Inducing Broadly Neutralizing Antibodies to Protect Against HIV

About This Grant

AI97990A1 “Inducing Broadly Neutralizing Antibodies to Protect Against HIV” ABSTRACT Current HIV-1 vaccine strategies seek to engage naïve precursors of broadly neutralizing antibodies (bNAbs), such as the CD4-binding site (CD4bs) targeted ‘VRC01 class’ unmutated common ancestor (UCA), then drive its aKinity maturation toward breadth. In early studies, VRC01 UCAs did not bind to native HIV envelope glycoprotein (Env) trimers. However, a number of soluble Envs, including eOD-GT8, 426c gp120 core and BG505 SOSIP GT1.1 trimers were developed to successfully prime VRC01 class UCAs. These priming immunogens were engineered for increased sensitivity to VRC01-class UCAs. Changes include deletions of the N-linked potential glycosylation sites at Env position 276 (N276) and in the V5 loop, changes in loop D (Env positions 275-283), and/or other engineered changes to improve sensitivity. Boosting immunogens must be native or near native to be able to mature activated VRC01 class UCAs to become bNAbs. To date, no boosting immunogen has been able to successfully mature precursor ‘VRC01 class’ Abs toward bNAb status. Current boosting immunogens appear to lack the stringency needed to mature VRC01 activated UCAs fully accommodate the N276 glycan in functional Env trimers. A second limitation of current ‘VRC01 class’ bNAb lineage development strategies is that ‘oK-target’ epitopes on HIV-1 Env immunogens may dampen responses to desired sites. To address these challenges, we engineered native gp120/gp41 Env trimers to engage bNAb UCA B cells to induce the VRC01 lineage, thus increasing the possibility of maturing the UCAs to bNAb status with our cocktail of native trimer boosting immunogens. We will test our immunogens in appropriate animal models via delivery by nucleic acid in an authentic context to trigger and boost VRC01 UCAs to overcome the N276 glycan. Our Specific Aims are: 1. To express pure or nearly pure native membrane trimers that engage the VRC01 UCA. 2. To use native trimers to induce broad and potent bNAbs in VRC01 knock-in mice. 3. To define the maturation pathway of bNAbs elicited by native trimers in rhesus NHPs. We hypothesize that pure or nearly pure native trimer immunogens will provide the requisite stringency to stimulate VRC01 UCAs and guide them to become bNAbs. Our overall goal is to design and test a ‘native trimer’ prime-boost series to induce VRC01 class bNAbs. Our scientific premise is that native trimers, as the exclusive targets of NAbs provide an ideal format to induce NAbs.