Lecture 35 - HIV/AIDS Flashcards
1
Q
Outline the HIV epidemic
A
- First case 1959
- Epidemic in late 80’s
- Endemic in Sub-Saharan Africa
- 1992-95: most common cause of death in young people is the US
- Economic
- Retards economic growth
- Exacerbates poverty
2
Q
Outline the phylogeny of HIV
A
- Two major categories
-
HIV-1
-
Group M
- Clades A-K
- Group N
- Group O
- Group P
-
Group M
- HIV-2
-
HIV-1
3
Q
Describe the features of the HIV virion
A
- Lentivirus
- Slowly replicating
- Retrovirus
- RNA genome reverse transcribed into DNA
- Genome
- LTR
-
Gag
- MA, CA
-
Pol
- Polymerases: RT, IN, PR
-
Env
- gp120
- gp41
- Structure
- Envelope
- gp120/gp41
- Nucleocapsid
- RNA genome
- Enzymes
- Integrase
- Reverse transcriptase
- Protease
- Envelope
4
Q
Polio vaccine and HIV transmission?
A
- There was some thought that HIV was transmitted from Chimpanzees to humans through contaminated polio vaccine
- This has been shown to be false
5
Q
Describe the clinical manisfestations of HIV infection
A
- Flu-like illness
- 1-2 weeks after infection
- Sometimes asymptomatic
- ⇒ seroconversion
- Clinical latency
- Slow depletion of CD4+ T cells
- AIDS
- <200 CD4 T cells / ml blood
- Opportunistic infections
- Candida
- Pneumocystic carinii
- Mycobacterium avium
- CMV
- Herpes simplex
- Varicella
- Kaposi sarcoma
- B cell lymphomas (EBV)
- Dementia
6
Q
Describe the HIV replicative cycle & invasion of cells
A
- gp120 binds to CD4 on CD4+ T cells
- Conformational change in gp120: exposure of co-receptor binding site
- CCR5/CXCR4 (coreceptor) binds exposed co-receptor binding site
- Fusion of HIV envelope with CD4 T cell membrane
- Uncoating of nucleocapsid
- Reverse transcription of RNA into ds cDNA
- Viral cDNA enters nucleus
- LTR-dependent integration of cDNA into host genome
- T cell activation → Transcription of pro-viral genes
- NFKB dependent
- Multiple splicing of viral mRNA
- Translation of Tat and Rev
- Tat amplifies transcription of viral RNA
- Rev increases transport of singly spliced RNA
- Translation of other viral proteins
- gp160
- Pol
- Gag
- Assembly of virus
- Virions bud out of the cell
7
Q
Describe the expression of CCR5 and CXCR4
A
- CCR5
- Major co-receptor
- Expressed on effector and memory CD4 T cells
- ie those cells that are enriched at mucosal sites
- Binds RANTES and MIP-1a
- on Macrophages and DCs
-
R5 tropic stains
- Major infective strain
- CXCR4
- Expressed on naïve CD4 T cells
- Binds CXCL12
-
X4 tropic strains
- Not naturally transmitted
- Evolve through mutation, later on in disease
8
Q
Describe infection with HIV
A
- HIV (R5 strain) introduced in mucosal tissue
- HIV binds DC
- DC drains to LN
- HIV infects activated CD4 T cells
- + effector memory CD4 T cells in the tissue
9
Q
Describe the progression to AIDS
Describe the virus titre & CD4 T cell count across time
A
- Acute infection (6-12 weeks)
- High viral load
- Drop in CD4 T cell numbers
- Seroconverions
- A robust immune response is launched, and the virus drops down to undetectable levels
- Clinical latency (1-15+ yrs)
- Clearance of virus (still present though)
- Recovery of CD4 T cell numbers (somewhat)
- Progressive increase in virus titre and decrease in CD4 T cell numbers
- ’Wobble’ in CD4 T cell numbers reflects that the virus is constantly mutating and trying to reactivate
- AIDS
- V. high virus titre
- V. low numbers of CD4 T cells
10
Q
Describe the role of CD4 T cells in immunity
A
- Play a central role in coordinating the immune repsonse
- B cells
- CD40L ligation allows CSR and SHM
- Allows production of various isotypes and high affinity Ab
- APCs
- CD40L ligation licenses APCs for more effective CD8 T cell activation
- CD8 T cells
- Activated through licensed APCs
- B cells
11
Q
Outline the ways in which CD4 T cells are depleted during HIV infection
A
- Cytopathic effects of virus
- Direct infection with HIV causes CD4 T cells to die
- Killing by HIV-specific CD8 T cells
- Infected CD4 T cell presents HIV Ag in the context of MHC I
- Increased sensitivity to apoptosis
- Infected activated CD4 T cell expresses high levels of Fas
- Ligation with FasL results in apoptosis
- Formation of syncytia
- Fusion of infected & uninfected CD4 T cells
- Through gp120 expression on infected cell & CD4 on uninfected cell
- → dysfunctional, multinucleated cell
- These are prevalent in biopsies of HIV+ individuals
- ADCC
- Abs against HIV antigens bind infected CD4 T cells
- NK cells kill infected cells
12
Q
Describe resistance to HIV
A
- CCR5 mutation
- HIV can’t infect T cells
- Berlin patient
- BM transplant from individual homozygous for CCR5 mutation
- Strong HIV-specific CD4/8 T cell responses
- Long term non-progression
- Not associated with antibody response, rather cellular response
- Relatively rare
- T cells from these patients are multi-functional
- Secrete a great range of cytokines
13
Q
Describe immune responses in HIV infection
A
- Acute
- HIV-specific CD8 T cell response
- Chronic
- Ab response: anti-gp120
In general, the immune response controls viral replication, but does not eliminate
14
Q
Why does HIV infection persist despite the robust immune response?
A
Viral evasion strategies
- Integration into host genome, viral latency
- Silent infection: undetected by the immune response
- Formation of reservoirs in activated resting memory CD4 T cells, DCs and FDCs
- Avoidance of neutralising antibody
- Mutation in Ab epitopes
- In non-critical binding domains
- Steric hindrance
- Glycosylation (N-glycan shielding) over antigenic sites on gp120 so that Abs can no longer bind
- Mutation in Ab epitopes
- Mutation of CD8 T cell epitopes
- Residues for TCR recognition
- Abolishes peptide recognition by T cells
- Residues for presentation in MHC
- Abolishes peptide presentation
- Residues for TCR recognition
15
Q
Describe treatment of HIV infection
A
- HAART: highly active anti-retroviral therapy
- Cocktail of various anti-retrovirals
- Prevents selection of resistant mutants
- Target various stages of HIV repication cycle
- Classes:
- Nucleoside analogues
- Protease inhibitors
- CCR5 antagonists
- New class
- Expensive
- $10-15 000 per annum
- Not viable for sub-saharan Africa
- Ineffective against latently infected cells
- Cocktail of various anti-retrovirals
