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Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations.

ABSTRACT: 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.

SUBMITTER: Williams WB

PROVIDER: S-EPMC5701043 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations.

Williams Wilton B WB Zhang Jinsong J Jiang Chuancang C Nicely Nathan I NI Fera Daniela D Luo Kan K Moody M Anthony MA Liao Hua-Xin HX Alam S Munir SM Kepler Thomas B TB Ramesh Akshaya A Wiehe Kevin K Holland James A JA Bradley Todd T Vandergrift Nathan N Saunders Kevin O KO Parks Robert R Foulger Andrew A Xia Shi-Mao SM Bonsignori Mattia M Montefiori David C DC Louder Mark M Eaton Amanda A Santra Sampa S Scearce Richard R Sutherland Laura L Newman Amanda A Bouton-Verville Hilary H Bowman Cindy C Bomze Howard H Gao Feng F Marshall Dawn J DJ Whitesides John F JF Nie Xiaoyan X Kelsoe Garnett G Reed Steven G SG Fox Christopher B CB Clary Kim K Koutsoukos Marguerite M Franco David D Mascola John R JR Harrison Stephen C SC Haynes Barton F BF Verkoczy Laurent L

Nature communications 20171123 1

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 CD4 ...[more]

PMID: 29170366

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Project description:The trimeric envelope spikes on the HIV-1 virus surface initiate infection and comprise key targets for antiviral humoral responses. Circulating virions variably present intact envelope spikes, which react with neutralizing antibodies; and altered envelope structures, which bind non-neutralizing antibodies. Once bound, either type of antibody can enable humoral effector mechanisms with the potential to control HIV-1 infection in vivo. However, it is not clear how the presentation of neutralizing vs. non-neutralizing epitopes defines distinct virus populations and/or envelope structures on single particles. Here we used single-virion fluorescence correlation spectroscopy (FCS), fluorescence resonance energy transfer (FRET), and two-color coincidence FCS approaches to examine whether neutralizing and non-neutralizing antibodies are presented by the same envelope structure. Given the spatial requirements for donor-acceptor energy transfer (≤10 nm), FRET signals generated by paired neutralizing and non-neutralizing fluorescent Fabs should occur via proximal binding to the same target antigen. Fluorescent-labeled Fabs of the neutralizing anti-gp120 antibodies 2G12 and b12 were combined with Fabs of the non-neutralizing anti-gp41 antibody F240, previously thought to mainly bind gp41 "stumps." We find that both 2G12-F240 and/or b12-F240 Fab combinations generate FRET signals on multiple types of virions in solution. FRET efficiencies position the neutralizing and non-neutralizing epitopes between 7.1 and 7.8 nm apart; potentially fitting within the spatial dimensions of a single trimer-derived structure. Further, the frequency of FRET detection suggests that at least one of such structures occurs on the majority of particles in a virus population. Thus, there is frequent, overlapping presentation of non-neutralizing and neutralizing epitope on freely circulating HIV-1 surfaces. Such information provides a broader perspective of how anti-HIV humoral immunity interfaces with circulating virions.

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Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations.

Publications

Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations.

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