Anti-V2 antibodies virus vulnerability revealed by envelope V1 deletion in HIV vaccine candidates

Silva de Castro, Isabela; Gorini, Giacomo; Mason, Rosemarie; Gorman, Jason; Bissa, Massimiliano; Rahman, Mohammad A.; Arakelyan, Anush; Kalisz, Irene; Whitney, Stephen; Becerra-Flores, Manuel; Ni, Eric; Peachman, Kristina; Trinh, Hung V.; Read, Michael; Liu, Mei-Hue; Van Ryk, Donald; Paquin-Proulx, Dominic; Shubin, Zhanna; Tuyishime, Marina; Peele, Jennifer; Ahmadi, Mohammed S.; Verardi, Raffaello; Hill, Juliane; Beddall, Margaret; Nguyen, Richard; Stamos, James D.; Fujikawa, Dai; Min, Susie; Schifanella, Luca; Vaccari, Monica; Galli, Veronica; Doster, Melvin N.; Liyanage, Namal P.M.; Sarkis, Sarkis; Caccuri, Francesca; LaBranche, Celia; Montefiori, David C.; Tomaras, Georgia D.; Shen, Xiaoying; Rosati, Margherita; Felber, Barbara K.; Pavlakis, George N.; Venzon, David J.; Magnanelli, William; Breed, Matthew; Kramer, Josh; Keele, Brandon F.; Eller, Michael A.; Cicala, Claudia; Arthos, James; Ferrari, Guido; Margolis, Leonid; Robert-Guroff, Marjorie; Kwong, Peter D.; Roederer, Mario; Rao, Mangala; Cardozo, Timothy J.; Franchini, Genoveffa

The efficacy of ALVAC-based HIV and SIV vaccines in humans and macaques correlates with antibodies to envelope variable region 2 (V2). We show here that vaccine-induced antibodies to SIV variable region 1 (V1) inhibit anti-V2 antibody-mediated cytotoxicity and reverse their ability to block V2 peptide interaction with the α(4)β(7) integrin. SIV vaccines engineered to delete V1 and favor an α helix, rather than a β sheet V2 conformation, induced V2-specific ADCC correlating with decreased risk of SIV acquisition. Removal of V1 from the HIV-1 clade A/E A244 envelope resulted in decreased binding to antibodies recognizing V2 in the β sheet conformation. Thus, deletion of V1 in HIV envelope immunogens may improve antibody responses to V2 virus vulnerability sites and increase the efficacy of HIV vaccine candidates.