HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions
David Easterhoff, et al.
David Easterhoff, et al.
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Research Article AIDS/HIV

HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions

Abstract

In the RV144 HIV-1 phase III trial, vaccine efficacy directly correlated with the magnitude of the variable region 2–specific (V2-specific) IgG antibody response, and in the presence of low plasma IgA levels, with the magnitude of plasma antibody-dependent cellular cytotoxicity. Reenrollment of RV144 vaccinees in the RV305 trial offered the opportunity to define the function, maturation, and persistence of vaccine-induced V2-specific and other mAb responses after boosting. We show that the RV144 vaccine regimen induced persistent V2 and other HIV-1 envelope–specific memory B cell clonal lineages that could be identified throughout the approximately 11-year vaccination period. Subsequent boosts increased somatic hypermutation, a critical requirement for antibody affinity maturation. Characterization of 22 vaccine-induced V2-specific mAbs with epitope specificities distinct from previously characterized RV144 V2-specific mAbs CH58 and CH59 found increased in vitro antibody-mediated effector functions. Thus, when inducing non-neutralizing antibodies, one method by which to improve HIV-1 vaccine efficacy may be through late boosting to diversify the V2-specific response to increase the breadth of antibody-mediated anti–HIV-1 effector functions.

Authors

David Easterhoff, Justin Pollara, Kan Luo, Benjamin Janus, Neelakshi Gohain, LaTonya D. Williams, Matthew Zirui Tay, Anthony Monroe, Kristina Peachman, Misook Choe, Susie Min, Paolo Lusso, Peng Zhang, Eden P. Go, Heather Desaire, Mattia Bonsignori, Kwan-Ki Hwang, Charles Beck, Matina Kakalis, Robert J. O’Connell, Sandhya Vasan, Jerome H. Kim, Nelson L. Michael, Jean-Louis Excler, Merlin L. Robb, Supachai Rerks-Ngarm, Jaranit Kaewkungwal, Punnee Pitisuttithum, Sorachai Nitayaphan, Faruk Sinangil, James Tartaglia, Sanjay Phogat, Kevin Wiehe, Kevin O. Saunders, David C. Montefiori, Georgia D. Tomaras, M. Anthony Moody, James Arthos, Mangala Rao, M. Gordon Joyce, Gilad Ofek, Guido Ferrari, Barton F. Haynes

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Figure 5

Structural analysis of ALVAC/AIDSVAX-induced V2-specific mAbs.

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Structural analysis of ALVAC/AIDSVAX-induced V2-specific mAbs. Crystal s...
Crystal structures of the RV305 Fab DH815 (A, heavy chain in light blue, light chain in pale green), RV305 Fab DH813 (B, light chain in green, heavy chain in blue), RV305 Fab DH822 (C, light chain in teal, heavy chain in marine), and RV144 Fab DH827 (D, light chain in orange, heavy chain in violet), in complex with an HIV-1 V2 peptide (yellow) encompassing HIV-1 gp120 residues 165–186. Upper right: Close-up views rotated 90° relative to the orientation on the left. Residues of V2 peptide that form hydrogen bonds or salt bridges with the respective mAbs are shown in stick representation. Plots of buried interactive surface area per residue on the bound V2 peptide are shown at lower right for each mAb. Interactions with residue K169 are plotted in red and with each respective integrin binding site are plotted in magenta and orange, respectively. Ordered V2 residues in the respective structures are underlined in the shown peptide sequences.