The Role of Immunoglobulin Genetic Diversity in the Development of Neutralizing Antibodies Against HIV Env Protein

Abstract The humoral immune system relies on the rich diversity of the antibody binding repertoire to generate targeted responses to the vast array of antigens one may encounter, and much work has been done to characterize the factors generating this diversity. However, allelic variation at the highly polymorphic immunoglobulin heavy chain (IGH) gene locus has remained largely unexplored as a factor impacting the specificity of antibody responses to both infection and vaccination. While many antigens are capable of eliciting strong neutralizing responses across the population regardless of IGH haplotype, recent studies have shown that certain alleles encoding IGH gene segments impact the magnitude of neutralizing antibody responses to viral antigens in humans. Differential development of neutralizing antibody titers in response to HIV immunogens across individuals is well documented, with only around 20% of HIV infected individuals developing broadly neutralizing antibodies (bNAbs). Similarly, BG505.SOSIP.664, a tier 2 HIV envelope glycoprotein (env) immunogen, has been shown to elicit a wide range of humoral responses in rhesus macaques (RM), with some developing high titers of nAbs capable of protection against autologous SHIV challenge, while others develop very low nAb titers not capable of such protection. We hypothesize that germline IGH polymorphisms and allelic representation within the antigen specific B cell repertoire contribute to the variation in Nab titers observed in response to BG505 SOSIP.664 vaccination. The goal of this project is to determine how allelic variation at IGH genes in rhesus macaques affects the development of nAbs, in the following two Specific Aims: (1) to identify IGH polymorphisms in RM vaccinated with BG505SOSIP.644 associated with differential development of nAb titers (2) to identify the epitope specificity of the antibody repertoire encoded by alleles associated most strongly with high nAb titers. These experiments will uncover a factor contributing to the diversity of humoral immune responses at the population level, and in doing so we will contribute to the establishment of a non-human primate model for studying the effects of genotype on antibody responses to vaccines against various human pathogens. Our results will greatly enhance the rational design and development of germline targeting vaccines.