18. Herpesvirus 2 Flashcards by Zara Jalil

oncogenic EBV - 3 types

many animal herpesviruses are oncogenic
African Burkitt’s lymphoma
Nasopharyngeal carcinoma in East Asian people

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example of oncogenic animal herpesvirus

Marek’s disease virus in chickens –> must vaccinate chickens

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indication of burkitt’s lymphoma and nasopharyngeal carcinoma

both are positive for episomal EBV DNA and EBV-specific antigens

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is EBV infection required for malignancy?

yes, but infection alone will not cause malignancy

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what 2 other things contribute to malignancy of EBV

genetics
Malaria

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what happens in infectious mono?

polyclonal increase in both B and T lymphocytes

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what happens early in mono?

B/T ratio = 4:1

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why are there more B cells early in mono?

EBV infects and transforms B cells which become immortal in vitro and can produce human monoclonal antibodies

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what happens later in mono?

T/B ratio = 4:1

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why are there more T cells later in mono?

cytotoxic lymphocytes kill EBV-infected B cells

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what happens normally with EBV-induced infectious mononucleosis?

normally, polyclonal B cell lymphocytic leukemia lymphoma which can be controlled by immune system

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what happens with EBV infection in ppl with severe T cell defects or organ transplant patients?

can manifest as progressive B cell lymphoproliferative disease which behaves like lymphomas

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when does EBV infection occur in organ transplant patients and treatment

normally occurs long after transplant –> can only treat by stopping immunosuppressive drugs

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describe attachment of HSV to cell surface

NON-SPECIFIC btwn proteoglycans of cell surface and virus glycoprotein C

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how does HSV enter the cell?

fusion

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what happens once HSV fuses into cell?

viral capsid migrates to nuclear pores along cellular microtubules with cellular transport machinery

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how does HSV genome enter nucleus?

viral DNA is injected thru a pore while capsid proteins remain in cytoplasm

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does HSV encode its own RNA pol?

yes, part of late gene

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are herpes viruses old or young? age?

OLD –> 400 million years old

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where are herpes virus found?

EVERYWHERE! and many different types

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do herpes viruses insert their genome into host genome?

normally no, but very few can!

what is herpes virus integration called?

STRATEGIC SOMATIC GENOME INTEGRATION

what is strange about herpes virus?

that we haven’t found an endogenous herpes virus

describe primary infection

infection is seen in lips
- virus can then travel thru sensory neurons with long axis to trigeminal ganglion

describe recurrent infection

reactivation of virus, travels retrograde along axon to initial site of infection

where does latent infection and reactivation occur?

in sensory neurons

describe how virus becomes latent (5 steps)

1. virus enters neurons at periphery and genome travels up axon to neuronal nucleus 2. virus replications and destroys some neurons, but most neurons survive 3. viral genome as an EPISOME becomes associated with host histones and forms MINI-CHROMOSOMES 4. viral gene expression remains absent during latent infection 5. some latent infected neurons express a HSV transcript

what is LAT?

Latency Associated Transcript --> encoded in repeat regions of genome

describe how LAT contributes to latency

- LAT domain transcribed to RNA - 2kb intron is spliced - this intron is stable in nucleus of neuron and persists as circular RNA (lariat)

does LAT involve expression of protein?

describe the experiment with rabbits about the function of LAT

compared trigeminal ganglia of rabbits infected by WT HSV1 vs rabbits infected by HSV1 without LAT - no LAT = lots of apoptosis!

describe the experiment with introducing LAT gene in cells

in primary human lung cells, monkey kidney cells, murine neuroblastoma cells --> introducing LAT protects cells from apoptosis

does the reactivation event involve killing neurons?

unknown

how does the frequency of reactivation change with time?

most evidence suggests it decreases

does chromosomal integration always happen?

no --> rare event, only in <0.1% of infected cells

describe integration in HHV6

normally hard to detect chromosomal integration, but in HHV6, integrated virus is transmitted thru gametes so offspring have viral copy in every cell

what do we know about consequences of herpesvirus integration?

unknown

what directly AND indirectly affect latency and reactivation?

cytokines and inflammatory state of host

effects of IL-4/IL-13 and IFN

transcription factors downstream of these cytokines may have direct effects on ORF 50 of MHV68

3 other ways that immune system may affect reactivation/latency? how?

1. altered autophagy in macrophages 2. altered HOIL-1 expression 3. M2 expression in B cells by affecting host inflammation

how can other infections change the latency/reactivation of herpesvirus?

if there's a co-infection that changes inflammatory state, this might affect latency/reactivation

what happens when KSHV-infected cell line was treated with IL-4

IL-4 treatment of KSHV-infected cell induced production of viral genome and lytic transcripts

what is HOIL-1 deficiency associated with?

hyper inflammation and mild immunodeficiency

what happens when HOIL-1-deficient mice are infected with MHV68?

hyperinflammation

what does latent infection with MHV68 in HOIL-1-deficient mice lead to?

latent MHV68 protects the HOIL-1-deficient mice from otherwise lethal bacterial infection

describe how herpesvirus infections affect disease caused by HOIL-1 deficiency

disease caused by HOIL-1 deficiency may be modified by presence of chronic herpes infection --> therefore there is variability btwn ppl with same immunodeficiency and diff ppl

what is unknown about herpes and inflammation?

is the systemic inflammation induced by herpes really inflammation or is it the normal, basal state of the immune system?

how can inflammation induced by herpes indicate a basal level of inflammation?

if >90% of the human population is infected with herpesvirus, the inflammation caused by virus may reflect the basal inflammation level

3 treatments for herpesvirus

1. acyclovir 2. famiciclovir 3. valacyclovir

how do herpesvirus treatments work? 3 steps

- mimic GUANOSINE 1. drug gets phosphorylated in cells with HSV thymidine kinase 2. but host kinases cannot phosphorylate it 3. acts as chain terminator and binds more tightly to DNA pol to inhibit it