1. bNAbs Antibodies
1.1. They have unusual characteristics, including odd physical structures (e.g., elongated antigen-binding loops) and remarkably high levels of mutation that affect antibody–antigen binding and structural domains.
1.1.1. These changes accumulate over years of infection as exposure to diverse viral variants drives antibody evolution
1.1.1.1. Resulting in the generation of a set of antibodies that bears little similarity to their original antigen-naive B-cell ancestors (i.e., germline sequences)
2. Universal Vaccines
2.1. Are the ones that elicit cross-reactive and broadly neutralizing antibodies (bNAbs)
2.2. Are also the ultimate goal of efforts to provide protective immunity against both the influenza virus and the human immunodeficiency virus (HIV).
2.2.1. The circulating diversity of HIV is greater than that of influenza by orders of magnitude, posing a tremendous challenge to the achievement of vaccine-mediated protection.
3. Two key events distinguished the interaction of B-cell and virus during the developing natural history of this bNAb.
3.1. First, whereas in most scenarios the naive B-cell population cannot bind to HIV, the naive B-cell repertoire in this infected person bound to the earliest incoming virus (the transmitted virus), which suggests that early rapid diversification of the B-cell response was initiated very soon after infection.
3.2. Second, the rapid evolution of mutations affecting antibodies, which is required for potent antibody neutralization, occurs simultaneously with the rapid diversification of the virus in the first few months of infection.
3.2.1. This occurrence suggests that the timing of the exposure to diverse viral variants may be crucial to the induction of protective antibody immunity.
4. Conclusions
4.1. Together, these studies highlight key features of the immune system’s natural induction of bNAbs.
4.1.1. First, effective initiation of the antibody response depends on the early interactions between the virus and the naive B-cell repertoire.
4.1.2. Second, an explosion of viral diversity can drive the molecular evolution of a bNAb.
4.1.3. Finally, neutralization potency arises in an unanticipated way — by means of mutations affecting structural regions of the antibody.
5. Suggesting that vaccine-induced bNAbs could provide sterilizing immunity if they were present before infection
6. New Hope
6.1. New hope for a universal sterilizing HIV vaccine arose several years ago with the evidence that bNAbs emerge in 10 to 30% of infected persons.
6.2. Because these bNAb responses typically appear after 2 to 3 years of infection, they fail to control established infection
6.3. These bNAbs have provided protection from infection at remarkably low doses in animals.
7. Liao et al
7.1. They tracked the evolution of a single bNAb and the counter-evolution of an HIV virus starting in the first weeks of infection.
7.1.1. Given that the B-cell receptor is simply a membrane-bound antibody, Liao et al hypothesized that the parallel sequencing of B-cell receptors and viral diversity could elucidate the interplay of host and pathogen, evasion and adaptation, that resulted in a broadly neutralizing antibody.
7.1.1.1. Specifically, as the virus evolves (Panel A), so does the B-cell receptor (Panel B), resulting in point mutations initially in the antigen-binding domain but eventually in the structural domain, as shown by Klein et al allowing for enhanced antibody neutralizing activity.
7.2. Their findings offer a roadmap for the induction of bNAbs through vaccination.
7.2.1. Suggest that next-generation HIV vaccines could be modeled on the natural history of broadly neutralizing antibodies.
7.2.1.1. Early recognition of the transmitted virus by a naive B cell (in blue) leads to the selection, expansion, and diversification of the antigenspecific population, followed by exposure to a rapidly diversifying viral quasi-species and leading to the rapid mutation and down-selection of the most potent B-cell population
7.2.1.1.1. Accordingly, immunogens could be designed to interact with specific germline-naive B-cell receptors and coax B cells along specific maturation pathways
8. In a recent publication
8.1. Although the early evolution of the antibody response predominantly occurred within the antigen-recognition site, Liao et al. found that later evolutionary changes in the antibody occurred in structural regions, which are thought to have a limited role in antigen recognition.
8.2. However, in a recent publication by Klein et al the authors report that mutations affecting these structural regions can potentiate antibody function.
8.2.1. The authors found that among a set of diverse bNAbs, mutations affecting the structural regions are not just incidental to extensive mutation but are actually critical to neutralization