Development of a synthetic antibody based on the HIV receptor and co-receptor that is optimized for highly efficient killing of HIV-infected cells by ADCC

DESCRIPTION provided by applicant Eliciting antibodies that neutralize human immunodeficiency virus type HIV by vaccination is a daunting challenge due to features of the HIV envelope glycoprotein Env that render it inherently resistant to antibody responses and the extraordinary antigenic diversity that has accrued since the beginning of the HIV pandemic To circumvent these formidable obstacles we are pursuing durable in vivo expression of a synthetic neutralizing antibody by gene therapy as an alternative to conventional vaccine approaches This synthetic antibody eCD Ig is based on the Env binding determinants of the viral receptor CD and the viral coreceptor CCR Consequently eCD Ig neutralizes of strains of HIV and simian immunodeficiency virus SIV tested thus far protects rhesus macaques from infection with simian human immunodeficiency virus SHIV and is itself a poor target for host immune responses Antibody functions in addition to virus neutralization including antibody dependent cell mediated cytotoxicity ADCC may substantially augment the ability of eCD Ig to prevent systemic infection following exposure to HIV The goal of this project is to maximize the capacity of eCD Ig to direct the elimination of virus infected cells by ADCC The resulting ADCC optimized version of eCD Ig may confer greater protection against HIV infection reduce the concentration of eCD Ig that must be sustained in plasma and the mucosa to reliably prevent HIV infection and may increase its effectiveness as a therapeutic in people already infected with HIV PUBLIC HEALTH RELEVANCE A vaccine against HIV could one day end the public health catastrophe this virus continues to cause but conventional vaccine approaches rely on the very immune responses HIV has evolved to evade Expression of a synthetic antibody eCD Ig by gene therapy may provide an alternative route to a safe and effective vaccine against HIV The proposed project to maximize the ability of eCD Ig to direct the killing of virus infected cells may improve its power to prevent HIV infection