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.
