214 Derivation and Characterization of Novel Anti-HIV Envelope Monoclonal Antibodies from Macaques Vaccinated With a Constrained HIV Gp120 Immunogen and Challenged with SHIV162p3

Abstract

An approach to the development of an effective vaccine to HIV will be to generate antibodies that recognize conserved HIV envelope domains and thereby afford protection against heterologous infection. We have been exploring the approach of targeting epitopes located in the HIV-1 envelope glycoprotein (gp120) that are exposed on transition state structures formed after attachment to the CD4 receptor. These so-called CD4-induced (CD4i) epitopes comprise some of the most conserved and functionally important domains on the viral envelope including the co-receptor binding site; further, cognate antibodies appear in most HIV infected individuals and are cross-reactive for neutralizing and other antiviral activities against heterologous HIV strains in vitro. Towards this goal, rhesus macaques were vaccinated with a gp120 immunogen that is constrained into a transition state structure by covalent linkage to macaque CD4 (rhesus full-length signal-chain; rhFLSC) in order to favor the immunogenicity of CD4i epitopes. These animals developed conventional cross-reactive neutralizing activities and exhibited non-sterilizing control of heterologous mucosal challenge with SHIV162P3 that correlated with stronger responses to CD4i epitopes in the rhFLSC-vaccinated animals. Further, viremia associated with infection significantly boosted conventional neutralizing and CD4i responses. To census and characterize the antibody specificities in these animals, we employed a new algorithm to isolate monoclonal antibodies (Mabs) from rhesus macaques. So far, we have isolated several anti-CD4i epitope Mabs from vaccinated/challenged animals that showed the most broadly neutralizing responses following vaccination and/or challenge. Antibodies with other specificities for the HIV envelope have also been identified. The variable (V)-gene usage, CDR-H3 length, potency and breadth of neutralization exhibited by various Mabs will be presented.