Qualitative Characteristics of HIV-1-Specific CD4+ T Cells Responses Associated With Broadly Neutralizing Antibody Response

Abstract

The underlying mechanism responsible for the development of broadly neutralizing antibodies (bNAbs) in natural infection is poorly understood. Current findings suggest that a sufficient help of CD4+ T cells to B cells is required in the development of bNAbs. At the clinical level, it is unclear whether bNAbs generating individuals exhibit more robust HIV-1-specific CD4+ T cells responses, thereby providing better help to B cells during infection. We hypothesized bNAbs response generating individuals to possess superior qualitative characteristics in their HIV-1-specific CD4+ T cells responses compared to non-neutralizers. In this study, in vitro stimulation assay that allows the evaluation of the combined CD4-orchestrated cellular immune response to HIV-1 antigens was performed. CD8+ depleted peripheral blood mononuclear cells (PBMCs) of chronically HIV-infected subjects with different capability of generating bNAbs response were stimulated with Gag peptide pools for 48 hours. Qualitative characteristics of HIV-1-specific CD4+ T cells are analyzed based on 34 chemokines and cytokines secretion in the supernatant. HIV-1-specific CD4+ T cells from broad neutralizers showed to have a unique capacity to stimulate production of the cardinal cytokine CXCL13 that has been previously associated with germinal center formation and development of broadly neutralizing antibodies against HIV. Linear discriminant analysis (LDA) and partial least square discriminant analysis (PLSDA) also showing CXCL13 to be positively correlated with neutralization. Immunofluorescence staining of the lymph node section showed that CXCL13 was exclusively found in the follicle. Although CXCL13 is thought to be a natural ligand for CXCR5, not all cells that expressed CXCL13 have CXCR5 co-staining. It may suggest that CXCL13 is not exclusively expressed by CXCR5+ CD4+ T cells in the germinal centers and other follicular cell subset may contribute.