ILC 1.13: Herpesviruses

Question 1

how are herpesviruses categorized?

Answer 1

α, β and γ

Question 2

where do α herpesviruses establish latency?

Answer 2

neurons

Question 3

which herpes strains are in the α group?

Answer 3

1. HHV-1 = herpes simplex virus type 1 (HSV-1)
2. HHV-2 = herpes simplex virus type 2 (HSV-2)
3. HHV-3 = varicella zoster virus (VZV)
4. Herpesvirus B

Question 4

where do β herpesviruses establish latency?

Answer 4

T cells

sometimes macrophages too

Question 5

which herpes strains are in the β group?

Answer 5

1. HHV-5 = cytomegalovirus (CMV)
2. HHV-6 = human herpesvirus 6
3. HHV-7 = human herpesvirus 7

Question 6

which herpes strains are in the γ group?

Answer 6

HHV-4 = EBV

Question 7

what is the structure of the herpesvirus virion?

Answer 7

1. icasahedron capsid
2. linear dsDNA
3. matrix proteins present
4. enveloped

Question 8

what is tegument?

Answer 8

aka matrix proteins, they just have a specific name when it comes to herpes viruses

Question 9

describe the genome of the herpesvirus

Answer 9

linear, dsDNA with repeat sequences at the ends

this means that the virus will circularize at some point during the replication process!

the repeats will be maintained during replication process, they’re intentional

Question 10

how does the herpesvirus enter a cell?

Answer 10

pH independent OR pH dependent manner

Question 11

what mechanism does the herpesvirus use to replicate?

Answer 11

rolling circle mechanism

like toilet paper

Question 12

what is a persistent infection?

Answer 12

viral infection does not result in cell death

instead there is continuous production of low titers

mechanisms leading to this situation are unknown

Question 13

what is a latent infection?

Answer 13

involves maintenance of the viral genome without replication

so there’s a primary lytic cycle but then it just stops replicating and goes to sleep

you might not have an antibody response during this phase because no virus is being produced

latently-infected cells can be reactivated, often by stress, or during periods of impaired immunity

reactivation is characterized by new virus production

Question 14

how do you know when HSV-1 is in a latent phase?

Answer 14

latency is characterized by the generation of untranslated mRNAs called latency-associated transcripts (LAT)

Question 15

how do you know when CMV is in a latent phase?

Answer 15

there is no detectable RNA or protein synthesis

Question 16

when herpesvirus resurfaces after a latent phase, where does it appear?

Answer 16

in the same spot!!

HSV-1 and HSV-2 are α-herpesviruses that go latent in neurons so usually its the innervating neuron associated with the primary infection

Question 17

what are the most common clinical features of HSV?

Answer 17

• vesicular rashes
• oral herpes = HSV-1
• genital herpes = HSV-2
• fetal infection in utero is often fatal

most infections are symptomatic so you can physically see that someone has herpes unlike other viruses that go under-diagnosed because they don’t have as many presenting symptoms

Question 18

how can you differentiate between HSV-1 and HSV-2?

Answer 18

they’re both α-herpesviruses

but HSV-1 is usually oral herpes = above the waistline

HSV-2 is usually genital herpes = below the waistline

Question 19

what are some other clinical presentations of HSV?

Answer 19

1. herpes pharyngitis
2. eye infection
3. finger infection
4. skin infection
5. herpes encephalitis = most common cause of fatal sporadic encephalitis cases

Question 20

how do you diagnose HSV?

Answer 20

1. distinct vesicular blisters
2. Tzanck smears = scrape the bottom of a lesion and look at it under a microscope –> you’ll see balooned cells and Cowdry inclusion bodies

Cowdry inclusion bodies = intranuclear inclusions where virus is replicating

3. other diagnostic methods include virus isolation/culture in cell lines, electron microscopy, immunofluorescence, and PCR

Question 21

what is the pathogenesis of HSV?

Answer 21

initial acute infection with the virus replicating at the site; you’ll have a normal replication cycle where lots of virus is being procued

then the cell dies; lots of times with HSV there is disease associated with this

after the initial infection, the virus will infect innervating neurons and hide in the neuron = not an acute infection anymore

the virus changes its replication program so that it’s no longer replicating like it does in the epithelium and fibroblasts

then when the conditions are right, the virus will come out of the neuron and travel back up the axon and infect those same epithelial cells

Question 22

how do you prevent HSV?

Answer 22

there is no vaccine against HSV-1 or HSV-2….

health-care workers should use latex gloves to prevent infection

condoms help, but may not always be fully protective

patients with a history of HSV infection must abstain from sexual contact while they have prodromal symptoms or lesions; the latter must be fully reepithialized

Question 23

how do you treat HSV?

Answer 23

acyclovir

acyclovir is phosphorylated by HSV-encoded thymidine kinase and acts as a terminator of viral DNA synthesis

other options include valacyclovir, penciclovir and famciclovir

Question 24

what type of herpesvirus is VZV?

Answer 24

alpha herpesvirus

VZV = varicella zoster virus

Question 25

what are the 2 disease outcomes of the VZV virus?

Answer 25

1. chickenpox (varicella) | 2. shingles (herpes zoster)

Question 26

what are the clinical features of varicella?

Answer 26

varicella = chickenpox may be asymptomatic but usually you get an exanthem (rash) fever, followed by a maculopapular rash more severe in the trunk than in the limbs each lesion develops to become a vesicle - the hallmark of varicella – and later becomes pustular and crusts finally, scabbed lesions appear

Question 27

how do you distinguish smallpox from varicella?

Answer 27

with varicella you get a rash that shows up in various stages; there are initial lesions and by the time it scabs up new ones have shown up on the other hand, smallpox lesions are all the same age and all scab over/fall off at the same time

Question 28

why does someone get shingles?

Answer 28

shingles = zoster if there is VZV reaction and migration to the skin during adulthood

Question 29

where does the shingles rash appear on the body?

Answer 29

so the varicella rash is all over the body so it's traveling everywhere and infecting T cells; the infected T cells in your skin are what cause the rash eventually the infected T cells will infect a neuron and the virus will lie latent in the neurons; usually its neurons in the trunk the area innervated by the infected neurons becomes painful and the skin breaks with vesicles that are similar to those observed during chickenpox when the virus reactivates, it's usually in one spot that's localized and extremely painful

Question 30

which population is prone to zoster?

Answer 30

elderly patients immunocompromised patients

Question 31

how do you diagnose VZV?

Answer 31

- rash - Tzanck smears - ELISA - PCR

Question 32

how do you prevent VZV?

Answer 32

there is a highly effective, live-attenuated vaccine against chickenpox and one against zoster composition is the same, the difference is dosage you just have to be careful not to give it to immunocompromised patients since it's a live vaccine immunosuppressed patients may be treated with varicella-zoster immunoglobulin prepared from sera of seropositive people

Question 33

how do you treat VZV?

Answer 33

1. acyclovir | 2. pain may be managed with analgesics or topical anesthetics

Question 34

what are some of the complications of VZV?

Answer 34

1. can be fatal in immunocompromised people 2. postherpetic neuralgia = chronic nerve pain that can persist for years due to damage caused by VZV it's confined to the dermatomic area following shingles outbreak

Question 35

what are the characteristics of herpesvirus B?

Answer 35

only zoonotic alpha-herpesvirus 4 practices for virus research normally just effects monkeys but it could be transmitted to humans potentially infection may be unapparent, or result in vesicular lesions transmission by bite can lead to fatal encephalomyelitis (80% CFR is untreated)

Question 36

what class of herpesvirus is CMV?

Answer 36

beta herpesvirus

Question 37

what is the largest herpesvirus?

Answer 37

CMV so this means it expresses many proteins to evade host antiviral responses

Question 38

which virus is the most common viral cause of congenital birth defects?

Answer 38

CMV

Question 39

which virus is the most common viral cause of solid organ transplant rejection?

Answer 39

CMV especially renal allografts

Question 40

which population is at risk for CMV?

Answer 40

it's increasingly prevalent in immunocompromised patient, in which it establishes opportunistic infections

Question 41

what does TORCH stand for?

Answer 41

Toxoplasma gondii Other (HIV, syphilis, Zika, VZV, etc.) Rubella CMV HSV/HIV

Question 42

what are TORCH viruses?

Answer 42

they're transmitted from mother to child each type of infection has a different prognosis the stage of the pregnancy at the time of infection also can change the effect on the newborn

Question 43

what are common effects of TORCH viruses?

Answer 43

intrauterine growth restriction (IUGR) microcephaly intracranial calcifications conjunctivitis hearing loss rash hepatosplenomegaly thrombocytopenia

Question 44

what can CMV develop into?

Answer 44

CMV is a sexually-transmitted disease and is usually asymptomatic like 90% of us have CMV but there's no symptoms because it's just latent in T cells! however, some patients may develop mononucleosis with symptoms similar to EBV

Question 45

how can you differentiate EBV and CMV that's turned into mononucleosis?

Answer 45

in CMV there won't be large/swollen lymph nodes! pharyngitis and lymphadenopathy are less severe or absent but both will have mononucleosis

Question 46

what is congenital CMV?

Answer 46

CMV is the most common viral cause of congenital defects about 1% of babies born in US with congenital CMV and of those 10-20% with have symptoms but most are asymptomatic! symptoms can be mild or severe: hearing/vision loss, microcephaly, muscle and brain development, mental disability, death -- so its presenting in a lot of different places we only treat symptomatic newborns

Question 47

which symptoms are immunocompromised CMV patients at risk for?

Answer 47

penumonia retinitis colitis

Question 48

how do you diagnose CMV?

Answer 48

1. ELISA, testing for the presence of IgM (for in utero infections) or IgG antibodies 2. virus can be isolated from blood, urine and saliva, and propagated in human fibroblasts 3. histology of CMV-infected cells is very characteristic, and shows enlarged cells containing “owl’s eye” inclusions = viral nuclear inclusions 4. immunofluorescence 5. PCR

Question 49

what is the pathogenesis of CMV?

Answer 49

pathogenesis of CMV is similar to that of other herpesviruses and infections are often inapparent virus is capable of establishing a persistent infection or, alternatively, latency in T cells and macrophages spread occurs when the infected cells travel throughout the body (this is why CMV symptoms involve so many different parts of the body) infected individuals shed virus in bodily fluids intermittently, but for life reactivation, often with severe consequences, usually follows immunosuppression.

Question 50

how is CMV spread?

Answer 50

it's transmitted by most bodily fluids and secretions

Question 51

how do we prevent CMV?

Answer 51

CMV vaccines are in all stages of clinical trials maternal antibodies do no confer protection

Question 52

which drugs treat CMV?

Answer 52

1. ganciclovir/valganciclovir 2. cidofovir 3. foscarnet

Question 53

what do ganciclovir/valganciclovir do?

Answer 53

used to treat CMV same mechanism as acyclovir the drug is activated when phosphorylated by a CMV-encoded kinase (UL97) and act as terminators of DNA synthesis

Question 54

what does cidofovir do?

Answer 54

used to treat CMV it's a cytidine analog that does not require phosphorylation to be active it's approved to treat CMV retinitis, especially in AIDS patients

Question 55

what does foscarnet do?

Answer 55

used to treat CMV inhibits the DNA polymerase by mimicking the pyrophosphate in dNTPs it's selective because the viral polymerase is 100X more sensitive than human polymerase it's used with ganciclovir-resistant infections, especially AIDS and transplant recipients

Question 56

what are the characteristics of herpesvirus 6?

Answer 56

two variants: HHV61 and HHV6B HHV6B causes the childhood exanthem: exanthem subitum or roseola (high fever and rash) HHV6B reactivation associated with transplant recipients HHV6A can be neurovirulent and associated with neuroinflammatory diseases like multiple sclerosis

Question 57

what are the characteristics of herpesvirus 7?

Answer 57

mononucleosis lymphadenopathy

Question 58

which class of herpesvirus are HHV 6 and 7?

Answer 58

beta

Question 59

which class of herpesvirus is EBV?

Answer 59

gamma

Question 60

how is EBV transmitted?

Answer 60

saliva it's the kissing disease

Question 61

where is EBV latent?

Answer 61

Infection/latency in B cells (CD21 receptor)

Question 62

what is the main characteristic of EBV?

Answer 62

its ability to immortalize cells if EBV can keep cells growing, since the infected cells are B cells this can lead to B cell cancers

Question 63

what are the clinical features of EBV?

Answer 63

causes infectious mononucleosis symptoms include: - fatigue due to lymphocyte activation and proliferation - lymphadenopathy - splenomegaly - pharyngitis - high fever is frequent - rash is possible

Question 64

what happens when immunocompromised people get EBV?

Answer 64

in people with low immunity EBV infection can be life-threatening and induce several lymphoproliferative diseases 1. African Burkitt’s lymphoma 2. Hodgkin’s lymphoma 3. nasopharyngeal carcinoma also, a rare result of EBV infection is hairy oral leukoplakia, which results in mouth lesions seen in AIDS patients

Question 65

what's the difference between EBV and CMV?

Answer 65

EBV can effect young healthy people.... also EBV will have a positive monospot test and CMV won't

Question 66

how do you diagnose EBV?

Answer 66

1. monospot positive 2. presence of Downey cells (atypical T cells, 10-80% of WBC count) 3. PCR

Question 67

how does the monospot test for for EBV?

Answer 67

EBV stimulates infected B cells to make non-specific heterophile antibodies that can be detected by agglutination of sheep RBCs when the sheep RBCs clump, this is a positive monospot test

Question 68

which antigens can be used for diagnosis of EBV?

Answer 68

1. EA = early antigen 2. VCA = viral capsid antigen 3. EBNA = nuclear antigens 4. MA = glycoproteins of the membrane

Question 69

how do you prevent EBV?

Answer 69

you can't, there's no vaccine

Question 70

how do you treat EBV?

Answer 70

there's no treatment.... EBV does not code for a thymidine kinase, so ACV is not useful

Question 71

what are some potential complications of EBV?

Answer 71

recurring replication can result in a disease similar to chronic fatigue syndrome EBV can cause neurological complications and rupture of the spleen the latter can be avoided by instructing the patient to rest

Question 72

EBV vingette

Answer 72

A 17-year-old high school student has had low-grade fever and malaise for several days, followed by sore throat, swollen cervical lymph nodes, and increasing fatigue. The patient also notes some discomfort in the left upper quadrant of the abdomen. The sore throat, lymphadenopathy, and fever gradually resolved over the next two weeks, but the patient’s full energy level does not return for another 6 weeks. 1. low-grade fever 2. swollen cervical lymph nodes 3. fatigue 4. LUQ discomfort

Question 73

CMV vingette

Answer 73

A 36-year-old man was brought to the hospital for complaints of persistent high fever, dry cough, and worsening shortness of breath for a week. He had been diagnosed with acute myelogenous leukemia 6 months before, and he received an allogeneic bone marrow transplant 6 weeks before. He was taking Bactrim for prophylaxis of pneumocystis pneumonia. Histopathology of lung biopsy specimens showed intranuclear inclusions in pneumocytes. 1. high fever 2. dry cough 3. worsening shortness of breath for a week 4. BM transplant 6 weeks before

Question 74

VZV vingette

Answer 74

A 32-year-old man presents to the emergency department with an itchy and painful rash on the back of his left leg. About 7 days ago, he began to feel an intense, burning pain behind his left knee. Over the subsequent days, small blisters began to pop up over the area but were the worst behind the knee itself. He treated the lesion with an over-the-counter antibiotic ointment and acetaminophen, but they did not relieve the pain. Any contact, however slight, with the apparent blisters immediately intensifies the pain. The patient reports having fevers, sneezing, and a runny nose over the last 2 weeks. He does not report any cough, shortness of breath, headaches, or fatigue. He also reports extreme stress at work with many deadlines and an ongoing threat of job loss because of continuing downsizing due to overseas corporate operations. Lesions are observed on the back of the left knee, and similar but smaller lesions appear in a band-like distribution along the posterior length of his left leg up to the buttock region. The affected leg is neurovascularly intact. Remaining findings on neurologic examination, cardiorespiratory examination, and the review of systems are unremarkable. 1. intense, burning pain 2. small blisters 3. stress 4. band-link distribution

Question 75

which class of herpesvirus is Kaposi's sarcome herpesvirus?

Answer 75

gamma herpesvirus

Question 76

what are the characteristics of KSHV?

Answer 76

KSHV = Kaposi's sarcome herpesvirus linked to Kaposi sarcoma and other proliferative disorders…systemic disease that can present with cutaneous lesions/tumors tumors originate due to immortalization of endothelial cells at multiple sites most primary infections are asymptomatic, and the disease is the result of viral reactivation in addition to the better-known skin lesions, KSHV can result in lung infection!! associated with HIV-1 infections

Question 77

which populations is KSHV common in?

Answer 77

high prevalence among elderly men of Mediterranean (specially Jewish and Italian) and Eastern European ancestry

Question 78

how is KSHV transmitter?

Answer 78

mainly transmitted by sexual contact but non-sexual transmission is possible

Question 79

how do you diagnose KSHV?

Answer 79

symptoms PCR serology

Question 80

KSHV vingette

Answer 80

A 31-year-old man presents with mucocutaneous lesions, breathlessness, cough, a fever, and wheezing. Chest X-rays are obtained and shown in the image. This patient is immunocompromised due to immunoaglobulinemia 1. lung infection = cough and wheezing 2. immunocompromised KSHV is HIGHLY asscociated with immunocompromised patients; it's not usually a healthy person that has KSHV