Mutational fitness landscapes reveal genetic and structural improvement pathways for a vaccine-elicited HIV-1 broadly neutralizing antibody.
Vaccine-based elicitation of broadly neutralizing antibodies holds great promise for preventing HIV-1 transmission. However, the key biophysical markers of improved antibody recognition remain uncertain in the diverse landscape of potential antibody mutation pathways, and a more complete understanding of anti-HIV-1 fusion peptide (FP) antibody development will accelerate rational vaccine designs. Here we survey the mutational landscape of the vaccine-elicited anti-FP antibody, vFP16.02, to determine the genetic, structural, and functional features associated with antibody improvement or fitness. Using site-saturation mutagenesis and yeast display functional screening, we found that 1% of possible single mutations improved HIV-1 envelope trimer (Env) affinity, but generally comprised rare somatic hypermutations that may not arise frequently in vivo. We observed that many single mutations in the vFP16.02 Fab could enhance affinity >1,000-fold against soluble FP, although affinity improvements against the HIV-1 trimer were more measured and rare. The most potent variants enhanced affinity to both soluble FP and Env, had mutations concentrated in antibody framework regions, and achieved up to 37% neutralization breadth compared to 28% neutralization of the template antibody. Altered heavy- and light-chain interface angles and conformational dynamics, as well as reduced Fab thermal stability, were associated with improved HIV-1 neutralization breadth and potency. We also observed parallel sets of mutations that enhanced viral neutralization through similar structural mechanisms. These data provide a quantitative understanding of the mutational landscape for vaccine-elicited FP-directed broadly neutralizing antibody and demonstrate that numerous antigen-distal framework mutations can improve antibody function by enhancing affinity simultaneously toward HIV-1 Env and FP.
['Madan|Bharat|B|0000-0002-7376-9991', 'Zhang|Baoshan|B|', 'Xu|Kai|K|0000-0001-5412-6942', 'Chao|Cara W|CW|', "O'Dell|Sijy|S|", 'Wolfe|Jacy R|JR|', 'Chuang|Gwo-Yu|GY|', 'Fahad|Ahmed S|AS|', 'Geng|Hui|H|', 'Kong|Rui|R|', 'Louder|Mark K|MK|0000-0001-7540-9263', 'Nguyen|Thuy Duong|TD|0000-0003-4567-6162', 'Rawi|Reda|R|', 'Schön|Arne|A|0000-0002-2015-2090', 'Sheng|Zizhang|Z|0000-0002-3253-3309', 'Nimrania|Rajani|R|', 'Wang|Yiran|Y|', 'Zhou|Tongqing|T|', 'Lin|Bob C|BC|', 'Doria-Rose|Nicole A|NA|', 'Shapiro|Lawrence|L|', 'Kwong|Peter D|PD|', 'DeKosky|Brandon J|BJ|0000-0001-6406-0836']
D016915:AIDS Vaccines D000080908:Broadly Neutralizing Antibodies D015483:HIV Antibodies D015497:HIV-1 D006801:Humans D009154:Mutation D054299:env Gene Products, Human Immunodeficiency Virus
broadly neutralizing antibodies fusion peptide yeast display somatic hypermutation HIV-1 vaccines