L21- Acquired Immunodeficiency Syndrome (AIDS)

Question 1

History of AIDS

Answer 1

1981- Unusual infections observed in US. Individuals with the disease had low numbers of CD4+ T cells.
(certain groups of people: homosexuals, drug users, blood transfusions)

1982- Named it AIDs
1983- HIV1 found
1986- HIV2 found

Question 2

What are differences between HIV-1 and HIV-2?

Answer 2

HIV1= from chimpanzees, more virulent, responsible for most of AIDS worldwide
(4 strains. M= main group)

HIV2= from sooty managabey, less virulent, western Africa

Question 3

What does HIV virus cause in primates and humans?

Answer 3

Primates- doesn’t cause disease for them

Humans- untreated infection leads to death following clinical latency of 7-12 years

Question 4

Describe HIV virus

Answer 4

• RNA genome
• nucleocaspid core which has reverse transcriptase, protease and integrase inside as well as the genome, to allow it to invade and replicate.
• Surrounded by a lipid membrane which has viral proteins spiking out made of gp120env and gp41. (spike proteins)
• within membrane also have host MHC protein, complement receptors to evade host immune system.

Question 5

How do the spike proteins help HIV evade the immune system?

Answer 5

around 14 surface spikes per virion on HIV which makes it harder for an antibody to cross-link it.

Question 6

HIV transmission?

Answer 6

• Primarily by bodily fluids.
• Major route of entry via mucosal surfaces of genitals and GI tract.
• This is the site of intense early viral replication.

(also vertically mother to child)

Question 7

Which cells does HIV infect?

Answer 7

HIV infects cells expressing CD4:
CD4 T cells
Monocytes/macrophages
Dendritic cells

Question 8

How does HIV attach to the cell?

Answer 8

The gp120 from the spike protein attaches onto CD4.
This isn’t enough. This causes a conformational change which allows its co-receptor to bind.
The co-receptor can be one of two chemokine receptors: CCR5 or CXCR4 on cell.

Question 9

If a virus binds to CCR5 what is it known as?

What type of cells will the virus have a preference for?

Answer 9

R5-tropic

The type of cells it will have a preference for are: activated effector/memory CD4 T cells, immature DCs, monocytes/macrophages)

Question 10

If a virus binds to CXCR4 what is it known as?

What type of cells will the virus have a preference for?

Answer 10

X4-tropic

Have a preference for:
naive CD4 T cells, mature DCs

Question 11

When a virus enters a host what do they tend to be?

What do they become?

Answer 11

Founder viruses tend to be R5.
(bind to CCR5 receptor).

As the infection progresses, the HIV undergoes a lot of mutations and tends to switch from being R5-tropic to X4-tropic.

Question 12

When are viruses more likely to get across epithelial barrier?

Answer 12

Few viruses will make it across an intact epithelial barrier but transmission rate is increased if the mucosal barrier is damaged.

Question 13

What are the steps in trasmission?

Answer 13

1. Through epithelial barrier
2. Local propagation in a few cells
3. Transfer to draining Lymph nodes, rich source of T cells and so rapid rise in viral production
4. systemic dessimation-> peak viral load in plasma, massive killing of CD4+ memory T cells in gut (GALT)

Question 14

Once the virus has been transmitted and gone through the systemic dessimation phase, why is the immune system too late?

Answer 14

The virus has established a latent reservoir and it is now a self-sustaining infection

Question 15

HIV replication cycle

7 steps

Answer 15

1. Fusion of HIV to host cell (gp41 mediates fusion)
2. Viral proteins enter the host cell
3. Viral DNA is formed by reverse transcriptase
4. Viral DNA is transported across the nucleus and integrates into host DNA. (as a provirus)
5. New viral RNA is used as genomic RNA and to make viral proteins.
6. New viral RNA and proteins move to the cell surface and a new, immatue HIV forms.
7. The virus matures by protease releasing indivudal HIV proteins.

Question 16

How many errors are made in replication?

Answer 16

About 1 error per genome, so mutates quickly.

Question 17

What are the features of HIV replication which make it difficult for immune system to completely clear the virus?

Answer 17

1. high replication rate
2. high mutation rate
3. can hide from the immune system for long periods as a provirus (latent reservoir)

Question 18

What is the HIV genome flanked by?

Answer 18

By LTR regions. So this will be incorporated into the DNA.

Question 19

What are the main features of HIV genome?

Answer 19

9 genes
3 gene products are proteolytically active

host transcription factors such as NFkb and NFAT upregulated in activated cells, bind to the LTR-> activates of transcription of latent viral RNA by host RNA polymerase II

Question 20

What happens to CD4+ counts during the disease?

Answer 20

In flu-like disease at first the cd4 cell is dramatically reduced and then goes up a bit and goes into latent asymptomatic stage. Slow loss of cd4 cells over about 10 years. Then when they’re pretty low-> symptomatic phase. will see opportunistic diseases e.g. thrush.
When they’re really low. Under 200 per microlitre-> AIDS.

Question 21

What’s the basis of the majority of the HIV tests?

Answer 21

Seeing HIV-specific antibodies in the blood plasma. This is really high from the asymptomatic stage onwards

Question 22

Describe what happens to levels of the virus, t cells and antibody over the course fo infection? (start)(best to look at slide graph)

Answer 22

1. Rapid early viral replication. Large early loss of GALT T memory cells.
2. Activation of virus specific CTL-> depletion of infected CD4 T cells.
3. After initial peak of viral load, it’s contained by immune responses so get viral set-point, stays relatively low for the 10 year asymptomatic period. and get moderate rebound of CD4 T cells. recovery is poor in the GALT.
4. Antibody response later- due to high variation of the virus the epitopes may no longer be present to be bound to
5. Asymptomatic phase is dynamic! Get lots of virus replication and provirus activation
6. Slow decline of T cells

Question 23

What happens in the immunological course of infection at the end of the asymptomatic period?

Answer 23

Eventually there is a collapse of CD4 counts and loss of CD4 function. Both impact help for CTLs and B cells.
Virus is no longer contained- s increase in viral levels.

Question 24

What are the 3 types of people in terms of progression of the virus?

Answer 24

1. Progressors= high viral set-point, progress to aids quickly
2. Viraemic Controllers= low viral set-point, progress to AIDS more slowly
3. Elite Controllers= very rare, control virus to extremely low levels, do not progress to AIDS

Question 25

What genetic features have been associated with controllers that rarely progress?

Answer 25

CCR5-delta32= highly resistant to infection

because deletion in that protein so the HIV can’t bind to it so hard for it to enter

Question 26

What study was a “cure” for HIV?

Answer 26

Man had HIV and leukaemia. Bone marrow stem cell transplant from someone who was homozygous CCR5 Delta32.
The patient stopped antirviral therapy and still remained without viral rebound for 20 months. So shows how important ccr5 is in maintaining HIV-1 infection

Question 27

What do anti-retroviral drugs do?

Answer 27

These drugs act on viral proteins essential for viral spread

Question 28

Examples of anti-retroviral drugs?

Answer 28

Highly Active Anti-Retroviral Therapy (HAART)

Combinations of: Viral protease inhibitors, reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, co-receptor binding inhibitors

Question 29

What will failure to maintain anti-retroviral drug treatment allow?

Answer 29

Allows REBOUND of virus and return to loss of CD4+ T cell counts

Question 30

What is HAART used for?

Answer 30

Interfere with and significantly delay progression to AIDS within an infected individual.

Reduced viral load decreases the chances of transmission between couples and vertical transmission to child

Question 31

The Mississipi infant

Answer 31

Baby with HIV given drugs.
Parents stopped giving it drugs.
After 12 months of not taking the drugs there was no viral rebound in the babby.
However at 27.9 months after stopped taking it there was a rebound. Latency is big issue

Question 32

What is shock and kill therapy?

Answer 32

Idea to combat latency where you drive activation of all the infected resting cells that make up the Latent reservoir so that all the hidden virus is exposed to anti-retroviral drug therapy and cleared.

Doesn’t seem to work atm

Question 33

What did the RV114 Prime-boost strategy do to provide some protection as a vaccine?

Answer 33

Increased HIV-specific IgG3 antibody against a consevred region of the v1v2 loops of gp120 (involved in interaction for entry).

the antibodies did not block entry
they did bind to the surface of HIV infected cells and mediate Fc dependent antiviral activities e.g. ADCC and phagocytic uptake