Safety and Durability of Integrase Defective Lentiviral vector for an HIV Vaccine

Duke University, Durham NC

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Abstract

The overall goal of this HIVRAD proposal is to provide the scientific basis for the development of Integration- Defective Lentiviral Vectors (IDLV) with a strategic immunogen as an improved delivery system for HIV antigens that will lead to an effective HIV vaccine. The central hypothesis is that delivery of novel envelope immunogens via IDLV results in safe and sustained expression of the antigen in vivo, allowing induction of long-term antigen-specific response, including maturation of broadly neutralizing antibodies (bnAbs). Project 1 will focus on components by addressing safety (non-integrating and non-replicating), sustained antigen expression and the durability of the immune response. Preliminary data obtained following a single injection using a SIV-based IDLV in non-human primates (NHP) has demonstrated for the first time prolonged, high humoral and cellular responses, setting the stage for further evaluation of this promising antigen delivery system in NHP. Specific aim 1 will construct, produce and validate each batch of the IDLV vaccine preparation before in vivo immunization by determining antigen expression, non-integration in vitro and absence of replication competent lentivirus (RCL) in vitro. Specific aim 2 will focus on demonstrating the persistence and safety of IDLV in vivo in NHP. RNA and protein expression of HIV envelopes will be assessed over time following intramuscular delivery in NHP (protocol A, Core B). The in vivo safety of the vector will be assessed using sensitive assays to determine integration status and the absence of RCLs in vivo. Specific aim 3 will use the murine system to evaluate biodistribution, safety, persistence of antigen expression and presentation after intramuscular immunization with IDLV and to identify cells expressing the transgene in vivo. Analysis of innate and adaptive immune response both locally (at the site of injection) and systemically (spleens and LN) will be correlated with duration of antigen expression to understand the basis of IDLV-induced persistence of immune response. Information derived from this project will be integrated with antibody maturation analysis (project 2) to determine the full potential of an IDLV-based strategy for a HIV vaccine.