Fusion peptide specific B cell responses and the role of follicular T cells in accelerated antibody maturation

University Of California At Davis, Davis CA

Investigators

Abstract

Project 1. Abstract: Different regions of HIV Env have been identified as targets of broadly neutralizing Ab activity. The maturation, magnitude and breadth of such bNAb is a critical challenge for HIV vaccine development as the evolution of these responses to broad neutralization requires a lengthy and complex maturation process with rounds of somatic mutations in the B-cell follicle. This is also the case for the Fusion Peptide region in Env, which has emerged as a promising vaccine target. Among others, vaccine immunogen persistence and dose are considered important factors in the maturation process for bNAb, possibly linked to the need for durable helper function provided by follicular T cells. The main hypothesis of Project 1 is that bNAb activity early in infection, referred to here as accelerated neuralization, is dependent on strong Tf help, which could not only be mediated by CD4+ Tfh cells but also by CD8+ Tfc. Indeed, while envelope-specific follicular CD4+ T-helper (Tfh) have been shown to provide help for B cell responses, concerns exist that these cells may also facilitate breakthrough infections. For that reason, across all three projects, the inclusion of CD8+ Tfc that could supplement or even substitute such CD4+ Tfh is a central theme. In Project 1, we will use human samples from unique clinical trial and cohort studies, to identify Env- and FP-derived sequence variants associated with broad neutralization and ask whether these or other targets in Env/FP serve as targets for an effective CD4+ and/or CD8+ Tf response. Through innovative in vitro experimentation, we will validate these in vivo observations and functionally test whether and how these cells drive the maturation of broadly neutralizing Ab responses. A successful outcome of our work will produce a more complete picture of the role that FP targeting and Tf cells play in the development of effective humoral immunity to HIV and clarify whether CD8+ Tfc are a specific subset of the total CD8+ T cell response to viral infections that can be leveraged by vaccination. These insights would provide the base for fundamentally new prophylactic HIV vaccine strategies that de-risk current approaches and that aim to mobilize all possibly available follicular help and Env/FP-immunogen variants to effectively accelerate the extraordinarily complex maturation of HIV specific B cell immunity.