Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike
Ronald Derking, Joel D. Allen, Christopher A. Cottrell, Kwinten Sliepen, Gemma E. Seabright, Wen-Hsin Lee, Yoann Aldon, Kimmo Rantalainen, Aleksandar Antanasijevic, Jeffrey Copps, Anila Yasmeen, Albert Cupo, Victor M. Cruz Portillo, Meliawati Poniman, Niki Bol, Patricia van der Woude, Steven W. de Taeye, Tom L.G.M. van den Kerkhof, Per Johan Klasse, Gabriel Ozorowski, Marit J. van Gils, John P. Moore, Andrew B. Ward, Max Crispin, Rogier W. Sanders
Abstract
Artificial glycan holes on recombinant Env-based vaccines occur when a potential N-linked glycosylation site (PNGS) is under-occupied, but not on their viral counterparts. Native-like SOSIP trimers, including clinical candidates, contain such holes in the glycan shield that induce strain-specific neutralizing antibodies (NAbs) or non-NAbs. To eliminate glycan holes and mimic the glycosylation of native BG505 Env, we replace all 12 NxS sequons on BG505 SOSIP with NxT. All PNGS, except N133 and N160, are nearly fully occupied. Occupancy of the N133 site is increased by changing N133 to NxS, whereas occupancy of the N160 site is restored by reverting the nearby N156 sequon to NxS. Hence, PNGS in close proximity, such as in the N133-N137 and N156-N160 pairs, affect each other's occupancy. We further apply this approach to improve the occupancy of several Env strains. Increasing glycan occupancy should reduce off-target immune responses to vaccine antigens.