Persistent Immunogenicity of IDLV delivering Gag and membrane tethered HIV-1 Envelope Trimers - ABSTRACT Halting the spread of HIV-1 infection with a protective vaccine continues to be a global health priority. Passive immunotherapy with broadly neutralizing antibodies (bnAbs), and vaccine-induced autologous tier 2 nAbs, have proven effective in preventing simian-human immunodeficiency virus (SHIV) infection in non-human primates (NHPs). Thus, eliciting nAbs, preferably bnAbs, is thought to be required for a protective vaccine against HIV-1 infection, but inducing high titers of nAbs that persist for long period of time is a difficult task. Our group has developed both HIV-1 and SIV-based Integrase-Defective Lentiviral Vectors (IDLVs) to deliver a broad range of antigens (Ag) for induction of durable antigen (Ag)-specific immune responses in both mice and NHPs. IDLVs offer significant advantages in addressing limitations shown by other vaccine platforms. IDLV persistently expresses the encoded-Ag, and induces higher magnitude antibody responses with extended durability compared to other common vaccine platforms, including DNA, protein and mRNA. To elicit protective, durable immune responses with vaccination, we will optimize two crucial aspects toward an effective HIV vaccine: the vaccine delivery platform and a multi-antigen Gag-Env strategy to elicit durable neutralizing antibodies and T cell responses. The overall hypothesis to be tested in these studies is that a vaccination strategy where a trimeric stabilized HIV-1 Env is persistently expressed by IDLV will lead to initiation and affinity maturation of nAb B cell lineages in Rhesus Macaques (RMs). Furthermore, we hypothesize that the presentation of these stabilized Env trimers by IDLV in a membrane tethered conformation will enhance immunogenicity. Additionally, the inclusion of SIV-Gag will stimulate strong CD4 and CD8 T cell responses that will enhance protection from SHIV challenge. The overall strategy will be to use the RM model systems to elucidate the mechanisms driving IDLV’s persistent immunogenicity by performing in depth immune responses analysis in longitudinal blood, lymph nodes and bone marrow samples. We will combine transcriptomics with flow cytometry functional assays to study the landscape of immune cells in IDLV vaccinated RMs that is associated with vaccine-induced nAb responses. We will also study the ontogeny and dynamics of B cells using BCR sequencing over time to look for evidence of increased mutation rates and clonal expansion. Results from this project will significantly advance our understanding of how the delivery modality and immunogen strategy contribute to durability and efficacy of vaccine induced immune responses.
