Broadly neutralizing Antibodies (bnAbs)
Control of HIV remains challenging in many regions of the work, such as sub-Saharan Africa.
Some 40 years since identification of the HIV virus, there is no vaccine to prepare the immune system to fight off infection.
This is because the HIV virus replicates and mutates rapidly within the host, thus evading antibodies.
The HIV spike, the target of most antibodies, is shielded by easily mutable (low fitness cost) residues.
Adopted from: Burton et al, Cell (2012)
Rare individuals, after several years and in low amounts, produce broadly neutralizing Antibodies (bnAbs),
capable of inactivating a broad range of viral mutants by targeting the conserved (CD4 binding) region.
Can we devise a strategy to guide affinity maturation to create bnAbs?
A potential strategy is to vaccinate with multiple mutant spikes sharing the same conserved elements.
Our computational model of affinity maturation suggests that a cocktail of such variants leads to low yields, with little breath:
Simultaneous presence of variant antigens leads to conflicting selection forces that frustrate affinity maturation
Simulations suggests successful outcome if the antigens are administered in sequence
Sequential immunization can focus B cell interactions on the conserved residues
This prediction was successfully tested in mice (with Wittrup & Burton labs) [Wang et al, Cell 160, 785 (2015)] (off-line)
Essence of the challenge is to avoid termination of affinity maturation as well as a specialized outcome
A general strategy to elicit (control) bnAbs must:
Avoid frustration (leading to extinction of GC) [J.S. Shaffer, P.L. Moore, MK & AKC, PNAS 113, E7039 (2016)] (off-line)
Avoid rapid specialization to mutable epitopes
Boost B-cell lineages that can mutate towards conserved epitopes
A general strategy to elicit (control) bnAbs must:
Avoid frustration (leading to extinction of GC) [J.S. Shaffer, P.L. Moore, MK & AKC, PNAS 113, E7039 (2016)] (off-line)
Avoid rapid specialization to mutable epitopes
Boost B-cell lineages that can mutate towards conserved epitopes