Lecture 28 - HIV vaccine? Flashcards
How many people are currently infected with HIV?
35.3 million
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
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
Describe the structure of HIV
Icosahedral capsid - cone shaped Envelope Glycoproteins - envelope spikes Matrix
What is notable about enveloped viruses?
Labile in the environment
Describe the genome of HIV
Two copies of RNA genome
Covered by nucleocapsid
What is the CA capsid?
This is what makes up the icosahedral capsid of HIV
What proteins does HIV make?
- gag: structural proteins
- pol: enzymes (reverse transcriptase etc)
- env: glycoproteins
Describe how HIV replicates
- Surface glycoproteins
- Fusion
- Uncoating
- Reverse transcription
- Insertion into host genome
- Transcription and translation
- Budding
Which cells does HIV infect?
Why these cells in particular?
CD4+ T cells
Virus surface proteins bind to CD4 protein
What is important about RT?
Reverse transcriptase
Very error prone
One mistake everytime the genome is reverse transcribed
What does ‘Integrated provirus’ mean?
It’s genome is inserted into the host genome
What are the phases of HIV infection?
- Primary
- Clinical latency
- Symptomatic disease
- AIDS
Describe primary infection
- Shortly after infection, lasts a few weeks
- High numbers of circulating virus
- Rapid loss of CD4+ in blood and lymph nodes
What happens during clinical latency?
- Virus continues to replicate
- Immune system keeps levels quite low
- Ongoing decline in CD4+ T cells
What happens after a number of years of clinical latency?
- Very few CD4+ left
* Immune system no longer able to control opportunistic infections
What are the yellow nodules seen in the gut?
Healthy Peyer’s patches with lymphocytes
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
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
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
Describe what happens once the HIV escapes the immune system
Loss of T cells
No help for
• B cells
• macrophages
Describe macrophage activity during HIV infection
Decreased:
• phagocytosis
• chemotaxis
• removal of pathogens
What sort of infections occur later on?
- Fungal infections
* Sarcomas
When do people start to feel sick with HIV infection?
After years of infection
What factors affect outcome of infection?
Virus
Immune response
Co-morbidity
What are the targets of HIV antivirals?
Replication cycle: • reverse transcriptase enzyme inhibitors • protease inhibitors • integrase inhibitors • entry inhibitors
What sort of things kills HIV+ people nowadays?
Diseases as a result of chronic immune activation
• Liver disease
• Non-AIDS Cancers
• Heart disease
What is HAART?
Highly active anti-retroviral therapy
Many antivirals given
Less chance of resistance
Quite expensive
Describe the efficacy of HAART
With use of HAART, HIV+ people increase their life span dramatically
Life expectancy only 10 less than HIV- people
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
What happens when HAART is stopped?
Virus comes back
How can we prevent HIV?
- Preventative vaccine -
Treatment Microbicides Condoms Pre-exposure prophylaxis Voluntary male circumcision
What are the pros of treatment as opposed to vaccine development?
- direct
- short time span
- can see the result
- tolerate side effects
What are the issues with vaccine development?
- only see the negative effects
- healthy people
- indirect
- no markers
- high risk
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
Compare the diversity of HIV with influenza
More diversity in one HIV patient that influenza all over the world
What would the ideal HIV vaccine be?
- prevents transmission
- safe, minimal reactions
- single dose
- long lasting
- cheap
- stable
- theraputic
What immune responses do we want?
• strong T cell responses
→ CTL kill infected cells
• broad neutralising antibody responses
What does neutralising antibody target in HIV?
Envelope proteins, structured trimers
What was in the first HIV vaccine?
What types of vaccine were they?
Envelope protein subunit
Virus like particles
Whole inactivated virus
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
What is in the current HIV vaccine?
Live attenuated virus
What are the stages in vaccine development?
Phase I
Phase II
Phase III
More and more volunteers in each phase
Describe what happened to the B clade vaccine
Didn’t get past phase I
Because there was poor CD8+ and CD4+ responses
Describe RV144 vaccine
Low expectations
However, 31% efficacy
• lower rates of infection
• some prevention of transmission
What did RV 144 tell us about protection from infection?
Protection greatest when treated early in low risk patients
What should we focus on while we still don’t have a vaccine?
- Minimise transmission
- Microbicides
- Antiretroviral therapy
Describe the characteristic of broad neutralising antibodies
- Many mutations
- Long loop to access the epitopes on HIV surface spikes
- self-reactive
Describe the efficacy of male circumcision against HIV?
More effective than the most effective vaccine to date
No used in Africa
What is viral load?
The amount of virus in an involved body fluid
A measure of severity
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
Which cells of the immune system have reduced function due to HIV infection?
- Neutrophils
- Phagocytes
- Natural Killer cells
- T cells
- B cells
Describe the effects of increased immune activation
Leads to other diseases:
• cariovascular disease
• liver disease
• non-AIDS cancers
Describe which proteins were used in the ‘dead protein’ vaccines.
gp120 (which is highly glycosylated)
What is the most successful mechanism of preventing transmission to date?
Why?
HAART
• reduces viral load
• reduced inoculum in the community
“Treatment as Prevention”
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
