Rabson - HIV And AIDS

Question 1

What is AIDS

Answer 1

Profound immunodeficiency leading to development of opportunistic infections such as bacterial, fungal, protozoan, and viral
Also increased number of malignancies

Question 2

What is the cause of AIDS

Answer 2

Infection with HIV

Question 3

What is the rate of disease progression influenced by?

Answer 3

Host genetic makeup
Viral genome
Co-factors such as other infections
Host immune response

Question 4

How is HIV spread

Answer 4

Contact with bodily fluids

• sex
• blood products
• sharing of needles
• perinatal infection during delivery

Question 5

How do you diagnose HIV

Answer 5

ELISA or PCR with confirmation then by western blot.

- the issue is that there is a window of insensitivity post-infection for about 30 days but could be longer.

Question 6

How does the western blot work?

Answer 6

They lyse the patients cells that are suspected to be infected with HIV and then incubate it with antibodies from a patient who had HIV and made the proper antibodies. If the patient has HIV, they will have those HIV proteins (Env, Gag, Pol, etc.) and then the antibodies will bind to them.

Question 7

when would you test someone for HIV

Answer 7

• clinical suspicion

- everyone should be tested at least once at some point

Question 8

What is the shape of the HIV virion?

Answer 8

Conical shaped

Question 9

Why is HIV so difficult to completely cure?

Answer 9

The provirus can remain latent in the cell for a very long time so even if you could kill the viruses, you can’t really get the virus DNA that is in the various cells.

Question 10

NF-kB

Answer 10

Master regulator of immunity and inflammation but it is also a regulator of the HIV provirus.
- so, every time the immune system gets revved up, the HIV provirus gets transcribed more often as well.

Question 11

Tat

Answer 11

Strong activator of HIV transcription.

• it binds to “TAR” RNA at the 5’ end of the HIV RNAs
• this then activates transcription through recruitment of various cell proteins that cause increased phosphorylation of the tail of RNA pol-II and increases the transcription of the RNA.

Question 12

Rev

Answer 12

promotes nuclear export of large unsliced or singly spliced RNAs

• it is essentially the “go to jail” card in immediately. You stop what you are doing and leave the nucleus.
• without Rev, the transcript will get spliced into a million small pieces.

Question 13

Regulation of RNA export through Rev

Answer 13

Basically in the beginning there is not that much Rev made, so almost all of the proteins made are small and are required for RNA transcription (Rev, Tat, and Nef). Once Rev is made now, it can go back and ensure that longer RNA strands are made.

Question 14

Rev mechanism

Answer 14

Basically Rev exports the long RNA directly to the nuclear pore.

Question 15

Nef

Answer 15

2 main roles:

• increased infectivity of the virus particles
• inhibiting anti-HIV immune response

It is required for the disease development. People who hate Nef mutants are non-progressors.

Question 16

How does Nef inhibit anti-HIV immune response

Answer 16

• Down regulates cell surface proteins such as MHC1

- down-regulates surface CD4 levels (less important)

Question 17

Vif

Answer 17

Viral infectivity factor

• strongly enhances replication of virus in primary cells by inhibiting a cellular antiviral protein called “APOBEC3G”.
• Vif binding to APOBEC3G causes proteosomal degradation to occur leading to virion incorporation.

Question 18

APOBEC3G

Answer 18

Innate cellular defense that is inhibited by Vif.

• it is a cytosine deaminase against ssDNA, and leads to massive mutations of the viral DNA and thus degradation.
• when Vif binds it is degraded proteosomally.

Question 19

VPU

Answer 19

Counteracts the action of tetherin.
- usually when a virus particle is going to bud off of the cell, a protein called tetherin holds onto the virus particle with dear life and then sequesters it back into the cytosol. VPU counteracts the action of Tetherin.

Question 20

What cells does HIV target?

Answer 20

CD4+ T cells

Monocytes and macrophages

Question 21

What type of cells does HIV have a preference for?

Answer 21

Activated T cells because then there are more targets.

- increased nucleotide pool

Question 22

How exactly does HIV cause death of CD4+ T cells?

Answer 22

• direct killing by cytopathic infection - virus just kills the cell
• immune “exhaustion” - in chronic immune response, the normal T cells can become exhausted from fighting the HIV infection and just die
• immune destruction of infected cells - immune restriction of infected cells that haven’t yet produced virus but did put virus proteins on their surface. CTLs will kill them
• death of bystander cells - HIV toxic gene products such as envelope or Tad can cause killing of cell

Question 23

How does one get HIV Encephalopathy

Answer 23

infection of monocytes and/or microglia - causes pro-inflammatory cytokines release in CNS, which causes Pathogenesis.

Question 24

HIV infection of dendritic cells

Answer 24

Dendritic cells can be infected or they can carry HIV to CD4 T cells on the surface or to the lymphoid tissue.

Question 25

HIV Pathogenesis timeline

Answer 25

1) primary infection (first few days) leads to initial rise in HIV RNA copies and initial drop in CD4+ T cells (Very infectious at this time)
2) Over the course of the next few weeks the NK cells, CTLs, and then neutralizing antibodies kick in and the viral load begins to decrease dramatically.
3) eventually their is a clinical latency period where the CD4+ numbers stabilize and the HIV RNA numbers stabilize to almost undetectable levels.
4) Then, things start to happen and the CD4 cell count decreases rapidly and viral production goes way up so numbers are high in the blood. CD4+ cells go way down too. This can cause opportunistic disease and possibly death.

Question 26

Acute HIV infection

Answer 26

Mononucleosis-like symptoms

Associated with high levels of HIV particles in the blood.

Question 27

Early HIV infection

Answer 27

Breaches the mucosal barrier with infection of a small founder population, which then explodes in the lymphoid tissue. This causes a massive depletion of memory CD4+CCR5+ T cells mostly in the gut.

Question 28

Initial immune response to HIV

Answer 28

Initial NK cell activity
Antibody production doesn’t start till 3-7 weeks though and by that time it has already taken up home in the lymph nodes and there is already viremia.
CTL is initially effective.

Question 29

A symptomatic period of HIV infection

Answer 29

Clearance of virus from the blood to low set point of HIV levels.

• but remember, the HIV is still replicating in the lymphoid tissue
• although at t his point they may be clinically latent they may not be virologically latent because the provirus is still integrated into the cells and is just chilling there.

Question 30

What’s the area of the HIV virus that the neutralizing antibodies act on? What is important about this region?

Answer 30

V3 region of the envelope
- this region is very variable though so we can’t really give antibodies against it because the region is so variable each time.

Question 31

Factors in HIV progression

Answer 31

Levels of viral replication

• levels of CD4 tells you where you are in the infection - whether you are early, latent, or asymptomatic
• HIV RNA blood levels predict where you are going.

Immune response to HIV

Development of viral variants

Role of co-factors that may increase viral replication

Question 32

with regards to co-receptors what is the early one and what is the late one?

Answer 32

• In early infections, the co-receptor is CCR5 and usually affects monocytes and memory T cells.
• eventually there is emergence of CXCR4-binding viruses late in the disease. These kill T cells

Question 33

HAART therapy

Answer 33

Antiretroviral therapy

• biphasic decay curve where initially three is rapid decay and then there is slower decay.
• once you stop the drugs the virus comes back because it doesn’t affect the reservoirs.

Question 34

Issues with making A HIV vaccine

Answer 34

• correlated of protective immunity is slowly being defined
• genetic diversity especially within envelope variability
• latent reservoir means you need to block the initial infection
• what is an acceptable animal model? Acceptable protection rate? Can’t use live attenuated vaccines.