There is a critical need for a preventative vaccine against human immunodeficiency virus (HIV). Despite continued structural refinement, immunization with soluble HIV envelope glycoprotein (Env) trimer has yet to elicit the desired broadly neutralizing antibodies (bNabs). This delay may in part be due to the inefficient delivery of Env trimer to the follicles of secondary lymphoid organs. The heavy glycosylation of Env, poor complement fixation, and instability in sera all contribute to inefficient trafficking. Previous work to array Env trimer on the surface of liposomes has revealed improved antibody responses following immunization. Here we seek to target Env-displaying liposomes to relevant cell populations native to the lymph node follicle with the goal of increased neutralizing antibody production. We hypothesize that improved targeting of Env trimer to the lymph node will bias the antibody repertoire towards neutralizing phenotypes. This will be accomplished by targeting liposome-bound Env trimer to the two cell populations directing germinal center (GC) B cell affinity maturation. First, the antigen reservoir of follicular dendritic cells will be targeted, allowing for continual exposure of GC B cells to neutralizing epitopes. During natural infection, sustained antigen presentation to GC B cells has been shown to stimulate somatic hypermutation, affinity maturation, and the development of unusually long heavy chain complementary determining region 3 (HCDR3), characteristic of bNabs. Second, antigen-specific cognate T follicular helper (Tfh) cell populations will be increased by targeting immunogen to CLEC9A+XCR1+ dendritic cells, responsible for activating Tfh cells. Previous work has shown that a large Tfh cell population may reduce competition between neutralizing and non-neutralizing epitope-specific B cells, favoring the development of neutralizing antibodies.
Aim 1 focuses on the delivery of intact Env trimer to the follicular dendritic cell antigen reservoir, while Aim 2 looks to target delivery to CLEC9A+XCR1+ dendritic cells with the goal of expanding the antigen specific Tfh cell population.
The final Aim looks to characterize the Tfh and B cell response to immunization with each targeting approach alone and in combination. If successful, this work will provide a flexible platform for targeted antigen delivery capable of boosting neutralizing antibody production against HIV. !
Current approaches to HIV vaccine design focus on the refinement of the HIV envelope trimer structure with less consideration of the efficiency of immunogen delivery to and retention in lymph nodes. This project seeks to develop particulate arrays by liposomal presentation of Env trimer to target intact immunogen to the follicular dendritic cell antigen reservoir and to enhance the engagement of antigen-specific T follicular helper cells. If successful, this work will provide a flexible platform for lymph node targeting of multiple vaccine immunogens with the aim of maximizing neutralizing antibody production. !
