There are approximately 2.6 million new infections of human immunodeficiency virus type 1 (HIV-1) and 1.8 million AIDS-related deaths reported annually. Anti-HIV inhibitors are available that can control viral loads, but they are not widely available worldwide and do not eliminate or prevent infection. Thus, an effective vaccine is needed to prevent the continuing spread of HIV. A protective antibody response is generated in about 30% of infected individuals. These potent broadly neutralizing antibodies (bNAb) have been found to target a small number of conserved epitopes on the HIV envelope spike, which is composed of trimeric heterodimers of gp120 and gp41. Presenting these epitopes as heterologous antigens to the immune system provides the best opportunity to re-elicit bNAb's that can protect against HIV infection. Attempts to re-elicit neutralizing antibodies against the gp120 and gp41 epitopes has focused on presenting them as peptides, engineered trimers, and unstructured or structured insertions in heterologous monomeric proteins or virus-like particles. These studies have met with limited success indicating that the structural environment of the cognate epitopes needs to be more faithfully reproduced using control over a wider selection of properties, including the ability to orient and expose key residues and structural features for antibody recognition. We propose a novel strategy for presenting the gp41 epitopes of monoclonal antibodies 4E10 and 10E8 on chimeric virus-like particles (VLPs) engineered to present specific structures on their surfaces. The epitopes will be precisely grafted onto well characterized and highly exposed surface regions of the insect virus Flock House virus (FHV) and bacteriophage PP7 capsids, both proven platforms for displaying biologically active foreign epitopes and protein domains as polyvalent particulate arrays that induce potent antibody responses. The particles will then be used to vaccinate rabbits and the resulting sera characterized by ELISA, in-solution virus capture and neutralization assays. The immunized rabbits are expected to generate neutralizing antibodies whose specificity will be determined in competition experiments. The proposed approach using structure-specific display on VLPs, if successful, could lead to a significant advance in HIV vaccine development.
In this application we propose a new strategy to generate broadly neutralizing antibodies against the MPER region of HIV gp41, which is known to give rise to such antibodies, although only very inefficiently. To increase the potency of the MPER region, we will graft it onto the surface of a virus-like particle that is known to induce a very strong immune response, and the ability of the particles to induce broadly neutralizing antibodies against HIV will then be tested in rabbits and with in vitro assays. The long term goal is to develop one or more particles into an effective vaccine for use in humans.
