Flashcards in Lecture 13 - HIV - Virology, Epidemiology, Immunology Deck (60):
How many people in the world are currently living with HIV?
Which parts of the world are most affected by HIV?
Sub-saharan Africa (~25 million)
Describe the trend in rate of:
• HIV infection
• Death due to AIDS
• Diagnoses in Australia
over the last 10 years.
What is this due to?
Rate of infection: steadily dropping since 1997
Rate of death due to AIDS: peak in 2004, but has been dropping
Rate of diagnoses in Australia: has been steadily rising since 1999, but is much less than in the late 80's
This is due to the increased access to anti-retroviral therapy
When did treatment coverage really start for AIDS in the third world?
Which groups are most commonly represented with new HIV infection?
•Men who have sex with men (MSM)
• Heterosexual contact
What are some factors associated with the HIV epidemic?
Behavioural & social:
• little/no condom use
• multiple, overlapping sexual partners
• large sexual networks
• high STI rate → predisposes to HIV and other STIs
• low rates of male circumcision
In which family is HIV?
What are some features of this family?
Lentiviridae family (cause disease slowly)
• icosahedral capsid symmetry
• ssRNA, + sense
• genome replicated in the nucleus
• capsid assembled in the cytoplasm
What are the two major categories of retroviruses?
To which does HIV belong to?
HIV belongs to the primate category
What can be said about + sense RNA?
Same as mRNA, and thus can be translated directly
Outline the HIV genome
• + sense
• 3 main genes:
Describe the three main genes of HIV
(NB there are many others)
1. Gag: structural proteins
2. Pol: viral enzymes:
• Reverse transcriptase (RT)
• Integrase (IN)
• Protease (PR)
3. Env: gp120 and gp41; the entrance tetramer that binds CD4, leading to entry
Describe the structure of the HIV virion
Env: gp120, gp41
What are HIV clades?
What can we say about their global distribution?
These are the HIV subtypes
US, Europe & Australia share clade
Subsaharan Africa & India share clades
Describe the life cycle of HIV
1. CD4 - gp120 binding
2. CoR engagement
4. Reverse transcription of viral genome into DNA
5. Integration of proviral DNA into host genome
6. Transcription of DNA into viral RNA
10. Maturation into new HIV virion
What are the key features of HIV replication?
• error prone (RT)
Describe the engagement of receptors that leads to fusion of the HIV virion with the host cell
1. gp120 binds CD4
2. Conformational change, revealing CoR binding site
3. CoR binds gp120-CD4 complex
What and where is the CoR?
It is on the CD4+ T cell
What are the various chemokine receptors on CD4+ T cells that HIV can bind to?
These are the Co-receptors
• Engaged by R5-HIV
• Engaged by X4 HIV
NB D/M HIV expressed gp120 that can bind both CCR5 & CXCR4
This ability to infect both cells occurs over time
Describe a case of natural resistance to HIV
• There exists a mutation in CCR5: CCR5 Δ32
• delayed progression to AIDS / death
Homozygous for the mutation
• rare infection with R5
NB The CCR5 Δ32 mutation does not affect immune function
Describe the global prevalence of CCR5 Δ32 mutation
What is the proposed origin of this mutation?
1. US, Europe, Australia:
• Heterozygous: ~10-15
• Homozygous: 1%
2. Africa, South America, Southern Asia
European origin around 1000 years ago
Possibly due to selection by a pandemic pathogen:
• Bubonic plague
Which cells does HIV infect?
Cells expressing CD4:
• 'helper' T cells
• monocytes & macrophages
What is APOBEC3G? What does HIV do to it?
• Host protein that edits RNA
• HIV protein vif inhibits it
What is TRIM 5α?
• Host protein that blocks uncoating of retroviruses
• HIV capsid proteins impervious to TRIM5α
What is Tetherin?
• Host protein that blocks release of virus
• HIV vpu inhibits it
What is LEDGF?
• Host protein that tethers HIV to host chromatin
• HIV Integrase facilitates integration
What are the host anti-HIV proteins?
When is the initial peak of viraemia?
1-2 weeks after exposure
Describe the macroscopic infection of HIV
1. Virions introduced to vaginal epithelium.
Microtears allow the virion to cross the epithelium
2. Local proliferation: DCs, resting & activated CD4+ T cells become infected
3. Dissemination to lymph nodes; infection of many CD4+ T cells
4. Local proliferation, viraemia, CD4+ memory cell loss
Extensive loss of CD4+ T cells in MALT
5. Partial immune control:
Describe the partial immune control of HIV
What is the time scale?
Over the months following infection
• Activation of CTLs
• Neutralising Abs
How does HIV evade the immune system?
• Sequence variation
• Altered antigen presentation
• Loss of effector cells
• Privileged sites of replication
Describe altered antigen presentation in HIV infection
HIV proteins down regulates MHC I expression.
→ reduced activation of CTLs
In which cells does HIV remain latent?
Resting T cells
In which sites is HIV replication privileged?
Blocks migration of HIV-specific T cells to these sites
Describe the situation in Botswana
Anti-retroviral coverage has greatly improved since 2005
→ Infection rates rapidly dropping
Why was there a big increase in new HIV diagnoses in the mid-80's?
This is when the test came out
Why is there very low rates of infection in injecting drug users in Australia?
Access to clean needles as soon as the pandemic emerged
What sort of transmission is most commonly seen?
• Heterosexual (in Africa)
• Injecting drug users (in certain parts of the world, Eastern Europe, the US)
What is the effect of male circumcision on HIV acquisition?
Reduction by about 70%
What is SIV?
Simian Immunodeficiency Virus
Virus that affects monkeys, causing an AIDS like illness
Which type of HIV is seen in Australia?
HIV-2 is only seen in West Africa
What did HIV-1 arise from?
What differs between the various types of HIV?
The regulatory proteins that control the life cycle
What is the name of the product of reverse transcriptase?
In general, why can't we cure HIV infection?
The proviral DNA is integrated into the host DNA, and remains there for the lifespan of the cell
Where does maturation of the HIV virion occur?
Outside the host cell
What do we call the million different versions of the virus seen after HIV infection?
Describe the result of HIV infection of the various CD4+ T cells
Activated CD4+ T cell → death of cell
Resting CD4+ T cell → latent infection
With which type of HIV are most people initially infected?
(i.e. infects T cells w/ CCR5)
Where are most activated T cells located?
In the GIT
Describe the host 'innate immune response' to viruses
The host has various proteins (e.g. APOBEC3G, Tetherin etc.) that have natural antiviral function
What is the effect of HIV-specific CTLs and HIV-neutralising Ab?
Markedly decreases viraemia, but never actually clears it.
Which molecules lead to altered antigen presentation?
Tat, Vpu, Nef
Altered MHC class I expression
Globally, what is the biggest risk factor for HIV infection?
Describe HIV infection of macrophages
• Long lived, slow release of virus
• Macrophages express CD4 and CCR5, so HIV can infect
• Become chronically infected & serve as a reservoir
Describe HIV infection of DCs
• Allow entry
• But productive infection is rare
What are the phases of the early infection?
Indicate the time scale
Hours: crossing the barrier
3-4 days: local expansion
Days-Weeks: Dissemination to lymphatics
1-2 weeks: Local proliferation
Weeks-months-years: partial immune control
What are the features of R5 HIV virions?
Compare w/ X4 HIV virions
• Enter host cells w/ CCR5 co-receptor
• Most commonly cause infection
• Cause less T cell destruction
• Rarely are transmitted
• Enter host cells w/ CXCR4 co-receptor
• Emerge late in infection
Where is HIV-2 seen?
Only seen in West Africa
Which genes in HIV are highly variable?
Gag and Env
(pol not highly variable)