L21- Acquired Immunodeficiency Syndrome (AIDS) Flashcards
History of AIDS
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
What are differences between HIV-1 and HIV-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
What does HIV virus cause in primates and humans?
Primates- doesn’t cause disease for them
Humans- untreated infection leads to death following clinical latency of 7-12 years
Describe HIV virus
- 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.
How do the spike proteins help HIV evade the immune system?
around 14 surface spikes per virion on HIV which makes it harder for an antibody to cross-link it.
HIV transmission?
- 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)
Which cells does HIV infect?
HIV infects cells expressing CD4:
CD4 T cells
Monocytes/macrophages
Dendritic cells
How does HIV attach to the cell?
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.
If a virus binds to CCR5 what is it known as?
What type of cells will the virus have a preference for?
R5-tropic
The type of cells it will have a preference for are: activated effector/memory CD4 T cells, immature DCs, monocytes/macrophages)
If a virus binds to CXCR4 what is it known as?
What type of cells will the virus have a preference for?
X4-tropic
Have a preference for:
naive CD4 T cells, mature DCs
When a virus enters a host what do they tend to be?
What do they become?
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.
When are viruses more likely to get across epithelial barrier?
Few viruses will make it across an intact epithelial barrier but transmission rate is increased if the mucosal barrier is damaged.
What are the steps in trasmission?
- Through epithelial barrier
- Local propagation in a few cells
- Transfer to draining Lymph nodes, rich source of T cells and so rapid rise in viral production
- systemic dessimation-> peak viral load in plasma, massive killing of CD4+ memory T cells in gut (GALT)
Once the virus has been transmitted and gone through the systemic dessimation phase, why is the immune system too late?
The virus has established a latent reservoir and it is now a self-sustaining infection
HIV replication cycle
7 steps
- Fusion of HIV to host cell (gp41 mediates fusion)
- Viral proteins enter the host cell
- Viral DNA is formed by reverse transcriptase
- Viral DNA is transported across the nucleus and integrates into host DNA. (as a provirus)
- New viral RNA is used as genomic RNA and to make viral proteins.
- New viral RNA and proteins move to the cell surface and a new, immatue HIV forms.
- The virus matures by protease releasing indivudal HIV proteins.
How many errors are made in replication?
About 1 error per genome, so mutates quickly.
What are the features of HIV replication which make it difficult for immune system to completely clear the virus?
- high replication rate
- high mutation rate
- can hide from the immune system for long periods as a provirus (latent reservoir)
What is the HIV genome flanked by?
By LTR regions. So this will be incorporated into the DNA.
What are the main features of HIV genome?
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
What happens to CD4+ counts during the disease?
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.
What’s the basis of the majority of the HIV tests?
Seeing HIV-specific antibodies in the blood plasma. This is really high from the asymptomatic stage onwards
Describe what happens to levels of the virus, t cells and antibody over the course fo infection? (start)(best to look at slide graph)
- Rapid early viral replication. Large early loss of GALT T memory cells.
- Activation of virus specific CTL-> depletion of infected CD4 T cells.
- 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.
- Antibody response later- due to high variation of the virus the epitopes may no longer be present to be bound to
- Asymptomatic phase is dynamic! Get lots of virus replication and provirus activation
- Slow decline of T cells
What happens in the immunological course of infection at the end of the asymptomatic period?
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.
What are the 3 types of people in terms of progression of the virus?
- Progressors= high viral set-point, progress to aids quickly
- Viraemic Controllers= low viral set-point, progress to AIDS more slowly
- Elite Controllers= very rare, control virus to extremely low levels, do not progress to AIDS
