Comparing CD8+ T cell ENV epitopes of two HLA class I alleles associated with different outcomes of HIV-1 infection with broadly neutralizing antibodies epitope targets discovered to date.

The HIV vaccine field has swung between humoral-based to cell-mediated approaches; however the consensus has evolved toward the understanding that an induction of both may be important for optimal protection. HLA class I molecules present viral epitopes to initiate CD8+ T cell responses to HIV-infected cells while broadly neutralizing antibodies (bNAbs) primarily target free virions. In this study, we systematically compared HIV-1 ENV CD8+ T cell epitopes restricted by two HLA class I alleles associated with divergent HIV-1 infection outcomes with bNAb epitopes reported to date in the literature. To our knowledge, this represents one of the first attempts of examining and reconciling the targets of cellular and humoral immunity in the context of differing HIV infection outcomes. Among 1820 peptides overlapping HIV-1 clades A and D ENV, A*01:01 (associated with slower HIV-1 acquisition) bound to 20, while B*07:02 (associated with susceptibility) bound to 64. No significant differences in affinity or off-rate were noted between A*01:01 and B*07:02 epitopes, and a higher proportion of A*01:01 epitopes are located within constant ENV regions than B*07:02 epitopes (C:V ratio 3:1 versus 2:1, respectively). Of the epitopes and variants discovered in this study, 7 of 20 (35%) A*01:01 and 11 of 64 (17%) B*07:02 binders overlapped with known bNAb target sites. All CD8+ T cell epitopes overlapping CD4-binding site clusters were also bNAbs targets. Notably, all A*01:01 T cell epitopes overlapping bNAb epitopes were within conserved ENV regions, and all but one involved glycan-dependent bNAb binding. The epitope landscape analysis therefore showed the allele associated with slower HIV-1 infection rates presents a narrower repertoire of ENV CD8