Lecture 28 - HIV vaccine? Flashcards Preview

MIIM20002 - Microbes, Infections, Responses > Lecture 28 - HIV vaccine? > Flashcards

Flashcards in Lecture 28 - HIV vaccine? Deck (56):
1

How many people are currently infected with HIV?

35.3 million

2

How many people have died due to HIV?
Compare this to other things

42 million

Many more than world wars combined, Black death, Influenza outbreaks

3

How many people have been cured from HIV?

Berlin patient: seems to have largely cleared the virus

Atlanta baby: also seems to have cleared the virus

4

Describe the structure of HIV

Icosahedral capsid
- cone shaped
Envelope
Glycoproteins
- envelope spikes
Matrix

5

What is notable about enveloped viruses?

Labile in the environment

6

Describe the genome of HIV

Two copies of RNA genome
Covered by nucleocapsid

7

What is the CA capsid?

This is what makes up the icosahedral capsid of HIV

8

What proteins does HIV make?

1. gag: structural proteins
2. pol: enzymes (reverse transcriptase etc)
3. env: glycoproteins

9

Describe how HIV replicates

1. Surface glycoproteins
2. Fusion
3. Uncoating
4. Reverse transcription
5. Insertion into host genome
6. Transcription and translation
7. Budding

10

Which cells does HIV infect?
Why these cells in particular?

CD4+ T cells
Virus surface proteins bind to CD4 protein

11

What is important about RT?

Reverse transcriptase

Very error prone

One mistake everytime the genome is reverse transcribed

12

What does 'Integrated provirus' mean?

It's genome is inserted into the host genome

13

What are the phases of HIV infection?

• Primary
• Clinical latency
• Symptomatic disease
• AIDS

14

Describe primary infection

• Shortly after infection, lasts a few weeks
• High numbers of circulating virus
• Rapid loss of CD4+ in blood and lymph nodes

15

What happens during clinical latency?

• Virus continues to replicate
• Immune system keeps levels quite low
• Ongoing decline in CD4+ T cells

16

What happens after a number of years of clinical latency?

• Very few CD4+ left
• Immune system no longer able to control opportunistic infections

17

What are the yellow nodules seen in the gut?

Healthy Peyer's patches with lymphocytes

18

What happens to the GALT in HIV+ patients?

• 60% of T cells in GALT are lost within days
• Loss of tight junctions
• Decreased cytokine production

→ increased infection from the GIT

19

Describe the immune response to HIV in general

Initial: After primary infection, the immune response can contain the virus to a certain extent
An equilibrium is reached

Later: HIV escapes immune system

• Immune system depletion

20

What allows HIV to eventually avoid the immune response?

The rapid mutation due to RT
• antibodies can't recognise new clones
• CD8+ doesn't recognise either

21

Describe what happens once the HIV escapes the immune system

Loss of T cells

No help for
• B cells
• macrophages

22

Describe macrophage activity during HIV infection

Decreased:
• phagocytosis
• chemotaxis
• removal of pathogens

23

What sort of infections occur later on?

• Fungal infections
• Sarcomas

24

When do people start to feel sick with HIV infection?

After years of infection

25

What factors affect outcome of infection?

Virus
Immune response
Co-morbidity

26

What are the targets of HIV antivirals?

Replication cycle:
• reverse transcriptase enzyme inhibitors
• protease inhibitors
• integrase inhibitors
• entry inhibitors

27

What sort of things kills HIV+ people nowadays?

Diseases as a result of chronic immune activation
• Liver disease
• Non-AIDS Cancers
• Heart disease

28

What is HAART?

Highly active anti-retroviral therapy

Many antivirals given
Less chance of resistance

Quite expensive

29

Describe the efficacy of HAART

With use of HAART, HIV+ people increase their life span dramatically

Life expectancy only 10 less than HIV- people

30

Describe the goal of UNAIDS

HAART is very expensive, and many people in the third world can't get therapy

This organisation aims to treat 15 million people by 2015

31

What happens when HAART is stopped?

Virus comes back

32

How can we prevent HIV?

- Preventative vaccine -

Treatment
Microbicides
Condoms
Pre-exposure prophylaxis
Voluntary male circumcision

33

What are the pros of treatment as opposed to vaccine development?

• direct
• short time span
• can see the result
• tolerate side effects

34

What are the issues with vaccine development?

• only see the negative effects
• healthy people
• indirect
• no markers
• high risk

35

What are the hurdles for an HIV vaccine?

• deplete natural immune response
• huge diversity
• avoids antibody neutralisation
• avoids NK responses
• avoids T lymphocyte responses
• latency

36

Compare the diversity of HIV with influenza

More diversity in one HIV patient that influenza all over the world

37

What would the ideal HIV vaccine be?

• prevents transmission
• safe, minimal reactions
• single dose
• long lasting
• cheap
• stable
• theraputic

38

What immune responses do we want?

• strong T cell responses
→ CTL kill infected cells
• broad neutralising antibody responses

39

What does neutralising antibody target in HIV?

Envelope proteins, structured trimers

40

What was in the first HIV vaccine?
What types of vaccine were they?

Envelope protein subunit

Virus like particles
Whole inactivated virus

41

What was the STEP trial?

Initially: Strong CD8+ and CD4+ responses

Later in phase III:
• higher rates of infection in vaccine group
• increased viral load

42

What is in the current HIV vaccine?

Live attenuated virus

43

What are the stages in vaccine development?

Phase I
Phase II
Phase III

More and more volunteers in each phase

44

Describe what happened to the B clade vaccine

Didn't get past phase I

Because there was poor CD8+ and CD4+ responses

45

Describe RV144 vaccine

Low expectations

However, 31% efficacy
• lower rates of infection
• some prevention of transmission

46

What did RV 144 tell us about protection from infection?

Protection greatest when treated early in low risk patients

47

What should we focus on while we still don't have a vaccine?

• Minimise transmission
• Microbicides
• Antiretroviral therapy

48

Describe the characteristic of broad neutralising antibodies

• Many mutations
• Long loop to access the epitopes on HIV surface spikes
• self-reactive

49

Describe the efficacy of male circumcision against HIV?

More effective than the most effective vaccine to date

No used in Africa

50

What is viral load?

The amount of virus in an involved body fluid
A measure of severity

51

What is the implication on B cell activity due to CD4+ depletion?

• general increase in antibody
• auto-antibody
• poor response to vaccines
• reduced killing of encapsulated bacteria

52

Which cells of the immune system have reduced function due to HIV infection?

• Neutrophils
• Phagocytes
• Natural Killer cells
• T cells
• B cells

53

Describe the effects of increased immune activation

Leads to other diseases:
• cariovascular disease
• liver disease
• non-AIDS cancers

54

Describe which proteins were used in the 'dead protein' vaccines.

gp120 (which is highly glycosylated)

55

What is the most successful mechanism of preventing transmission to date?
Why?

HAART
• reduces viral load
• reduced inoculum in the community

"Treatment as Prevention"

56

Why is it beneficial that bnAb are self-reactive?

HIV is an 'evolution machine', and has many anitgens that resemble self-antigens.

These antibodies thus recognise these self-antigens on HIV