Fusion peptide priming reduces immune responses to HIV-1 envelope trimer base
Angela R. Corrigan, Hongying Duan, Cheng Cheng, Christopher A. Gonelli, Li Ou, Kai Xu, Megan Demouth, Hui Geng, Sandeep Narpala, Sarah O’Connell, Baoshan Zhang, Tongqing Zhou, Manjula Basappa, Jeffrey C. Boyington, Steven J. Chen, Sijy O’Dell, Amarendra Pegu, Tyler Stephens, Yaroslav Tsybovsky, Jelle van Schooten, John Paul Todd, Shuishu Wang, Nicole A. Doria-Rose, Kathryn E. Foulds, Richard A. Koup, Adrian B. McDermott, Marit J. van Gils, Peter D. Kwong, John R. Mascola
Abstract
Soluble "SOSIP"-stabilized envelope (Env) trimers are promising HIV-vaccine immunogens. However, they induce high-titer responses against the glycan-free trimer base, which is occluded on native virions. To delineate the effect on base responses of priming with immunogens targeting the fusion peptide (FP) site of vulnerability, here, we quantify the prevalence of trimer-base antibody responses in 49 non-human primates immunized with various SOSIP-stabilized Env trimers and FP-carrier conjugates. Trimer-base responses account for ∼90% of the overall trimer response in animals immunized with trimer only, ∼70% in animals immunized with a cocktail of SOSIP trimer and FP conjugate, and ∼30% in animals primed with FP conjugates before trimer immunization. Notably, neutralization breadth in FP-conjugate-primed animals correlates inversely with trimer-base responses. Our data provide methods to quantify the prevalence of trimer-base responses and reveal that FP-conjugate priming, either alone or as part of a cocktail, can reduce the trimer-base response and improve the neutralization outcome.