Hemaptopoietic VIruses Flashcards
What is the general mechanism of most current antiviral drugs?
they inhibit viral genome replication by mimicing the shape of a nucleotide (or nucleoside) and plugging up the enzymes that replicate the viral genome.
What nucleoside does acyclovir mimic?
guanosine
What must happen to acyclovir for it to be active?
it has to be phosphorylated by viral thymidine kinase
after that, host kinases will continue the process until it can be incorporated
Why does acyclovir only work on cells that are actively proliferating?
Because expression of thymidine kinase only occurs when the cells enter S phase
What does viral pathogenesis involve in the acute phase? In the long term?
acute: cell death and inflammation
long term: malignancies and immune suppression (with opportunistic infections)
How can viruses cause cancer (in general terms)?
they express viral oncogenes that mimic and interact with the host cell’s normal replication machinery and promote uncontrolled cellular proliferation
What are the three stages viral oncogenes can act at?
- the G1-S phase checkpoint
- The regulation of cell death by apoptosis
- the immunological synapse
Activation of what molecule is the first step in progression to S phase?
Cyclin D/CDK4
What signalling pathway controls the cell’s normal apoptotic machinery?
In the mitohcondrial membrane, when Bid makes a complex with Bax, it forms a pore that allows cytochrome C release to the cytoplasm where it activates caspases and causes apoptotic cell death
Which complex opposes the Bid/Bax complex and inhibits cytochrome C release (antiapoptotic)?
Bcl2/Bid
What is the genomic organization of parvovirus
linear ssDNA (group 2)
Does parvovirus have an envelope?
no
What is the capsid symmetry of parvovirus
icosahedral
What is the tropism for parvovirus?
erythroid progenitor cells
How does parvovirus establish infection in the host cell?
- recognizes a p antgien (globoside) on progenitor cells
- binds to it
- internalized through coated pits
How does parvovirus replicate
enters nucleus and forms a hairpin structure which is a self primer for DNA replication
The relationship between the viral protein NS1 and pathogenesis is….
NS1 is a cytotoxic molecule and causes hemolysis of the RBC
A typical clinical presentation of erythema infectiosum is…
fifth’s disease: fever, slapped cheek and lacy rash on extremities
What is the treatment for parvovirus?
There is no effective antiviral, so supportive
Transient aplastic crisis can occur when…
If a person already has a baseline blood disorder and they get parvovirus - they pretty much get a total lack of RBCs
Other conditions caused by parvovirus are…
hydrops faetalis: birth defect causing eye disformity
or chronic anemia in immunosuppressed patients
How is parvovivur diagnosed? aka…what do you do assays for?
immunofluoescence antibody assay - there are three things you can test for: b19 DNA (the earliest detection) or b19 IgM (the usually test - but remains detectable for 3 months after infection), or PCR (detected for years after infection)
Colorado tick fever: genomic organization
segmented dsDNA
Colorado tick fever: enveloped?
naked
Colorado tick fever: capsid symmetry
icosahedral
colorado tick fever: tropism?
erythroblasts
Animal vector for colorado tick fever?
rocky mountain wood tick
Geography and season for colorado tick fever?
high altitudes
march - november (summer basically)
What is the clinical presentation of colorado tick fever?
biphasic fever, myalgia, light sensitivity, rash is uncommon, also uncommon is hemorrhagic disease, meningioencephalitis
What is the substrate of the Dicer/RISC complex for colorado tick fever
dsRNA is cleaved by dicer and then RISC is the thing that binds the complementary ssRNA, which will go to the complementary mRNA to break it down and halt translation
How does CTFV protect its genome from DICER/RISC
RNA replication occurs in cytoplasmatic viral factories - protects it from the complex
CTFV uses the ___ stand of its genome for transcription and as a template for replication of the ___strand.
+RNA of the -RNA strand
CTFV diagnosis?
immunofluorescent antibody test for CTFV IgMs
plus CBC with leukocytopenia and thrombocytopenia
CTFV treatment?
supportive - no effective antiviral
Associated conditions for CTFV?
Rocky mountain fever - very similar clinical presentation (but it’s bacterial)
CMV genomic organization
linear ssDNA
CMV envelope?
yes
CMV capsid symmetric?
icosahedral
CMV tropism? systemic? latent?
epithelial cells as systemic infection (lytic)
Latent in lineage-commited myeloid cells
How does CMV get into the host cell and replicate?
viral gycoproteins bind receptor on host cell and enter by endocytosis
How does CMV evade host immune response?
uses nuclear viral factories and the virus buds out through golgi bodies - so it’s never in contact with cytoplasm
A typical presentation of CMS infections mononucleosis…
same presentation as mono: fever, sore throat, lymphadenopathy, lymphocytosis
What’s the diagnosis for CMS
enzyme linked immuno assay - for protein pp65 found in neutrophils that are infected plus the present of owl eye’s cells in blood smear
What are the associated conditionsf or CMV?
microcephaly with fetal infections
CMV retinitis
hepatosplenomegaly and jaundice and meningioencephalitis
What’s the treatment for uncomplicated CMV infection?
supportive
WHat’s the treatment for severe systemic CMV infections?
ganciclovir
Why is acyclovir not effective against CMV?
CMV doesn’t have thymidine kinase
Human Herpes VIrus - genomic organization?
linear dsDNA
HHV envelope?
yes
HHV capsid symmetry?
icosahedral
HHV tropism?
CD4 T cells
How do HHV 6 and HHV7 differ?
6 - T cells, B cells, and NK -d detected in low levels of saliva
7 - mostly just T lymphocytes, high detection in saliva
WHat does HHV 6 use to enter host cell?
CD46
How does HHV 7 enter the cell?
binds to CD4
Most cases of exanthem subitum (roseola) occur in children of what age?
under 2
What are the symptoms of exanthem subitum?
nonpuritic morbiliform rash, usually on the trunk - always develops after a high fever (this is the happy rash kid)
Treatment for HHV6 or 7?
supportive - acet and ibu for fever
WHat happens in adults?
IT’s more of a mono-like illness.
What can the reactivated infection cause/
encephalitis
In immunocompromised patients, what can happen?
enephalitis, plus all the other normal symptoms
Treatment for severe HHV if encephaitis?
ganciclovir, foscarnet, and cytoforvir
Genomic orgnization of kaposi?
circular dsDNA
Kaposi envelopes? capsid?
yes - icosahedral
What are the malignancies associated with KSV?
Kaposi sarcoma
Primary effusion lymphoma
Multicentric Castleman’s disease
Who are affected by KSV?
People with immune compromise; especially HIV
subsaharan africa, 50% of people are infected
KSV tropism?
B cells
What is vFLIP a homologue of? What does it do?
FLICE (which normally regulate apoptosis by inhibiting it)….so it inhibits apoptosis ,thus causing cancer
What is KSV’s vBcl-2 a homolog of? What does it do?
Bcl-2 of the host cell (duh)
so it also inhibits apoptosis
KSV vGPCR is a homolog of what?
IL6 - which will increase B cell proliferation
KSV’s vCyclin is a homolog of what? what does it do?
host cyclin
so it will go thorugh the G1-S checkpoint and continue proliferating
What’s the treatment for KSV?
Ganciclovir, Cidofir and Foscarnet (just like HHV)
What is ganciclovir?
synthetic analog of 2’ deoxy guanosine that acts as a chain terminator in virally infected cell
What is cidofir?
a monophosphate nucleotide analog - acts as a competitive inhibitor of DNA polymerase to terminate chain
What is foscarnet?
binds to pyrophosphate analog that binding site of DNA polymerases - don’t affect human DNA polymerase at the levels given
What is the genomic organization of human T cell lymphotrophic virus
ssRNA+
Is HTLV enveloped? capsid?
yes - icosahedral
What is the tropism for HTLV? How are HTLV1 and 2 different in this regard?
T cells: HTLV1 does CD4 and HTLV2 does CD8
In what population is HTLV2 most common?
american indians and injection drug users
How does HTLV enter the host cell?
It binds to GLUT-1 on the T cells
How does HTLV become a provirus?
After it enters the host cells, the capsid uncoats and the virally encoded reverse transcriptase creates a DNA copy that is then integrated into the host genome under the influence of viral integrase
What does the transcription factor Tax doe for HTLV?
It upregulates expression of IL-2 and the IL-2 receptor, which induces proliferation of T cells (also protooncogenes c-fas, c-erg and then GM-CSF)
What cancer is associated with HTLV?
acute T-cell lymphoma (ATL)
What is the typical presentation of ATL?
lymphadenopathy, hypercalcemia, lytic bone lesions and cutaneous skin involvement: ranges from papules, nodules, plaques, pathces, and diffuse erythroderma
What is HTLV Associated Myelopathy (HAM)
It’s a chronic progressive demyelinating disease caused by auto-reactivity
What is the typical presentation of HAM?
4th decade of life…sublte onset of progressively stiff gait, gradually progressing to weakness, spasticity, back pain, urinary incontinence, apresthesias, hyperreflexia, clonus, babinski, etc.
