Honing a harder-hitting hammerhead improves broadly neutralizing antibody breadth and potency

Abstract

C o m m e n t a r yBroadly neutralizing antibodies: good or bad news for HIV-1 vaccination?PG9 was one of the first broadly neutralizing monoclonal antibodies (bnmAbs) isolated from an HIV-1-infected individual and was shown to potently neutralize more than 85% of HIV-1 isolates that it was tested against (1). Isolation of PG9 and the related bnmAb PG16 (1, 2) presaged an ongoing explosion in the knowledge of the HIV-1 epitopes recognized by bnmAbs (reviewed in refs. 3, 4; see ref. 5) and how bnmAbs evolve over the course of infection (reviewed in refs. 6, 7). In this issue, Willis and collaborators further extend this knowledge through their employment of a computer model to predict mutations that markedly improved the neutralization potency and breadth of PG9 (8). bnmAbs can be characterized in terms of their neutralization fitness, which herein refers to the combination of neutralization potency (half the maximal neutralization titer) and neutralization breadth (the percentage of representative viral panels neutralized) for a given bnmAB. Previous reports have shown that mixtures of bnmAbs with known specificity are able to potently neutralize essentially all variants in panels that represent circulating HIV-1 strains (9). Such results are promising because they suggest that a universal AIDS vaccine is possible, provided a suitable immunogen and immunization schedule can be found. Moreover, the goal of a universal vaccine has been made more likely, as the result of an increasingly clear picture of the epitopes recognized by neutralization-fit bnmAbs and recent studies that have also provided important insight into the HIV-1 envelope (Env) glycoprotein trimer structure (10-12), which is targeted by many bnmAbs, including PG9. The Env trimer consists of three copies of gp160, which comprises a receptor-binding domain (gp120) and a membrane-anchored domain (gp41) Unfortunately, neutralization-fit bnmAbs have only been observed in HIV-1-infected people (3) and SIV-infected rhesus macaques (23); these bnmAbs are not detectable until approximately 2 1/2 years (24) and two-thirds of a year (23) after infection, respectively. The convergence of several lineage studies indicates that neutralization-fit bnmAbs arise only in response to exposure to different viral variants over these time periods (6, 7). Thus, the emergence of bnmAbs is the result of a predator-prey interaction in which the bnmAbs become increasingly "fit" in response to the increased viral variation that emerges in response to antibody pressure. Many of the identified pathways to neutralization fitness differ among studies, and it is not yet clear whether these pathways can be recapitulated by vaccination. Currently, it appears that lengthy (and clinically cumbersome) immunizaRelated Article: p. 2523 Conflict of interest:The author owns shares in Profectus BioSciences, which is developing vaccines against HIV-1 and is a sub-contractor on NIH Small Business Innovative Research grants awarded to Profectus BioSciences; otherwise, there are no consulting ...

Envelope-specific B-cell populations in African green monkeys chronically infected with simian immunodeficiency virus

“…It is well described that HIV-specific antibodies isolated from infected humans that have broadly neutralizing activity are typically IgG, are highly somatically mutated and display long heavy chain complementarity-determining region 3 (HCDR3) 2 25 26 27 28 . Thus, to address the genetic characteristics and degree of antibody maturation of the Env-specific monoclonal antibodies isolated from AGMs, the newly identified AGM constant and variable regions of Ig heavy chain, κ-, and λ-light chain were used to annotate the isolated Ig heavy and light chain pairs, and calculate their somatic hypermutation (SHM) frequency in AGMs.…”