Immunization with HIV-1 trimeric SOSIP.664 BG505 or founder virus C (FVC(Env)) covalently complexed to two-domain CD4(S60C) elicits cross-clade neutralizing antibodies in New Zealand white rabbits

Background: An ongoing challenge in HIV-1 vaccine research is finding a novel HIV-1 envelope glycoprotein (Env)-based immunogen that elicits broadly cross-neutralizing antibodies (bnAbs) without requiring complex sequential immunization regimens to drive the required antibody affinity maturation. Previous vaccination studies have shown monomeric Env and Env trimers which contain the GCN4 leucine zipper trimerization domain and are covalently bound to the first two domains of CD4 (2dCD4(S60C)) generate potent bnAbs in small animals. Since SOSIP.664 trimers are considered the most accurate, conformationally intact representation of HIV-1 Env generated to date, this study further evaluated the immunogenicity of SOSIP.664 HIV Env trimers (the well characterized BG505 and FVC(Env)) covalently complexed to 2dCD4(S60C). Methods: Recombinant BG505 SOSIP.664 and FVC(Env) SOSIP.664 were expressed in mammalian cells, purified, covalently coupled to 2dCD4(S60C) and antigenically characterized for their interaction with HIV-1 bnAbs. The immunogenicity of BG505 SOSIP.664-2dCD4(S60C) and FVC(Env) SOSIP.664-2dCD4(S60C) was investigated in New Zealand white rabbits and compared to unliganded FVC(Env) and 2dCD4(S60C). Rabbit sera were tested for the presence of neutralizing antibodies against a panel of 17 pseudoviruses. Results: Both BG505 SOSIP.664-2dCD4(S60C) and FVC(Env) SOSIP.664-2dCD4(S60C) elicited a potent, HIV-specific response in rabbits with antibodies having considerable potency and breadth (70.5% and 76%, respectively) when tested against a global panel of 17 pseudoviruses mainly composed of harder-to-neutralize multiple clade tier-2 pseudoviruses. Conclusion: BG505 SOSIP.664-2dCD4(S60C) and FVC(Env)SOSIP.664-2dCD4(S60C) are highly immunogenic and elicit potent, broadly neutralizing antibodies, the extent of which has never been reported previously for SOSIP.664 trimers. Adding to our previous results, the ability to consistently elicit these types of potent, cross-neutralizing antibody responses is dependent on novel epitopes exposed following the covalent binding of Env (independent of sequence and conformation) to 2dCD4(S60C). These findings justify further investment into research exploring modified open, CD4-bound Env conformations as novel vaccine immunogens.