Current HIV-1 vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in ~20% of HIV-1-infected individuals, and details of their generation could provide a roadmap for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from time of infection. The mature antibody, CH103, neutralized ~55% of HIV-1 isolates, and its co-crystal structure with gp120 revealed a novel loop-based mechanism of CD4-binding site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the CH103-lineage unmutated common ancestor avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data elucidate the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies and provide insights into strategies to elicit similar antibodies via vaccination.
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Summary The RV144 HIV-1 trial of the canary pox vector (ALVAC-HIV) plus the gp120 AIDSVAX B/E vaccine demonstrated an estimated efficacy of 31%, that correlated directly with antibodies to HIV-1 envelope variable regions 1 and 2 (V1–V2). Genetic analysis of trial viruses revealed increased vaccine efficacy against viruses matching the vaccine strain at V2 residue 169. Here, we isolated four V2 monoclonal antibodies from RV144 vaccinees that recognize residue 169, neutralize laboratory-adapted HIV-1, and mediate killing of field isolate HIV-1-infected CD4+ T cells. Crystal structures of two of the V2 antibodies demonstrated residue 169 can exist within divergent helical and loop conformations, which contrasted dramatically with the beta strand conformation previously observed with a broadly neutralizing antibody PG9. Thus, RV144 vaccine-induced immune pressure appears to target a region that may be both sequence variable and structurally polymorphic. Variation may signal sites of HIV-1 envelope vulnerability, providing vaccine designers with new options.
SUMMARY Antibodies with ontogenies from VH1-2 or VH1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. Here we define with longitudinal sampling from time-of-infection the development of a VH1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%) and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary levels of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled VH1-2. We integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.
Development of a highly effective vaccine or antibodies for prevention and ultimately elimination of malaria is urgently needed. Here, we report the isolation of a number of human monoclonal antibodies (mAbs) directed against the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) from several subjects immunized with an attenuated whole sporozoite (SPZ) vaccine (Sanaria® PfSPZ Vaccine). Passive transfer of one of these antibodies, mAb CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. Stoichiometry and affinity of mAb CIS43 for PfCSP indicate two sequential multivalent binding events to six sites: the first 7-fold higher affinity binding event is to a unique “junctional” epitope positioned between the N-terminus and the central repeat domain of PfCSP. Moreover, mAb CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Crystal structures of the CIS43 fragment antigen binding (Fab) in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope’s conformational flexibility, and defined NPN as the structural repeat motif. The demonstration that mAb CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next generation rational vaccine design.
A preventive HIV-1 vaccine should induce HIV-1–specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3-glycan bnAb. Two autologous neutralizing antibody lineages selected for virus escape mutations and consequently allowed initiation and affinity maturation of a V3-glycan bnAb lineage. The nucleotide substitution required to initiate the bnAb lineage occurred at a low-probability site for activation-induced cytidine deaminase activity. Cooperation of B cell lineages and an improbable mutation critical for bnAb activity defined the necessary events leading to breadth in this V3-glycan bnAb lineage. These findings may, in part, explain why initiation of V3-glycan bnAbs is rare, and suggest an immunization strategy for inducing similar V3-glycan bnAbs.
We present a new version of the Protein-Protein Docking Benchmark, reconstructed from the bottom up to include more complexes, particularly focusing on more unbound-unbound test cases. SCOP (Structural Classification of Proteins) was used to assess redundancy between the complexes in this version. The new benchmark consists of 72 unbound-unbound cases, with 52 rigid-body cases, 13 medium-difficulty cases, and 7 high-difficulty cases with substantial conformational change. In addition, we retained 12 antibody-antigen test cases with the antibody structure in the bound form. The new benchmark provides a platform for evaluating the progress of docking methods on a wide variety of targets. The new version of the benchmark is available to the public at http://zlab.bu.edu/benchmark2.
The biophysical study of protein-protein interactions and docking has important implications in our understanding of most complex cellular signaling processes. Most computational approaches to protein docking involve a tradeoff between the level of detail incorporated into the model and computational power required to properly handle that level of detail. In this work, we seek to optimize that balance by showing that we can reduce the complexity of model representation and thus make the computation tractable with minimal loss of predictive performance. We also introduce a pair-wise statistical potential suitable for docking that builds on previous work and show that this potential can be incorporated into our fast fourier transform-based docking algorithm ZDOCK. We use the Protein Docking Benchmark to illustrate the improved performance of this potential compared with less detailed other scoring functions. Furthermore, we show that the new potential performs well on antibody-antigen complexes, with most predictions clustering around the Complementarity Determining Regions of antibodies without any manual intervention.
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