18. Herpesvirus 2 Flashcards
oncogenic EBV - 3 types
- many animal herpesviruses are oncogenic
- African Burkitt’s lymphoma
- Nasopharyngeal carcinoma in East Asian people
example of oncogenic animal herpesvirus
Marek’s disease virus in chickens –> must vaccinate chickens
indication of burkitt’s lymphoma and nasopharyngeal carcinoma
both are positive for episomal EBV DNA and EBV-specific antigens
is EBV infection required for malignancy?
yes, but infection alone will not cause malignancy
what 2 other things contribute to malignancy of EBV
- genetics
- Malaria
what happens in infectious mono?
polyclonal increase in both B and T lymphocytes
what happens early in mono?
B/T ratio = 4:1
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
what happens later in mono?
T/B ratio = 4:1
why are there more T cells later in mono?
cytotoxic lymphocytes kill EBV-infected B cells
what happens normally with EBV-induced infectious mononucleosis?
normally, polyclonal B cell lymphocytic leukemia lymphoma which can be controlled by immune system
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
when does EBV infection occur in organ transplant patients and treatment
normally occurs long after transplant –> can only treat by stopping immunosuppressive drugs
describe attachment of HSV to cell surface
NON-SPECIFIC btwn proteoglycans of cell surface and virus glycoprotein C
how does HSV enter the cell?
fusion
what happens once HSV fuses into cell?
viral capsid migrates to nuclear pores along cellular microtubules with cellular transport machinery
how does HSV genome enter nucleus?
viral DNA is injected thru a pore while capsid proteins remain in cytoplasm
does HSV encode its own RNA pol?
yes, part of late gene
are herpes viruses old or young? age?
OLD –> 400 million years old
where are herpes virus found?
EVERYWHERE! and many different types
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)
- virus enters neurons at periphery and genome travels up axon to neuronal nucleus
- virus replications and destroys some neurons, but most neurons survive
- viral genome as an EPISOME becomes associated with host histones and forms MINI-CHROMOSOMES
- viral gene expression remains absent during latent infection
- 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?
no
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?
- altered autophagy in macrophages
- altered HOIL-1 expression
- 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
- acyclovir
- famiciclovir
- valacyclovir
how do herpesvirus treatments work? 3 steps
- mimic GUANOSINE
- drug gets phosphorylated in cells with HSV thymidine kinase
- but host kinases cannot phosphorylate it
- acts as chain terminator and binds more tightly to DNA pol to inhibit it
