Investigating the Protective Efficacy of SIV/HIV T and B cell Immunity Induced by RNA Replicons

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ABSTRACT The development of a prophylactic vaccine for HIV would benefit from the generation of immunogens and vaccine delivery modalities that can induce a combination of highly functional CD8+ T cell responses towards mutation constrained epitopes and broadly neutralizing antibody responses to the HIV envelope trimer. Thus, in this proposal, we plan to leverage three components towards this goal: an approach known as structure-based network analysis that was used to identify a set of protective epitopes preferentially targeted by CD8+ T cell responses in spontaneous HIV controllers, 2) an envelope trimer that is capable of eliciting heterologous neutralizing antibody responses and 3) and an innovative vaccine delivery platform of self-amplifying RNA replicons that can elicit both robust CD8+ T cell and humoral immunity. Having applied structure-based network analysis to SIV protein structures, we have already identified a set of mutation constrained (‘highly networked’) SIV epitopes restricted by an array of Mamu class I alleles. In addition, we have also produced compelling data demonstrating the ability of RNA replicons to induce CD8+ T cell responses to highly networked SIV epitopes and strong trimer-specific antibody responses in rhesus macaques. What remains to be determined is whether functional CD8+ T cell responses towards highly networked SIV epitopes have a protective benefit against heterologous challenge, either individually or in tandem with antibodies. Thus, in Aim 1 of this proposal we will assess the protective efficacy of a RNA replicon vaccine immunogen comprised of highly networked SIV epitopes in a group of 20 rhesus macaques. These immunized macaques will be divided equally between those receiving mock immunization or highly networked SIV epitope immunization (10 per group). Following immunization, vaccine-induced CD8+ T cell responses directed against highly networked SIV epitopes will be assessed and vaccinated animals would then be subjected to repeated low dose SHIV.BG505 challenge. These SHIV challenged macaques will have viral load, CD4 count and CD8+ T cell phenotype assessments every 2 weeks during the challenge period and for 20 weeks following the challenge period as well. Go/No-Go criteria regarding T cell immunogenicity and the effects of vaccination on SHIV viral loads will be established and evaluated at the end of year 2. In Aim 2, we will assess the immunogenicity and efficacy of a combined RNA replicon-based vaccination with a highly networked SIV epitope immunogen and HIV Env trimer immunogen. These immunized macaques will be divided equally between those receiving mock immunization, HIV Env trimer + mock immunization and a combination of both HIV Env Trimer and highly networked SIV epitope immunogens (10 per group). These studies will help determine whether vaccine-induced CD8+ T cell responses directed towards highly networked epitopes can provide a protective benefit either individually or in combination with antibody- based vaccination. Additionally, this work will provide critical support of the self-amplifying RNA replicon vaccine delivery platforms towards the development of an effective, prophylactic HIV vaccine.