#7 Retro II Flashcards by Meghan May

For complex retro virus we see 6 accessory proteins of HIV

Vif, Vpr, Vpu, Nef, Tat, Rev

***key for pathogenesisi

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Regulatory Proteins =

crucial for viral replication and are good targets for therapy

Tat and Rev

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Accessory protein thats the transactivator of transcription—absolutely necessary for transcription

Tat:

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Regulator of Virion expression—allows structural gene expression by promoting transport of unspliced RNA from nucleus to cytoplasm

Rev

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Rev does:

Regulator of Virion expression—allows gene expression by promoting transport of unspliced RNA from nucleus to cytoplasm
“rev like reverend… promotes the ‘unholy (unspliced) RNA out of nucleus.. GET THEE OUT of the hold nucleus! !!

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Tat does:

Accessory protein thats the transactivator of transcription—absolutely necessary for transcription
“i’ll buy tat and tat and tat (think transactions!)

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Restriction Factor—viral proteins that overcome cell defenses or ‘restrictions’

Vif

Vpu

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: promotes virion release from cells.. .inhibits host protein ‘tetherin’ that inhbits viral release from cell

Vpu

“viron promotor usher” because he ushers people out

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causes cellular antiviral protein (deoxycytidine deanimase) to be degraded

Vif: Virion Infectivity Factor

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inhibits host protein ‘tetherin’ that inhbits viral relesase from cell

Vpu

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Why does Vif destory deoxycytidine deanimase

otherwise it’s encorporated into new virions where bock RT in next cell by inducing massive mutations in viral dsDNA

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Vif does:

destroys deoxycytidine deanimase bc when if its incorporated into new virions it blocks the RT~~ get bunch of mutations

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IG retroviruses have 1 receptor for HIV ______which is the initial receptor present on immune cells

—CD4

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main population depleated in AIDS

CD4T helpers

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Role of DC cells in HIV
can they bind?
are they infected?

DC can bind HIV but aren’t productivey infected; instead assist with viral dissemination (bring virus back to lymph node where there’s high populatuion of CD4 cells)

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These can be ________infected but not efficiently killed and serve as a reservior of virus produciotn

Macrophages

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***for HIV, CD4 binding is required but NOT sufficient to cause membrane fusion bc

NEED a co-R

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Infection of _______ in the brain infection~contribution to AIDS dementia

Microglia

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see these infect primarily T cells and macrophages but NOT T-cell lines

M-tropic

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a. responsible for initial infection, transmission, and predominates in Asymptomatic ind

M-tropic

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M-tropic infect

T cells and macros but NOT Tcell lines

cause initial infection/transmission/seen in asympotomatic ind

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infects primary T cells and T-cell lines, NOT macrophages

T-Tropic

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associated with disease progression, arise in AIDS stage of infection

T-Tropic

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T-tropic infects which cells

predominates when

primary T cells AND tcell lines but NOT macrohpages

disesease progression… seen during AIDS

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co-recpeotor for M-tropic HIV

CCR5

CCR5 receptor for chemokines: (name 3) can specifically inhibit M-tropic HIV by occupying the receptor

RANTES, MIP-1α, MIPβ—these chemokines

RANTES, MIP-1a, MIPB chemokines work to slow progression of HIV by

inhibiting M-tropic binding to CCR5 co receptor (they bind it themselves

co-receptor for T-Tropic

CXCR4:

natural ligand is cytokine stromal derived factor 1 (SDF-1) that can

block T-tropic HIV infection

What can block T-Tropic infection by competinv for CXCR4

cytokine stromal dereived factor | SDF-1

Basis for strain tropisms

a. Envelope sequence of di HIV types have preference for dif co-receptors b. Most concern is for M-tropic virus bt it is source of person-person transmission

Most concern is for ______ virus bt it is source of person-person transmission

M-tropic

rare ind remain seronegative despite high-risk behavior and presumed viral exposure dt

b. 32bp-depletion of CCR5 gene ∆32 | –see non-funx CCR5 (~10% of caucasions heterozygous and 1%homo)

c. WT: WT

—get infected and progress to disease normally

d. WT:∆32:

get infected and progress to disease more slowly (express ½ as much normal)

e. ∆32:∆32—

highly resistant to infection.. people are normal but don’t have CCR5 expressed on cells

Fusion Process— 1. Env initially contacts_____ and induce a conformation change in Evn 2. Change will cause exposure of the____ 3. _____ ‘fusion domains’ are exposed and fuse

CD4 co-receptor binding site gp41

______ peptides form and instert into cell

Fusion

Co-R engagement triggers a _______ of the N and C terminal helical regions of gp41 which brings membrane together and fuses them

‘snapback’

Fusion process overview

1. Env initially contacts CD4 and induce a conformation change in Evn 2. Change will exposure the co-receptor binding site 3. gp41 ‘fusion domains’ are exposed and fuse 4. Fusion peptides form and inster into cell 5. Co-R engagement triggers a ‘snapback’ of the N and C terminal helical regions of gp41 which brings membrane together and fuses them

How does snapback happen and what is it's purpose

Co-R engagement triggers a ‘snapback’ of the N and C terminal helical regions of gp41 which brings membrane together and fuses them ****like chinese finger trap!!

Can we block this Snapback mechanism?

YES! T20 (Fuzeon) can bind the N-term helical region to block snap-back

T20 (Fuzeon) can

bind the N-term helical region to block snap-back

HIV is IG at the mucosal surface or by blood products and is spread to lymph node via

DC cells biding and carrying HIV there

Once virus infects T cells in lymph nodes (thanks a lot DC cells.. ya fuckers) and spills into circulation causing

viremia

During asymptomatic phase, FCD traps virus, keeps viremia ____ but nodes (especially _____) are major site of replications

low | GALT

deteriorates in late infection

~~ GALT

What traps our virus in asymptomatic phase to viremia low

FCD

Direct killing of CD4 T by HIV is due to | massive reproduction =

mmb leakage and death

Whats the bystander effect to kill cells during HIV | c. Apoptosis induced by infection—some evidence that cells undergo apoptosis even if infection is unproductive

Syncytia (fuse cells) induced by fusion of infected cell w/ unifected cells -via Env or infected cell interacts with CD4/CCR5 on unifected cell); cells usually die and could kill uninfected cells

_____ (fuse cells) induced by fusion of infected cell w/ unifected cells -via Env or infected cell interacts with ______ on unifected cell); cells usually die and could kill uninfected cells

Syncytia | CD4/CCR5

Indirect effects on infected CD4 cells | --immune response

kills infected cells, important for clearing initial viremia

INdirect effects on infected CD4 cells | ________ may bind uninfected cells, now susceptible to ADCC

soluble gp120

Impairment of immune system fnx | CD4 T cell fnx altered, loss of CD4 and T cell help, leads to

severly compromised immune system

What happens to infected macrophages with HIV and ability to work effectively

b. Infected macrophages dysfunctional→ aberrant immune fnx

Acute infection and seroconversion | -initially we see burst of virus production coinciding with:

a. Initial burst of virus production coincides w/ decreased CD4T cells

Acute infection: Early vigorous CTL, subsequent humoral response with FCD help, clears viremia… immune response only ‘appears’ to control infection because

; high level of virus production persists in lymph/GALT

Asymptomatic phase: | contineud strong immune response, gradual decline in ______

CD4 counts | progression measured by CD4 counts and CD4:CD8 ratio

‘vial load’ by measuring _____ by PCR and pts with lower set point have better prognosis

RNA

a lower viral set point of RNA means patient has:

better outcome

Symptomatic/AID phase: late in infection CD4 cells depleted below _____and immune system begins to fail ~~viremia increases, pts suseptible to many opportunisti infections

200

Point of tests to detect HIV

indentify infected person to start tx identify carriers follow course of ts

Serology cannot detct newly infected until

4-6 weeks post infection

Seriology inclucdes Ab Elisa: Ag Elisa Western blot

Ab Elisa~ initial screeing, detect Ab to virus Ag ELISA: detects p24 capside antigen earlier then Ab Western blot: confimation test

Ag ELISA: detects _______earlier then Ab

p24 capside antigen

detects virus in blood

RNA RT-PCR

Use of reat time PCR

quantitateve virus in blood VERY sensitive and detects virus before seroconversion (for high risk/newborns) gauges viral load in asymptomatics at low titers

RT-PCR

RT inhibitor: nucleoside/nonnucleoside analogs:

(AZT ect >16 drugs) a. effective but drug resistant strains appear rapidly (billion virus replication per/day so they are prone to RT errors at 5errors/genome)

Protease inhibotors (>11 drugs):

exteremly effective, reduce viral load by 30-100 x alone, but still see resist.

Fusion inhibitors (T-20) aviable but

$$$$ and must be injected

Entry inhibitors:

Maraviroc—CCR5 co-R antagonist

Raltegravir

Integrase inhibitor

HAART is

Highly Active Anti-Retroviral Therapy | Considereable success of cocktails of triple therapy

a. viritually eliminates virus production in some ind for years w/ undetectable viral load, increase CD4 count and lots of clinical benefit ~~ long term its toxic

HAART

HAART helped us discover replication dynamics of HIV and HIV ½ life estimate time to clear free virus and infected T cells= other ‘compartments’ w/ longer ½ lives like Macrophage or FDC =

2 months (infected T cells) 1-2 years (macrophage of FCD)

Infected memory T cell: long lived, can detect virus from those on HAART for more then

5 years and would need 75 years to clear them!

Issues with HAART

a. not all pts respond to HAART drug regimen is hard to follow (but getting easiert w/ once a day pills) toxic effects seen in long term HAART users ‘inaccessbible’ pool of virus

Effort to devo drugs with less toxicity in the pipeline

New attacment inhibitors or anti-CD4 antibody New CXCR4 and ‘dual receptor’ inhibitors and anti-CCR5 antibody RT inhibitors to common drug resistant viruses New integrase inhibitors Maturation inhibitors that work on gag and gag-pol proteins

Vaccine for HIV

Saw a ‘prime boost’ approach… in thialand~ 30% less liekly to HIV/AIDS (51 if the 8,000) people given the vaccine and 74 of them received dummy shots --responders had a novel, broadly neutralizing antibody; hope is finely tuned vaccine can elicit it

#7 Retro II Flashcards

(80 cards)