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

Lecture 28 - HIV vaccine? Flashcards

1
Q

How many people are currently infected with HIV?

A

35.3 million

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2
Q

How many people have died due to HIV?

Compare this to other things

A

42 million

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

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3
Q

How many people have been cured from HIV?

A

Berlin patient: seems to have largely cleared the virus

Atlanta baby: also seems to have cleared the virus

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4
Q

Describe the structure of HIV

A 
Icosahedral capsid
- cone shaped
Envelope
Glycoproteins
- envelope spikes
Matrix
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5
Q

What is notable about enveloped viruses?

A

Labile in the environment

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6
Q

Describe the genome of HIV

A

Two copies of RNA genome

Covered by nucleocapsid

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7
Q

What is the CA capsid?

A

This is what makes up the icosahedral capsid of HIV

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8
Q

What proteins does HIV make?

A
  1. gag: structural proteins
  2. pol: enzymes (reverse transcriptase etc)
  3. env: glycoproteins
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9
Q

Describe how HIV replicates

A
  1. Surface glycoproteins
  2. Fusion
  3. Uncoating
  4. Reverse transcription
  5. Insertion into host genome
  6. Transcription and translation
  7. Budding
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10
Q

Which cells does HIV infect?

Why these cells in particular?

A

CD4+ T cells

Virus surface proteins bind to CD4 protein

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11
Q

What is important about RT?

A

Reverse transcriptase

Very error prone

One mistake everytime the genome is reverse transcribed

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12
Q

What does ‘Integrated provirus’ mean?

A

It’s genome is inserted into the host genome

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13
Q

What are the phases of HIV infection?

A
  • Primary
  • Clinical latency
  • Symptomatic disease
  • AIDS
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14
Q

Describe primary infection

A
  • Shortly after infection, lasts a few weeks
  • High numbers of circulating virus
  • Rapid loss of CD4+ in blood and lymph nodes
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15
Q

What happens during clinical latency?

A
  • Virus continues to replicate
  • Immune system keeps levels quite low
  • Ongoing decline in CD4+ T cells
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16
Q

What happens after a number of years of clinical latency?

A
  • Very few CD4+ left

* Immune system no longer able to control opportunistic infections

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17
Q

What are the yellow nodules seen in the gut?

A

Healthy Peyer’s patches with lymphocytes

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18
Q

What happens to the GALT in HIV+ patients?

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

→ increased infection from the GIT

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19
Q

Describe the immune response to HIV in general

A

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

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20
Q

What allows HIV to eventually avoid the immune response?

A

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

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21
Q

Describe what happens once the HIV escapes the immune system

A

Loss of T cells

No help for
• B cells
• macrophages

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22
Q

Describe macrophage activity during HIV infection

A

Decreased:
• phagocytosis
• chemotaxis
• removal of pathogens

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23
Q

What sort of infections occur later on?

A
  • Fungal infections

* Sarcomas

24
Q

When do people start to feel sick with HIV infection?

A

After years of infection

25
Q

What factors affect outcome of infection?

A

Virus
Immune response
Co-morbidity

26
Q

What are the targets of HIV antivirals?

A 
Replication cycle:
• reverse transcriptase enzyme inhibitors
• protease inhibitors
• integrase inhibitors
• entry inhibitors
27
Q

What sort of things kills HIV+ people nowadays?

A

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

28
Q

What is HAART?

A

Highly active anti-retroviral therapy

Many antivirals given
Less chance of resistance

Quite expensive

29
Q

Describe the efficacy of HAART

A

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

Life expectancy only 10 less than HIV- people

30
Q

Describe the goal of UNAIDS

A

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
Q

What happens when HAART is stopped?

A

Virus comes back

32
Q

How can we prevent HIV?

A
  • Preventative vaccine -
Treatment
Microbicides
Condoms
Pre-exposure prophylaxis
Voluntary male circumcision
33
Q

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

A
  • direct
  • short time span
  • can see the result
  • tolerate side effects
34
Q

What are the issues with vaccine development?

A
  • only see the negative effects
  • healthy people
  • indirect
  • no markers
  • high risk
35
Q

What are the hurdles for an HIV vaccine?

A
  • deplete natural immune response
  • huge diversity
  • avoids antibody neutralisation
  • avoids NK responses
  • avoids T lymphocyte responses
  • latency
36
Q

Compare the diversity of HIV with influenza

A

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

37
Q

What would the ideal HIV vaccine be?

A
  • prevents transmission
  • safe, minimal reactions
  • single dose
  • long lasting
  • cheap
  • stable
  • theraputic
38
Q

What immune responses do we want?

A

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

39
Q

What does neutralising antibody target in HIV?

A

Envelope proteins, structured trimers

40
Q

What was in the first HIV vaccine?

What types of vaccine were they?

A

Envelope protein subunit

Virus like particles
Whole inactivated virus

41
Q

What was the STEP trial?

A

Initially: Strong CD8+ and CD4+ responses

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

42
Q

What is in the current HIV vaccine?

A

Live attenuated virus

43
Q

What are the stages in vaccine development?

A

Phase I
Phase II
Phase III

More and more volunteers in each phase

44
Q

Describe what happened to the B clade vaccine

A

Didn’t get past phase I

Because there was poor CD8+ and CD4+ responses

45
Q

Describe RV144 vaccine

A

Low expectations

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

46
Q

What did RV 144 tell us about protection from infection?

A

Protection greatest when treated early in low risk patients

47
Q

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

A
  • Minimise transmission
  • Microbicides
  • Antiretroviral therapy
48
Q

Describe the characteristic of broad neutralising antibodies

A
  • Many mutations
  • Long loop to access the epitopes on HIV surface spikes
  • self-reactive
49
Q

Describe the efficacy of male circumcision against HIV?

A

More effective than the most effective vaccine to date

No used in Africa

50
Q

What is viral load?

A

The amount of virus in an involved body fluid

A measure of severity

51
Q

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

A
  • general increase in antibody
  • auto-antibody
  • poor response to vaccines
  • reduced killing of encapsulated bacteria
52
Q

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

A
  • Neutrophils
  • Phagocytes
  • Natural Killer cells
  • T cells
  • B cells
53
Q

Describe the effects of increased immune activation

A

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

54
Q

Describe which proteins were used in the ‘dead protein’ vaccines.

A

gp120 (which is highly glycosylated)

55
Q

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

A

HAART
• reduces viral load
• reduced inoculum in the community

“Treatment as Prevention”

56
Q

Why is it beneficial that bnAb are self-reactive?

A

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

These antibodies thus recognise these self-antigens on HIV

MIIM20002 - Microbes, Infections, Responses (32 decks)

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