Lecture - Infection and Immunity (HIV)

Question 1

How did HIV originate?

Answer 1

As a zoonotic infection

Question 2

1. What sort of virus is HIV? What is the further family?
2. What sort of envelope does it have? How does this help the virus?
3. What sort of genetic material does it have? And what does each region code for?

Answer 2

1. Retrovirus bc it goes from RNA to DNA
   - family is lentivirus (ny of a group of retroviruses producing illnesses characterized by a delay in the onset of symptoms after infection.)
2. Has a lipid envelope that is has acquired from cell during production of virus - makes it less susceptible to drying out and disinfectants. Also, it hides the antibody binding sites.
3. RNA genome and has two identical single strands with long terminal repeats at the ends. They are used by viruses to insert their genetic material into the host genome. On this RNA, GAG codes for the nucleocapsid (p24), ENV codes for the envelope glycoproteins (gp120 + gp41) annnnnnd POL (in the middle) codes for essential enzymes (integrase, protease and reverse transcriptase). There are also accessory proteins to be coded somewhere.

Question 3

Attachment:

1. What binds with CD4 on the cell surface? On what cells is the CD4 expressed on? Is it high affinity?
2. Then what happens? What is the name of co-receptor? What cells is it present on? What drug targets the co-receptor here?
3. What happens next? What drug can be used here?

Answer 3

1. gp120 binds with the CD4 receptor with high affinity. It is expressed on CD4+ T cells and on some macrophages and dendritic cells
2. Then there is a conformational change allowing binding of gp120 to co-receptor (CCR5 or CCR4). CCR5 is on the memory CD4+ T cells, macrophages, DCs. The CXCR4 are on T cells esp naive cells? idk. But the drug is maraviroc and it is a CCR5 inhibitor
3. Now the gp41 is exposed and the membrane fuses and there is the entry of the nucleocapsid. Enfuvirtide prevents the fusion so no entry

Question 4

What happens once the virus is inside the cell?

Answer 4

There is UNCOATING then the REVERSE TRANSCRIPTASE (that was already packaged in the virus nucleocapsid) will convert the RNA genome into cDNA and then there is the formation of the PRE-INTEGRATION COMPLEX (from the DNA) and then you have NUCLEAR IMPORT (aka it goes into the nucleus). Lastly, you have INTEGRATION of HIV cDNA into host genome by enzyme integrase (also already was packaged earlier). Then you have the formation of a PROVIRUS (the genetic material of a virus as incorporated into, and able to replicate with, the genome of a host cell)

Question 5

Explain the transcription process

• when does the virus transcript?
• how does it happen?
• by what enzyme?

Answer 5

It will only be involved in transcription once it is an integrated provirus and it only happens in activated cells. There is no transcription in resting cells (aka once that aren’t activated - they will only have up to integration).

What happens is that the transcription factors bind to promoters in the viral LTR and with RNA polymerase 2, you form mRNA.

Question 6

Translation:

Explain the process

Answer 6

Gag (nucleocapsid - codes for structural capsid proteins) and pol (codes for essential enzymes) are translated as polyproteins. The Env is translated to make gp160 and cleaved by host protease. Then there is viral assembly and release (aka the virus will get its shut together and bud off)

Then you’ll get maturation of it. The protease is activated with the budding and that will cleave the gag and gag-pol into respective proteins.

Question 7

Transmission - what are the possible ways it is transmitted?

Answer 7

1. Sexual transmission
2. Injection drug use
3. Exposure of blood and blood products via transfusion (although now they test blood so not a big problem)
4. Vertical transmission (mother to fetus/infant) so like through placenta or breast milk

Question 8

Tell me about sexual transmission of HIV

• common/rare?
• transmit easily?
• what enhances transmission?

Answer 8

1. It’s the most common route of HIV transmission
2. It doesn’t actually transmit that easily so like need it in semen or at mucosal surfaces
3. STI enhance transmission bc with STI, you have inflammation so more targets for HIV. You have disruption of mucosal barrier (ulcers) so virus easier to get in

Question 9

Describe the transmission of HIV across mucosal barriers

Answer 9

In the endocervix, rectum, penile urethra there is columnar epithelium. With this, the virus can come through physical abrasion, infection, transcytosis and transcription.

In vagina, ectocervix and foreskin, there is stratified epithelium and virus can get through physical abrasion here.

Question 10

1. What does HIV infect?

2. How is HIV transported to lymphoid tissue?

Answer 10

1. Infects sub-mucosal CD4+ T cells, macrophages and dendritic cells (local amplification)
2. Transport of HIV to lymphoid tissue by infected CD4+ T cells and dendritic cells

Question 11

What is virological synapse?

Answer 11

It’s like when the virus is transmitting from DC to T cell

Question 12

What happens first when you get HIV in terms of CD4+ cell count?

Answer 12

There is a massive depletion of memory CD4+ T cells in the intestine and large numbers of activated CD4+ T cells.

Question 13

Describe the pathogenesis of HIV as on the graph

Answer 13

First part: Early, massive depletion of CD4+ T cells from intestine

• Widespread dissemination of HIV to lymphoid tissues
• Depletion of CD4+ T cells from blood

Clinical latency: Not really any symptoms anymore and this can last for many years so asymptomatic but ongoing viral replication and ongoing CD4 loss. But then CD4 gets too low that you get infections you wouldnt normally get and cancers and of course, AIDS.

There is lots of active invasion going on

Question 14

What does the viral load correspond with?

Answer 14

Decline in viral load corresponds with onset of CD8+ T cell response

Here is infected cell and it’s presenting HIV proteins to niave T cells that recognsie that epitope from MHC-1 and there are upregulatoring co-stimilatory signals and other other sigals will lead to activation of T cells and proifteraiton of them and they’ll recognsie the viral epitope on MHC 1 and then will kill off

Question 15

Why do HIV specific CD8+ T cells fail to control infection?

Answer 15

Okay so remember how CD8 T cells recognise MHC Class 1? Yeah well, mutant epitopes are no longer recognised by the same CD8+ T cells. There is usually a single founder virus that’s transmitted but rapid evolution of virus begins but there is rapid evolution of virus and it begins at the peak of early HIV-specific CD8+ T cell response

Mutation in virus and this selection from immune system leading to multiple epitopes

Basically, there are high rates of mutation, viral turnover and so huge intra-individual diversity

Question 16

Why else does the immune system fail to deal with HIV?

Answer 16

CD4+ T cells help CD8+ cell responses and this help is hella important. If loss of CD4+ T cells then you impair CD8+ T cell responses

Also, CD4+ imp for B cell responses so loss of CD4+ impairs B cell responses (AB imp for neutralisation and AB-dependent cellular cytotoxicity

Question 17

Tell me about the neutralisation of HIV

Answer 17

There are a few conserved broadly neutralising epitopes that exist. Early virus is relatively sensitive to neutralisation (like a few glycosylation sites on gp120). But due to selection pressures, neutralisation sensitive virus is quickly replaced by neutralisation-resistant variants (the glycol shield will prevent binding of neutralising ABs too)

Question 18

Why is there persistent infection despite immune response?

Answer 18

1. You have a high rate of mutation thus get immune escape (from CD8 and B cells)
2. There is a glycol shield that prevents antibody binding to gp120
3. There is loss of CD4+ T cell help for B cells and CD8+ T cells

Question 19

What are cellular reservoirs of HIV infection?

Answer 19

Silent infection like in some CD4, virus integrates but cell not activated so not any transceiption and the immune system cant see it and these resting T cells - when they divide, the HIV remains in genome even in daughter cell and the immune system cant pick it up

In technical terms:

• You have latently infect CD4+ cells aka no expression of antigen so immune system doesn’t know that you have integrated virus
• these latently infected memory cells have long half-life
• HIV replicates when infected T cells are activated

Macrophages and DCs can also be infected by HIV without being killed

Question 20

Treatment suppresses virus but what happens if there is an interruption in treatment?

Answer 20

There is rapid viral rebound

Question 21

Depletion of CD4+ cells leads to what major thing and how do they deplete?

Answer 21

It leads to AIDS and it’sbc CD4+ cells killed by virus, by CD8+ cells and there is decreased production of them (3 things)

So in the symptomatic phase, you’ll see the patient get unusual cancers or get infected by unusual things

Question 22

More about how loss of CD4+ results in immunodeficiency (I think this is to do with AIDS):

1. Macrophages
2. CD8+ T cells
3. B cells

Answer 22

1. TH1 cells provide help to macrophage so the macrophages can get activated and that enhances killing of intracellular bacteria. When you don’t have that help then you have increased susceptibility to intracellular bacterial infection
2. CD4+ cells provide help to CD8+ T cells
   - there is increased susceptibility to intracellular infections (like viral, protozoan and toxoplasmosis) and increased cancer bc immune system can’t remove pre-malignant cells
3. CD4+ cells (especially TH2 cells) provide help to B cells
   - There is then increased susceptibility to mucosal infections