HIV-specific antibody responses Flashcards
1
Q
What is a neutralizing antibody?
A
- an antibody that reacts with an infectious agent and destroys or inhibits its infectiveness and virulence
2
Q
Structure of HIV envelope spike
A
- trimer of gp120/gp41 heterodimers
3
Q
Describe HIV-1 cell entry
A
HIV spike binds to CD4 and then to CCR5 on target cell
- membrane fusion (six-helix bundle formation)
4
Q
How can HIV-1 gp120/gp41 evade antibodies?
A
- sequence variability in gp120
- gp120 is shed
- gp120 carbohydrates hide protein epitopes
- antibodies are too big to access conserved regions of spike on a virion
5
Q
How HIV keeps IS busy
A
- infected cells release misfolded or incompletely assembled gp120s as decoys
6
Q
Describe the development of neutralizing antibody breadth
A
- rare
- happens incrementally
- can take 3-4 years
- does not offer any clinical benefit
7
Q
Describe memory B cells
A
- isotype switched or somatically mutated cells
- member of a clone that has responded to antigen by proliferation and remains in rested tate
- survival is independent of persisting T-cell help
- lower threshold for antigenic stim
8
Q
Describe plasma cells
A
- terminally differentiated, end stage cells
- no proliferative capacity
- lifespan = few days to years
- supported by niche environments which provide survival signals
9
Q
Describe somatic hypermutation
A
- modifies the variable region sequences of heavy and light chains
- antibodies have increased affinity for antigen
10
Q
Why bNAbs are rare?
A
- Abs with long Ab combining regions are frequently eliminated by tolerance mechanisms
- possibly takes long time to accumulate so many mutations
- self-reactive Abs usually eliminated
11
Q
Why are bNAbs important?
A
- potently protect rhesus macaques from challenge with SHIVs
12
Q
Strategies for designing immunogens that elicit broadly neutralizing Abs
A
- produce molecules that mimic mature trimer Env on virion surface
- produce Env molecules engineered to better present NAb epitopes
- generate stable intermediates of the entry process with the goal of exposing conserved epitopes to which Abs could gain access during entry
- produce epitope mimics of bNAbs determined from structural studie of Ab-antigen complexes
- mimic constant antigen stim/variation using repeated immunizations with different Env variants
13
Q
Mechanism of ADCC
A
- complex between IgG Fab portion of Ab bound to envelope protein on the cell surgace and Fc portion on Fc receptors on effector cells leads to lysis of infected cell
14
Q
How does B cell exhaustion work?
A
- shortened replication history
- decreased immunoglobulin diversity
- multiple inhibitory receptors expressed
- altered expression of homing receptors
- poor proliferative response
- enriched for virus-specific response
