Functional, Non-Clonal IgMa-Restricted B Cell Receptor Interactions with the HIV-1 Envelope gp41 Membrane Proximal External Region

The membrane proximal external region (MPER) of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specific broadly neutralizing antibodies like 2F5 and 4E10 is due to structural constraints with the gp41 MPER, or alternatively, if gp41 MPER epitope-specific B cells are lost to immunological tolerance. An equally important question is how B cells interact with, and respond to, the gp41 MPER epitope, including whether they engage this epitope in a non-canonical manner i.e., by non-paratopic recognition via B cell receptors (BCR). To begin understanding how B cells engage the gp41 MPER, we characterized B cell-gp41 MPER interactions in BALB/c and C57BL/6 mice. Surprisingly, we found that a significant (∼7%) fraction of splenic B cells from BALB/c, but not C57BL/6 mice, bound the gp41 MPER via their BCRs. This strain-specific binding was concentrated in IgMhi subsets, including marginal zone and peritoneal B1 B cells, and correlated with enriched fractions (∼15%) of gp41 MPER-specific IgM secreted by in vitro-activated splenic B cells. Analysis of Igha (BALB/c) and Ighb (C57BL/6) congenic mice demonstrated that gp41 MPER binding was controlled by determinants of the Igha locus. Mapping of MPER gp41 interactions with IgMa identified MPER residues distinct from those to which mAb 2F5 binds and demonstrated the requirement of Fc CH regions. Importantly, gp41 MPER ligation produced detectable BCR-proximal signaling events, suggesting that interactions between gp41 MPER and IgMa determinants may elicit partial B cell activation. These data suggest that low avidity, non-paratopic interactions between the gp41 MPER and membrane Ig on naïve B cells may interfere with or divert bnAb responses

Dr. Robert L. Bennett: pioneer and definer of modern physiatry.

Few physiatrists today would appreciate Dr. Robert L. Bennett’s contributions to our specialty, since he most commonly was associated with poliomyelitis, a cured disease for over a half century. Less are aware of the pioneering fusion of physical medicine in 1941 by Krusen’s first resident with the independent living environment of the Georgia Warm Spring Foundation (GWSF) created by a USA president. Bennett recognized polio/GWSF as the workshop and laboratory for showcasing the new specialty of Physical Medicine and Rehabilitation (PMR). He taught us that accurate muscle testing determined the plan of muscle reeducation, which led to functional training with a rehabilitation team and this approach was equally valid for complicated diseases such as spinal cord injury and traumatic brain injury. His leadership, as chair of the American Board of PMR for 10 years, is unequaled in tenure and vision. In over 100 articles, he defined Physiatry to all physicians and allied health professionals and predicted the physiatrist of tomorrow would need to be a complete physician who specialized in certain diseases that he could care for, because of his unique set of knowledge and skill. He founded the first department of Physical Medicine in the South at Emory University in 1945, trained over a hundred fellows and residents and played a role in the establishment of the Research and Training Center 20 years later. He taught and practiced as Professor of Rehabilitation Medicine until his death in 1983 and is still remembered by several generations that were inspired by his teaching

SPRINGFIELD’S “X” – FROM CROSSROADS TO CENTER

The work explores a community service learning strategy within the framework of two urban design studios with the goal of revitalizing the city of Springfield, Massachusetts, through design, planning, and engagement with the community. The studio worked in the Forest Park neighborhood around the “X” – on the intersection of three major street arteries. Our study contains a diverse catalogue of strategies to make the Forest Park Neighborhood a better place to live, work, and recreate where the most important streets meet. Through rerouting of the traffic patterns around the “X” the number of pedestrian crossings is increased and the possibilities enhance bikeability and walkability are largely enhanced. Other opportunities are created: places for local neighborhood commerce, new places for arts and culture, and housing close to the “X” and the greatest jewel: Forest Park

Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models

The events required for the induction of broad neutralizing antibodies (bnAbs) following HIV-1 envelope (Env) vaccination are unknown, and their induction in animal models as proof of concept would be critical. Here, we describe the induction of plasma antibodies capable of neutralizing heterologous primary (tier 2) HIV-1 strains in one macaque and two rabbits. Env immunogens were designed to induce CD4 binding site (CD4bs) bnAbs, but surprisingly, the macaque developed V1V2-glycan bnAbs. Env immunization of CD4bs bnAb heavy chain rearrangement (VHDJH) knockin mice similarly induced V1V2-glycan neutralizing antibodies (nAbs), wherein the human CD4bs VH chains were replaced with mouse rearrangements bearing diversity region (D)-D fusions, creating antibodies with long, tyrosine-rich HCDR3s. Our results show that Env vaccination can elicit broad neutralization of tier 2 HIV-1, demonstrate that V1V2-glycan bnAbs are more readily induced than CD4bs bnAbs, and define VH replacement and diversity region fusion as potential mechanisms for generating V1V2-glycan bnAb site antibodies

Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations

A strategy for HIV-1 vaccine development is to define envelope (Env) evolution of broadly neutralizing antibodies (bnAbs) in infection and to recreate those events by vaccination. Here, we report host tolerance mechanisms that limit the development of CD4-binding site (CD4bs), HCDR3-binder bnAbs via sequential HIV-1 Env vaccination. Vaccine-induced macaque CD4bs antibodies neutralize 7% of HIV-1 strains, recognize open Env trimers, and accumulate relatively modest somatic mutations. In naive CD4bs, unmutated common ancestor knock-in mice Env+B cell clones develop anergy and partial deletion at the transitional to mature B cell stage, but become Env− upon receptor editing. In comparison with repetitive Env immunizations, sequential Env administration rescue anergic Env+ (non-edited) precursor B cells. Thus, stepwise immunization initiates CD4bs-bnAb responses, but immune tolerance mechanisms restrict their development, suggesting that sequential immunogen-based vaccine regimens will likely need to incorporate strategies to expand bnAb precursor pools