The human immunodeficiency virus type 1 (HIV-1) pandemic continues to spread in the absence of a preventative vaccine. Broadly neutralizing antibodies (bnAbs) against HIV-1 can prevent infection of nonhuman primates, but have thus far not been elicited by vaccination. The HIV-1 envelope is covered by a dense array of host glycans that, if recognized by vaccine-induced antibodies, could generate bnAbs. BnAbs with these specificities arise in natural infection. However, to date, vaccine strategies for eliciting anti-Env glycan antibodies have shown glycan-dependent epitopes to be poorly immunogenic. In my studies of rhesus macaques vaccinated with a group M consensus envelope, CON-S, that contains a substantial proportion of high mannose sugars, I have identified macaque plasma antibodies that block the binding of anti-glycan bnAbs to HIV-1 Env. CON-S Env gp140-immunized macaques also possess sufficient antibody titers for detection of direct glycan binding in their plasma, and I have been successful in isolating glycan-reactive rhesus monoclonal antibodies from CON-S Env-vaccinated animals. The central hypothesis of this application is that immunization with a recombinant Env that is heavily glycosylated with high mannose glycans--similar to the glycoforms present on HIV-1 virions--can induce glycan-dependent neutralizing antibodies, a subset of which are in bnAb lineages. The objectives of this application are to define the development and anti-HIV-1 functions of these novel Env-induced plasma anti-Env glycan antibodies. Thus, in Aim 1, existing and new recombinant blood memory B cell antibodies directed to glycan-dependent HIV-1 envelope epitopes will be produced and their anti-HIV-1 activity characterized.
In Aim 2, we will profile the ontogeny of vaccine-induced anti-glycan antibodies both with recombinant mAb production, computational inference of lineage members, and next-generation VHDJH sequencing. Finally, in Aim 3, we will interrogate the vaccine-induced HIV-1 Env glycan antibody repertoire in secondary lymphoid organs and mucosal tissue after immunization with antigenic, stabilized CON-S gp140 trimers. The results from these studies will be a major step forward in our effort to understand the immunogenicity of HIV-1 envelope glycans that comprise bnAb epitopes. The antibodies characterized here will provide templates for B cell lineage design of immunogens that enhance the glycan-dependent antibody lineages induced by Env vaccination in rhesus macaques and humans.
