Oral Abstract Session 01 - Global HIV Vaccine Enterprise

Topic 3: B Cell Immunology and Antibody Functions
P03.05
Recognition and Penetration of the HIV-1 Env Glycan
Shield by Potent Broadly Neutralizing Antibodies
J. Julien 8 , L. Kong 8 , R. Pejchal 8 , R. Khayat 1 , J. Lee 1 , R.S. Stanfield 8 ,
L.M. Walker 2 , K.J. Doores 3 , E. Folkowska 3 , P. Poignard 2 ,
R. Depetris 4 , R.W. Sanders 5 , W.C. Koff 6 , J.P. Moore 4 , A.B. Ward 1 ,
D.R. Burton 7 , I.A. Wilson 8
1 Dept. of Molecular Biology, The Scripps Research Institute,
La Jolla, CA, USA; 2 Dept Imm & Microbial Sci & IAVI NAC, The
Scripps Research Institute, La Jolla, CA, USA; 3 The Scripps
Research Institute, Ragon Institute MIT, Boston, MA, USA;
4 Weill Medical College of Cornell University, New York, NY,
USA; 5 Weill Medical College of Cornell University, Academic
Medical Center, Amsterdam, Netherlands; 6 The International
AIDS Vaccine Initiative, New York, NY, USA; 7 Dept. Imm &
Microbial Sci and IAVI NAC TSRI, Ragon Institute MIT, USA;
8 The Scripps Research Institute, La Jolla, CA, USA
Background: Human monoclonal antibodies have been
characterized recently that potently neutralize HIV-1 isolates
across all clades. These exciting new antibodies (PGT series)
were derived from direct functional screening of B cells from IAVI
protocol G donors (Theraclone/Monogram) and are unusually
potent with binding predicted to be to novel glycan-dependent
epitopes on Env.
Methods: Structures of these new PGT antibodies are being
determined by x-ray crystallography and electron microscopy with
further characterization using binding and mutagenesis assays.
Results: The crystal and EM structures so far have been
elucidated for many of these antibodies. Work on the others are
in progress, focusing on Fab complexes with glycans, gp120 core
and fragment constructs, as well as Env trimers.
Conclusion: Structural characterization and biochemical analysis
of these antibodies have uncovered novel specificities to new
glycan-dependent epitopes and reveal further mechanisms
for viral neutralization. These new epitopes provide additional
insights for neutralization of HIV-1 and how antibodies can bind
and penetrate the glycan shield, a novel framework for structureassisted
vaccine design.
This study was supported by the International AIDS Vaccine
Initiative (IAVI), Ragon Institute of MGH, MIT and Harvard, and
NIH AI84817.
P03.06
AIDS Vaccine 2012
Posters
Neutralization and Enhancement of Trans Infection
by Erythrocyte-Bound HIV with Antibodies and
Complement
Z. Beck 1 , G.R. Matyas 2 , V.R. Polonis 2 , C.R. Alving 2
1 HJF / WRAIR / US Military HIV Research Program, Silver
Spring, MD, USA; 2 Walter Reed Army Institute of Research,
Silver Spring, MD, USA
Background: Antibodies to HIV envelope glycoproteins, with or
without neutralization when assayed in standard neutralization
assays, are reported to have potential to exert either inhibitory or
enhancing effects through interactions with complement and/or
Fc receptors. Although most of the standard neutralization assays
use free virus rather than carrier-bound HIV as the infectious
agent; a cell line as the target for infection; and no complement
(C), these conditions may not reflect in vivo events that would
include antibody-dependent innate effector mechanisms.
Methods: We investigated the Fc-receptor-mediated and the
complement-mediated antibody-dependent enhancement
in trans infection neutralization assays using two broadly
neutralizing monoclonal antibodies, 4E10 and b12; primary
HIV; PBMC target cells naturally expressing Fc receptors and
complement receptors; and with or without complement.
Results: In the absence of complement, the 4E10 mAb did not
neutralize erythrocyte-bound HIV, and the b12 mAb neutralized
erythrocyte-bound HIV less effective than the free virus. At
low concentrations, 4E10 caused enhancement of infection.
In contrast, in the presence of complement, 4E10 neutralized
erythrocyte-bound HIV, or caused enhancement of trans infection
of erythrocyte-bound HIV, depending on the mechanism of
binding of HIV to erythrocytes.
Conclusion: Our results are consistent with the concept that
the binding of HIV to erythrocytes represents a mechanism of
establishing a “safe harbor” for HIV from the adverse effects of
antibodies and complement that might otherwise be detrimental
to free circulating HIV. Our data shows that broadly neutralizing
antibody 4E10 can cause both C-mediated neutralization and
enhancement of trans infection. This suggests that erythrocytebound
HIV-1 serves as a sort of battleground between
neutralization and enhancement by antibodies in the presence
of C. Because of this, we propose that induction of neutralizing
vs. enhancing antibodies can only be differentiated by utilization
of a trans infection neutralization assay that might yield more
relevant results for in vivo conditions.
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POSTERS