Abstract
SummaryBroadly neutralizing antibodies (bNAbs) against HIV-1 envelope (Env) inform vaccine design and are potential therapeutic agents. We identified SF12 and related bNAbs with up to 62% neutralization breadth from an HIV-infected donor. SF12 recognized a glycan-dominated epitope on Env’s silent face and was potent against clade AE viruses, which are poorly covered by V3-glycan bNAbs. A 3.3Å cryo-EM structure of a SF12-Env trimer complex showed additional contacts to Env protein residues by SF12 compared with VRC-PG05, the only other known donor-derived silentface antibody, explaining SF12's increased neutralization breadth, potency, and resistance to Env mutation routes. Asymmetric binding of SF12 was associated with distinct N-glycan conformations across Env protomers, demonstrating intra-Env glycan heterogeneity. Administrating SF12 to HIV-1-infected humanized mice suppressed viremia and selected for viruses lacking the N448gp120 glycan. Effective bNAbs can therefore be raised against HIV-1 Env’s silent face, suggesting their potential for HIV-1 prevention, therapy, and vaccine development.
Highlights
Apart from an interventional study during which the subject started and stopped anti-retroviral therapy (ART) at set intervals from 1998–2001, the subject has been off ART (Figure 1A)
The individual’s purified immunoglobulin G (IgG) isolated from a 2005 time point was evaluated for neutralization against a 12-virus panel representative of the global epidemic (Figure 1B) and found to be both broad and potent with a coverage of 92% and an average median inhibitory concentration (IC50) of 92.3 mg/mL (Figure 1B)
From a starting number of 4.4 3 104 memory B cells, we identified seven B cells, six of which were members of a single clone, that showed potent anti-HIV-1 neutralizing activity against two indicator strains
Summary
DETAILSIgG isolation for polyclonal IgG neutralization testing IgG from subject 27845 was purified from heat-inactivated (1h 56C) plasma (late 2005 time point) using Protein G Sepharose 4 Fast Flow (GE Healthcare), buffer exchanged into phosphate buffered saline (PBS) using an Amicon Ultra 30 kDa (Millipore), and sterilefiltered.Neutralization fingerprinting analysis Neutralization fingerprinting (Figure 1B) of the polyclonal antibody response of subject 27845 was done using a panel of 20 diverse HIV-1 strains (Doria-Rose et al, 2017). The neutralization fingerprint of a serum/polyclonal IgG (the potency-defined pattern of neutralization of a set of diverse viral strains) is represented as a combination of the neutralization fingerprints of a reference set of bNAbs, grouped in ten epitope-specific clusters. Using this method, the prevalence of each of the ten antibody groups can be estimated for the given serum/polyclonal IgG, with prevalence scores ranging between 0 (low) and 1 (high). The correlations between the neutralization fingerprints (the antibody-specific pattern of neutralization of a set of diverse HIV-1 strains) were computed for each pair of antibodies. Antibodies that cluster closely together in the tree may indicate similar patterns of neutralization sensitivity/resistance for the given set of strains
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