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55 Cards in this Set
- Front
- Back
Why is the presence of intracellular restriction factors an important facet of the innate immune response?
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1) Lack factors necessary for virus
2) Have factors that interfere with the virus |
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What are restriction factors?
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Factors that are found in specific cells and that interfere with the viral cycle
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What are some host cell factors that are adversaries in HIV infection?
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IFNa
ISG15 (Basically different restriction factors) |
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What are some host cell factors that are accomplices in HIV infection?
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CCR5
Annexin III (receptors for the virus help with viral infection) |
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What is an example of a known restriction factor that can limit the replication of a mammalian retrovirus?
How? |
**APOBEC 3F/G
**Main fct: Deaminase |
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Where are APOBEC 3F/G usually found in the body?
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Many tissues
Both of these probably expressed together |
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What is the physiological fct of these APOBECs?
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Retroviral cDNA editing
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How do these 2 APOBECs edit the virus?
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DNA deaminase
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What role does APOBEC play in HIV-1 infection?
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APOBEC-3G inhibits HIV-1 infection
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How does HIV-1 still infect ppl if they have APOBEC?
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HIV-1 has ptn Vif (viral infectivity factor)
Vif suppresses APOBEC 3G |
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What happens if Vif is mutated in the virus?
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No spread of the infection
APOBEC 3G (CEM 15) comes in, incorporates itself into the the virus and deaminates it ==> Stops the spread of the infection |
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What happens if Vif is not mutated?
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Vif targets APOBEC for degradation by poly-UB
Sends APOBEC 3G to the proteasome |
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**What role does APOBEC play in the reverse transcription step of the retroviral genomes?
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APOBEC changes all the C's to U's in the NEGATIVE strand of DNA
When the positive strand is made, A's are put across from the U's (resulting in a G->A hypermutation) |
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What part of the immune response do restriction factors fall under?
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Innate response
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What is an example of a restriction factor?
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APOBEC
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How does APOBEC 3G restrict HIV-1 infection spread?
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Deaminating DNA of the nascent reverse transcript leading to a G --> A hypermutation
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When can APOBEC 3G actually work?
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Only in the absence of Vif
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What does Vif do to APOBEC?
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Sends it for proteasomal degradation
-If VIF is present, recruits APOBEC 3G to the ubiquiting E3 ligase complex, causing the polyUb of the 3G Leads to degradation of APOBEC through the proteasome |
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What kind of mutation of the viral genome is common?
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Hypermutation of G --> A
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What are TRIMs?
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Another kind of restriction factor
They have a difference in their N-terminal, which is important for viral restriction |
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What stage of viral infection do TRIMs 1 & 5 inhibit?
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Early stage: Uncoating
(also small effect on Reverse transcription/trafficking) |
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What stage do TRIMs 19 and 22 affect?
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Inhibit Transcription of the retrovirus
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What does TRIM 32 do?
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Bind Tat (viral ptn), but doesn't do anything
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Where is TRIM5a found?
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Cytoplasmic bodies (dynamic structures)
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What happens when the virus runs into TRIM5a?
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Its recruited to the proteasome and is degraded
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Do all the TRIMs have the same role in retroviral restriction?
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No, they have differential roles in retroviral restriction
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How does TRIM5a restrict HIV-1?
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By targetting its capsid to degradation by the proteasome
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At what step does TRIM5a act?
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Before retroviral transcription (important, since the viral DNA will never be produced)
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What is an example of how TRIMS have differential roles in retroviral restriction?
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TRIM11 plays a role HIV-1 and MLV
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What do TRIM5a variants with activity to HIV-1 do?
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Protect the cell from productive infection
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What was recently found about macTRIM5a mutations?
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Mutation of Arginine 332 on the TRIM5a on macs was enough to allow escape from infection
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What HIV-1 ptn counteracts the activity of host restriction factor Tetherin?
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Vpu ptn
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What does Tetherin do?
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Prevents viral spread
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How does Tetheing fct (what structure)?
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Fcts as a dimer
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How does Vpu target tetherin for degradation?
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Using the B-TrCP2 dependent path
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How does tetherin inhibit the spread of HIV1?
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Tetherin induces the retention of virus like particles (VLPs) at the plasma mb
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What is another way to counteract innate responses?
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Stress granules
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How are stress granules induced?
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Induced by env't stres, etc
Get stalled complexes |
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Can viruses inhibit formation of these stalled granules?
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Yes, many viruses (including HIV-1) can inhibit this granule formation
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What does HIV-1 have that may counter the innate immune response to viral expression?
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Formation of HIV-1 specific RNPs
=> HIV-1 produces different RNPs named SHRNPS: cellular and viral ptns |
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Why is it tha not everyone exposed to HIV is infected?
Why are there some ppl who get a rapid progression of the disease while others are long-term non-progressors? |
Host genetic makeup has an important role
-->Heterogeneity in innate, humoral and CMI responses |
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What is the host determinant that describe this heterogeneity?
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AIDS-restriction genes (ARG)
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What do ARGs depend on?
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Multifactorial, depend on a lot of influences
-->Env't, ppl, background etc |
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Why is CCR5 important for in HIV infection?
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coreceptor for the virus
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What happens if the allele 32 is deleted from CCR5?
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Get a very slow progression to AIDS from HIV (if the deletion is dominant)
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How is CCR5 related to the bubonic plague?
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Yesrinia pestis (causes the bubonic plague) and HIV-1 share the same entry receptor: CCR5
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Why are descendants of plague survivors resistant to HIV-1 infection?
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These ppl inherited the delta32-CCR5 allele
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What is Maraviroc?
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CCR5 inhibitor
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Why are restriction factors important?
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Part of the innate immune response
Can help determine viral tropism |
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Where are restriction factors expressed?
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By host cells that block viral replication at distinct steps of their replication cycle
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What is required for cross-species barriers to infection?
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Activity of several types of host ptns
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What do TRIM5a variants with activity vs HIV-1 do?
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Protecct the cell from productive infection
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What HIV-1 ptn counteracts Tetherin activity?
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Vpu
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What does tetherin do?
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Prevents viral spread by inducing retention of virus-like particles (VLPs) at the plasma mb
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What are some human genes that limit HIV-1 replication?
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Depends on the host genetic makeup
there are ARGs (AIDS-restriction gense) that allow the genetic makeup of the person to restrict HIV-1 infection and replication (These can be genes that encode cell surface receptors, cytokines, MHC or HLA) -->Need to understand how these cellular ptn fcts can be exploited for therapy |