Mimm 466: Lecture 13

Front 1

Why is the presence of intracellular restriction factors an important facet of the innate immune response?

Back 1

1) Lack factors necessary for virus
2) Have factors that interfere with the virus

Front 2

What are restriction factors?

Back 2

Factors that are found in specific cells and that interfere with the viral cycle

Front 3

What are some host cell factors that are adversaries in HIV infection?

Back 3

IFNa
ISG15
(Basically different restriction factors)

Front 4

What are some host cell factors that are accomplices in HIV infection?

Back 4

CCR5
Annexin III
(receptors for the virus help with viral infection)

Front 5

What is an example of a known restriction factor that can limit the replication of a mammalian retrovirus?
How?

Back 5

**APOBEC 3F/G
**Main fct: Deaminase

Front 6

Where are APOBEC 3F/G usually found in the body?

Back 6

Many tissues
Both of these probably expressed together

Front 7

What is the physiological fct of these APOBECs?

Back 7

Retroviral cDNA editing

Front 8

How do these 2 APOBECs edit the virus?

Back 8

DNA deaminase

Front 9

What role does APOBEC play in HIV-1 infection?

Back 9

APOBEC-3G inhibits HIV-1 infection

Front 10

How does HIV-1 still infect ppl if they have APOBEC?

Back 10

HIV-1 has ptn Vif (viral infectivity factor)
Vif suppresses APOBEC 3G

Front 11

What happens if Vif is mutated in the virus?

Back 11

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

Front 12

What happens if Vif is not mutated?

Back 12

Vif targets APOBEC for degradation by poly-UB
Sends APOBEC 3G to the proteasome

Front 13

**What role does APOBEC play in the reverse transcription step of the retroviral genomes?

Back 13

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)

Front 14

What part of the immune response do restriction factors fall under?

Back 14

Innate response

Front 15

What is an example of a restriction factor?

Back 15

APOBEC

Front 16

How does APOBEC 3G restrict HIV-1 infection spread?

Back 16

Deaminating DNA of the nascent reverse transcript leading to a G --> A hypermutation

Front 17

When can APOBEC 3G actually work?

Back 17

Only in the absence of Vif

Front 18

What does Vif do to APOBEC?

Back 18

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

Front 19

What kind of mutation of the viral genome is common?

Back 19

Hypermutation of G --> A

Front 20

What are TRIMs?

Back 20

Another kind of restriction factor
They have a difference in their N-terminal, which is important for viral restriction

Front 21

What stage of viral infection do TRIMs 1 & 5 inhibit?

Back 21

Early stage: Uncoating
(also small effect on Reverse transcription/trafficking)

Front 22

What stage do TRIMs 19 and 22 affect?

Back 22

Inhibit Transcription of the retrovirus

Front 23

What does TRIM 32 do?

Back 23

Bind Tat (viral ptn), but doesn't do anything

Front 24

Where is TRIM5a found?

Back 24

Cytoplasmic bodies (dynamic structures)

Front 25

What happens when the virus runs into TRIM5a?

Back 25

Its recruited to the proteasome and is degraded

Front 26

Do all the TRIMs have the same role in retroviral restriction?

Back 26

No, they have differential roles in retroviral restriction

Front 27

How does TRIM5a restrict HIV-1?

Back 27

By targetting its capsid to degradation by the proteasome

Front 28

At what step does TRIM5a act?

Back 28

Before retroviral transcription (important, since the viral DNA will never be produced)

Front 29

What is an example of how TRIMS have differential roles in retroviral restriction?

Back 29

TRIM11 plays a role HIV-1 and MLV

Front 30

What do TRIM5a variants with activity to HIV-1 do?

Back 30

Protect the cell from productive infection

Front 31

What was recently found about macTRIM5a mutations?

Back 31

Mutation of Arginine 332 on the TRIM5a on macs was enough to allow escape from infection

Front 32

What HIV-1 ptn counteracts the activity of host restriction factor Tetherin?

Back 32

Vpu ptn

Front 33

What does Tetherin do?

Back 33

Prevents viral spread

Front 34

How does Tetheing fct (what structure)?

Back 34

Fcts as a dimer

Front 35

How does Vpu target tetherin for degradation?

Back 35

Using the B-TrCP2 dependent path

Front 36

How does tetherin inhibit the spread of HIV1?

Back 36

Tetherin induces the retention of virus like particles (VLPs) at the plasma mb

Front 37

What is another way to counteract innate responses?

Back 37

Stress granules

Front 38

How are stress granules induced?

Back 38

Induced by env't stres, etc
Get stalled complexes

Front 39

Can viruses inhibit formation of these stalled granules?

Back 39

Yes, many viruses (including HIV-1) can inhibit this granule formation

Front 40

What does HIV-1 have that may counter the innate immune response to viral expression?

Back 40

Formation of HIV-1 specific RNPs
=> HIV-1 produces different RNPs named SHRNPS: cellular and viral ptns

Front 41

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?

Back 41

Host genetic makeup has an important role
-->Heterogeneity in innate, humoral and CMI responses

Front 42

What is the host determinant that describe this heterogeneity?

Back 42

AIDS-restriction genes (ARG)

Front 43

What do ARGs depend on?

Back 43

Multifactorial, depend on a lot of influences
-->Env't, ppl, background etc

Front 44

Why is CCR5 important for in HIV infection?

Back 44

coreceptor for the virus

Front 45

What happens if the allele 32 is deleted from CCR5?

Back 45

Get a very slow progression to AIDS from HIV (if the deletion is dominant)

Front 46

How is CCR5 related to the bubonic plague?

Back 46

Yesrinia pestis (causes the bubonic plague) and HIV-1 share the same entry receptor: CCR5

Front 47

Why are descendants of plague survivors resistant to HIV-1 infection?

Back 47

These ppl inherited the delta32-CCR5 allele

Front 48

What is Maraviroc?

Back 48

CCR5 inhibitor

Front 49

Why are restriction factors important?

Back 49

Part of the innate immune response
Can help determine viral tropism

Front 50

Where are restriction factors expressed?

Back 50

By host cells that block viral replication at distinct steps of their replication cycle

Front 51

What is required for cross-species barriers to infection?

Back 51

Activity of several types of host ptns

Front 52

What do TRIM5a variants with activity vs HIV-1 do?

Back 52

Protecct the cell from productive infection

Front 53

What HIV-1 ptn counteracts Tetherin activity?

Back 53

Vpu

Front 54

What does tetherin do?

Back 54

Prevents viral spread by inducing retention of virus-like particles (VLPs) at the plasma mb

Front 55

What are some human genes that limit HIV-1 replication?

Back 55

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