial Cells and adjacent Bcells. Rapidly establishes latency in resting memory Bcells. Transmitted to new host in saliva.

Question 14

3)list the steps of the general lytic replication cycle of herpesviruses

Answer 14

Attachment and entry > uncoating > gene expression > genome replication > virion assembly/ maturation

Question 15

Function of viral glycoproteins

Answer 15

Bind virion to cellular receptor, resulting in conformation change of viral glycoprotein and fusion of viral envelope with cell membrane. Mediate cellular tropism (which cells can be infected) and act as targets of adaptive immune response

Question 16

Transmission of herpes viruses

Answer 16

respiratory secretions: VZV only. Blood transfusions, BMT or SOT: CMV, HHV6, HHV7, EBV and KSHV. Oral/genital mucosa, abraded skin, saliva, cervical/vaginal secretions, semen, breast milk, urine: HSV-1, HSV-2, CMV, HHV6, HHV7, EBV, KSHV

Question 17

steps of viral gene expression and replication

Answer 17

Viral/cellular transactivators stimulate IE gene expression > IE viral proteins activate viral E gene expression > viral gene replication via viral DNA polymerase

Question 18

steps of virion assembly and egress

Answer 18

L protein synthesis of structural viral proteins including capsid result in packaging and egress through ER (tegument is acquired) and gogli, then out of the cell. Expression of capsid proteins in nucleus cause viral inclusions

Question 19

MOA of antiviral therapy for herpes

Answer 19

Nucleoside analogues terminate viral DNA synthesis by integrating into growing viral DNA and preventing chain elongation. They are prodrugs which must be activated by viral kinases (thymidine kinase from HSV and VZV, or UL97 protein kinase from CMV)

Question 20

List the common antivirals used for HSV, VZV and CMV

Answer 20

HSV and VZV: acyclovir. CMV: ganciclovir

Question 21

Describe innate responses to herpes infection

Answer 21

TLRs recognize virus and trigger interferon signaling and initiation of non specific NK and dendritic cells to control lytic infection

Question 22

describe adaptive responses to herpes infection

Answer 22

Primary mechanism of control for primary infection and reactivations is cellular response. T-cell CD8 responses eliminate infected cells. Neutralizing antibodies are generated to herpesvirus glycoproteins

Question 23

describe herpesvirus countermeasures to the innate immune response

Answer 23

block induction of type I interferons and
production of other cytokines. block dendritic cell maturation. prevent complement activation. alter NK cell functionsblock induction of type I interferons and
production of other cytokines. block dendritic cell maturation. prevent complement activation. alter NK cell functionsblock induction of type I interferons and
production of other cytokines. block dendritic cell maturation. prevent complement activation. alter NK cell functionsblock induction of type I interferons and
production of other cytokines. block dendritic cell maturation. prevent complement activation. alter NK cell functionsblock induction of type I interferons and
production of other cytokines. block dendritic cell maturation. prevent complement activation. alter NK cell functions

Question 24

describe herpes virus countermeasures to adaptive immune response

Answer 24

Cytokine and chemokine mimetics and
decoy receptors. Fc receptor binding proteins. Interfere with antigen presentation to T-cellsCytokine and chemokine mimetics and
decoy receptors. Fc receptor binding proteins. Interfere with antigen presentation to T-cellsCytokine and chemokine mimetics and
decoy receptors. Fc receptor binding proteins. Interfere with antigen presentation to T-cellsCytokine and chemokine mimetics and
decoy receptors. Fc receptor binding proteins. Interfere with antigen presentation to T-cellsCytokine and chemokine mimetics and
decoy receptors. Fc receptor binding proteins. Interfere with antigen presentation to T-cells

Question 25

define latency

Answer 25

Maintenance of viral genomes in a cellular reservoir in the absence of the production of infectious viral particles

Question 26

compare location of HSV1 vs HSV2 latency

Answer 26

HSV1- trigeminal ganglion. HSV2- lumbar sacral ganglion

Question 27

HSV pathogenesis

Answer 27

HSV invades through breaks in integument. Cells at and above basal layer are infected and lyse to cause an inflammatory response (papule). Lysis of many cells with resultant cytokines and inflammation leads to fluid production and a vesicle. Subsequent leukocyte response transforms this into a pustule, which dries to a scab. HSV ascends in the local sensory nerve to reach the dorsal root ganglia and remains there in a latent form for lifeHSV invades through breaks in integument. Cells at and above basal layer are infected and lyse to cause an inflammatory response (papule). Lysis of many cells with resultant cytokines and inflammation leads to fluid production and a vesicle. Subsequent leukocyte response transforms this into a pustule, which dries to a scab. HSV ascends in the local sensory nerve to reach the dorsal root ganglia and remains there in a latent form for lifeHSV invades through breaks in integument. Cells at and above basal layer are infected and lyse to cause an inflammatory response (papule). Lysis of many cells with resultant cytokines and inflammation leads to fluid production and a vesicle. Subsequent leukocyte response transforms this into a pustule, which dries to a scab. HSV ascends in the local sensory nerve to reach the dorsal root ganglia and remains there in a latent form for lifeHSV invades through breaks in integument. Cells at and above basal layer are infected and lyse to cause an inflammatory response (papule). Lysis of many cells with resultant cytokines and inflammation leads to fluid production and a vesicle. Subsequent leukocyte response transforms this into a pustule, which dries to a scab. HSV ascends in the local sensory nerve to reach the dorsal root ganglia and remains there in a latent form for lifeHSV invades through breaks in integument. Cells at and above basal layer are infected and lyse to cause an inflammatory response (papule). Lysis of many cells with resultant cytokines and inflammation leads to fluid production and a vesicle. Subsequent leukocyte response transforms this into a pustule, which dries to a scab. HSV ascends in the local sensory nerve to reach the dorsal root ganglia and remains there in a latent form for life

Question 28

HSV1 vs HSV2 location of infection

Answer 28

HSV1: above the belt. HSV2: below the belt

Question 29

describe oral HSV

Answer 29

usually HSV1 but can be HSV if oral-genital contact. Most have minor illness. 20% have systemic sx. Herpetic gingivostomatitis can occur, but responds to antivirals. Severe pharyngitis in older pts can b caused by HSV2.

Question 30

HSV shedding

Answer 30

Shedding of infectious virus can occur without any symptoms

Question 31

describe HSV reactivation and triggers

Answer 31

Prodrome of sensory symptoms (hours) followed by tender papule, vesicle then crusting. shortened course compared to first episode. Rarely systemic symptoms. Fever and sun exposure are recognized triggers. Antiviral therapy is not standard of care

Question 32

complications of HSV-1 in normal host and treatment

Answer 32

1. herpetic keratitis: infection of eye. 2.HSV encephalitis: latent virus in trigeminal ganglion can proceed towards meninges of middle and anterior fossa of skull and middle cerebral artery causing fever, headache, focal CNS findings (seizures). CSF shows mononuclear cells and HSV DNA by PCR. High dose acyclovir IV 8 hrs

Question 33

clinical course of genital HSV, treatment

Answer 33

HSV2 > HSV1. most patients have a minor illness- fever, headache, lesions, 20% have significant symptoms. Illness peaks in 7-10 days; heals in next 1- 2 weeks. Ameliorated by early antiviral therapy.

Question 34

complications of genital HSV

Answer 34

urethritis, meningitis, yeast superinfection, perianal/perirectal dz.

Question 35

recurrence of genital HSV

Answer 35

Shortened version of first episode infection. Prodrome phase, lasts 4-5 days Mean recurrence frequency is 3-4 recurrences/ year; declines over time. Psychosocial significance. Antiviral therapy decreases morbidity minimally, but is effective as prophylaxis

Question 36

Who is more susceptible to HSV infections

Answer 36

People with defective T-cell immunity (including newborns and immunosuppressed). High suspicion if chronic ulcer, chronic crusted lesion, chronic mouth sores

Question 37

Diagnosis of HSV

Answer 37

PCR is best (takes 1-2 days) and is the only method for detecting HSV in late lesions such as crusts and drying ulcers.. Immunocytology only takes 2-3 hrs but has low sensitivity

Question 38

VZV latency

Answer 38

paraspinal sensory nerve ganglia - dorsal and cranial

Question 39

VZV pathogenesis

Answer 39

doplet nuclei in the air or direct contact with fluid or fomites from lesions. Initially infects lymphoid tissue in pharynx where T cells are infected and enter blood to seed multiple organs and the skin.

Question 40

Varicella time course and incubation period

Answer 40

Incubation period: 10-21 days. Minor malaise > low grade fever > papules > vesicles > pustules > scabs. Fever ends in 4-5 days and new lesions stop appearing at this time. Lesions are mainly on face and trunk

Question 41

Chickenpox complications

Answer 41

Bacterial superinfection of skin lesions. Rare neurological complications (cerebellitis, encephalitis). Pneumonitis (adults). In immunocompromised can cause pneumonitis, hepatitis and encephalitis.

Question 42

VZV and pregnancy

Answer 42

VZV can cause fetal damage when it occurs during the first 16-20 weeks of pregnancy

Question 43

Diagnosis of VZV

Answer 43

Usually clinical. Can culture from skin lesions, stan early lesions or use PCR in older lesions/scabs. If dz is severe, PCR is commonly used

Question 44

Varicella prevention

Answer 44

live attenuated vaccine- two doses administered in childhood

Question 45

Zoster clinical syndrome

Answer 45

vesicular rash in a single dermatome (area of skin innervated by a single sensory nerve). Thus the rash does not cross the midline. Usually a painful prodrome in the affected area precedes the rash by 3-5 days. Systemic symptoms are uncommon. vesicular rash in a single dermatome (area of skin innervated by a single sensory nerve). Thus the rash does not cross the midline. Usually a painful prodrome in the affected area precedes the rash by 3-5 days. Systemic symptoms are uncommon. vesicular rash in a single dermatome (area of skin innervated by a single sensory nerve). Thus the rash does not cross the midline. Usually a painful prodrome in the affected area precedes the rash by 3-5 days. Systemic symptoms are uncommon. vesicular rash in a single dermatome (area of skin innervated by a single sensory nerve). Thus the rash does not cross the midline. Usually a painful prodrome in the affected area precedes the rash by 3-5 days. Systemic symptoms are uncommon.

Question 46

Zoster complications

Answer 46

local pain, bacterial superinfection, eye involvement when frist division of trigeminal nerve is affected, muscular weakness, post-herpetic neuralgia (prolonged pain in area of healed skin lesions that may persist for months)

Question 47

Zoster treatment

Answer 47

acyclovir- but post herpetic neuralgia remains common in older pts

Question 48

Zoster pathogenesis

Answer 48

Latent VZV in neurons reactivates throughout life, but T cell immunity prevents a breakout. As immunity declines with age or immune suppression, VZV propagation down a ganglion may occur. Prodromal pain occurs as the virus travels down the nerve. This boost in immune response usually insures that second cases are not common

Question 49

Zoster prevention

Answer 49

VZV vaccine after age 50 to boost immunity

Question 50

CMV latency

Answer 50

monocytes, endothelial cells, bone marrow progenitors (CD34+),

Question 51

CMV transmission and Sx - perinatal

Answer 51

Sero-positive pregnant women frequently shed CMV into the birth canal. The frequency of shedding increases toward term, and is a major source of initial CMV infection for children. Mothers also shed CMV into their milk. Children infected from the mother are generally asymptomatic or have a minor “viral” syndrome, which is rarely appreciated. Probably the newborn is partially protected by maternal antibody.Sero-positive pregnant women frequently shed CMV into the birth canal. The frequency of shedding increases toward term, and is a major source of initial CMV infection for children. Mothers also shed CMV into their milk. Children infected from the mother are generally asymptomatic or have a minor “viral” syndrome, which is rarely appreciated. Probably the newborn is partially protected by maternal antibody.Sero-positive pregnant women frequently shed CMV into the birth canal. The frequency of shedding increases toward term, and is a major source of initial CMV infection for children. Mothers also shed CMV into their milk. Children infected from the mother are generally asymptomatic or have a minor “viral” syndrome, which is rarely appreciated. Probably the newborn is partially protected by maternal antibody.

Question 52

CMV in early childhood- Sx. Transmission

Answer 52

Young children are generally infected by their playmates; infected young children have prolonged CMV shedding. Most children are asymptomatic or have a minor illness. Occasionally a sicker child will be investigated for prolonged fever or adenopathy. If this occurs hepatitis or pneumonitis may be appreciated.Young children are generally infected by their playmates; infected young children have prolonged CMV shedding. Most children are asymptomatic or have a minor illness. Occasionally a sicker child will be investigated for prolonged fever or adenopathy. If this occurs hepatitis or pneumonitis may be appreciated.Young children are generally infected by their playmates; infected young children have prolonged CMV shedding. Most children are asymptomatic or have a minor illness. Occasionally a sicker child will be investigated for prolonged fever or adenopathy. If this occurs hepatitis or pneumonitis may be appreciated.

Question 53

CMV in adolescence- Sx, transmission

Answer 53

CMV is sexually transmitted. Periodic shedding throughout life occurs in saliva and genital secretions of previously infected individuals. Infection rates vary with the extent and type of sexual activity

Question 54

Describe CMV mononucleosis- incubation period, Sx, labs

Answer 54

Primary CMV infection after puberty. 2-4 week incubation period. Fever, malaise, adenopathy, mild hepatitis, sore throat. Atypical lymphocytes in blood.

Question 55

contrast EBV vs CMV mono

Answer 55

In CMV mononucleosis, in contrast to EBV mononucleosis, there are no heterophil antibodies produced. Detecting these antibodies is a common diagnostic test for EBV mononucleosis.

Question 56

CMV diagnosis

Answer 56

Culture virus va spin-amplifactin method. Also can detect IgM antibody against CMV (recent infection vs IgG which indicates prior infection). PCR is also used

Question 57

Post transfusion syndrome

Answer 57

CMV is found in some circulating lymphocytes in previously infected people, thus can be present in donated blood. Thus, blood transfusions may lead to a febrile illness that sometimes resembles mononucleosisCMV is found in some circulating lymphocytes in previously infected people, thus can be present in donated blood. Thus, blood transfusions may lead to a febrile illness that sometimes resembles mononucleosisCMV is found in some circulating lymphocytes in previously infected people, thus can be present in donated blood. Thus, blood transfusions may lead to a febrile illness that sometimes resembles mononucleosis

Question 58

Who is more susceptible to severe CMV infections?

Answer 58

Pts with deficient T cell immunity- pts on steroids, chemo, radiation, post-transplant, HIV. Risk factors include prior infection with CMV (risk of reactivation) or CMV in donor blood. Severity is worse if CMV positive blood given to CMV seronegative recipient, older pts or severe immunosuppression

Question 59

CMV infection in immunocompromised patient- Sx

Answer 59

Interstitial pneumonia- severe, often fatal (50%). Can also infect the liver, colon, esophagus, bone marrow and retina

Question 60

CMV treatment

Answer 60

Ganciclovir. Acyclovir will not work because CMV does not have the enzyme needed to activate acyclovir. Foscarnet and cidofovir are antivirals with a different mechanism of action, and do not require the activation step, that can be used as an alternative therapy

Question 61

CMV prevention

Answer 61

Screen blood products/organs. Prophylactic ganciclovir and/or CMV hyperimmune globulin to inhibit clinical sx. Pre-emptive therapy- monitor CMV in blood regularly and when small amounts of CMV are detected start ganciclovir

Question 62

CMV Primary vs reactivation intrauterine infection and severity of Sx in neonate

Answer 62

When the mother is having her first CMV infection the baby is more likely (10%) to be symptomatic at birth and to have a serious illness (10-20% mortality). When the mother has reactivation disease the baby is rarely symptomatic, but is subject to non-fatal sequellae (hearing loss) later in childhood. This is due to maternal immunity When the mother is having her first CMV infection the baby is more likely (10%) to be symptomatic at birth and to have a serious illness (10-20% mortality). When the mother has reactivation disease the baby is rarely symptomatic, but is subject to non-fatal sequellae (hearing loss) later in childhood. This is due to maternal immunity When the mother is having her first CMV infection the baby is more likely (10%) to be symptomatic at birth and to have a serious illness (10-20% mortality). When the mother has reactivation disease the baby is rarely symptomatic, but is subject to non-fatal sequellae (hearing loss) later in childhood. This is due to maternal immunity

Question 63

Describe symptomatic newborn CMV infection

Answer 63

hepatitis, bone marrow suppression in the newborn. CMV that occurs early in pregnancy will interfere with development of brain, eyes and ears. Head is small, seizures common.

Question 64

Describe asymptomatic newborn CMV infection

Answer 64

normal at birth but has a chance of hearing loss.

Question 65

HHV 6 and HHV7 transmission

Answer 65

present in saliva of adults and children of all ages. HHV6 is in the genital tract of women at term and may be transmitted in utero or by breast feeding. Maternal antibody protects against infection early in infancy. HHV6 causes infection in most young children. HHV7 rises slowly through 4 years and peaks from teens to age 30

Question 66

HHV6 and 7 pathogenesis

Answer 66

These viruses infect tissues, probably epithelial cells, in the back of throat (?peritonsillar), where circulating B and T cells then become infected and spread virus throughout the body to cause the characteristic illnessThese viruses infect tissues, probably epithelial cells, in the back of throat (?peritonsillar), where circulating B and T cells then become infected and spread virus throughout the body to cause the characteristic illness

Question 67

HHV6 and 7 latency

Answer 67

B and T cells and their precursors

Question 68

HHV6 and 7 clinical presentation

Answer 68

Exanthema subitum (aka roseola infantum): children less than 2, high fever mild lethargy, irritability, injected pharynx, tonsils and tympanic membranes. Diarrhea/ vomiting may occur. Adenopathy of head and neck. Anterior fontanelle bulging in HHV6. Rash begins on trunk and spreads to face, neck, extremities as fever subsides. Rash has rose-pink macules or maculopapules, nonpruritic, coalescing and dissappear in 1-2 days without pigmentation or desquamation. Adults may have mono syndrome

Question 69

HHV6 and 7 in immune compromised

Answer 69

If T-cell mediated immunity is defective, multiorgan disease (pneumonia, colitis, hepatitis, bone marrow suppression, encephalitis) may occur

Question 70

HHV 6 and 7 diagnosis and treatment

Answer 70

Clinical assessment mainly, but can use PCR in immune compromised. Treatment: none if immune function is adequate. If immune compromised, treat like CMV

Question 71

EBV latency

Answer 71

EBNA1 (EB Nuclear antigen 1) links the viral genome to the cellular chromosome so that the virus genome is replicated and partitioned into dividing cells. EBNA2 is a transcription factor that controls EBV-driven transcription and growth, activating other viral latent genes and a range of cellular-activation genes including the oncogene c-myc.EBNA1 (EB Nuclear antigen 1) links the viral genome to the cellular chromosome so that the virus genome is replicated and partitioned into dividing cells. EBNA2 is a transcription factor that controls EBV-driven transcription and growth, activating other viral latent genes and a range of cellular-activation genes including the oncogene c-myc.

Question 72

Cancers associated with EBV

Answer 72

Burkitt Lymphoma, B cell lymphoma, leiomyosarcoma, nasopharyngeal carcinoma, gastric adenocarcinoma

Question 73

EBV epidemiology

Answer 73

>90% of adults have EBV.

Question 74

EBV pathogenesis

Answer 74

EBV from secretions infects epithelial cells in pharynx. B cells in lymphoid tissue (peritonsillar and around pharynx) are infected and viremia seeds lymphoid and reticulo-endothelial structures. T cell immunity develops and destroys EBV infected B cells, causing inflammation and tissue damage recognized as signs/sx of EBV infection. EBV becomes latent in memory B cells leading to salivary shedding

Question 75

EBV clinical manifestations

Answer 75

Young children have mild illness- irritability, sore throat, lymphadenopathy. Older pts have infectious mononucleosis- after 4-6 week incubation fever and malaise (released cytokines), exudative pharyngitis, lymphadenopathy, splenomegaly, hepatomegaly/heptatitis, rash (in pts treated with antibiotics), soft palate petechiae and eyelid edema

Question 76

EBV diagnosis

Answer 76

1. heterophil antibodies- aka monospot test. Pt makes antibodies that cross react with animal tissues such as sheep or horse RBCs. 2. EBV-specific antibodies- used if monospot is negative. IgG against EBV capsid indicates prior infection +/- acute. IgM against EBV capsid indicates current infection. IgG to EBV nuclear antigen indicates pas infection..

Question 77

EBV histology

Answer 77

Atypical lymphocytes (reactive T cells) seen on blood smear. Not specific for EBV

Question 78

EBV complications

Answer 78

Usually cleared within 14 days but may have prolonged fatigue. Pharyngeal swelling may obstruct airway. Neurological syndromes

Question 79

what is kaposis sarcoms

Answer 79

angioproliferative inflammatory lesion that is facilitated by suppressed immune function, and also probably by HIV proteins, and cytokines/ growth factors induced by HHV 8

Question 80

HHV8 transmission and latency

Answer 80

latency in B cells and is periodically shed asymptomatically in saliva- spread among families. Also sexually transmitted

Question 81

HHV8 clinical manifestations

Answer 81

kaposi's sarcoma, primary effusion lymphoma (B cell malignancy of serosal surfaces in HIV+), and multicentric castlemans disease (lymphoid tumor in both HIV + and -)

Question 82

HHV8 treatment

Answer 82

reduce immune suppression and cancer chemo