HIV-1 broadly neutralizing antibodies (bnAbs) are difficult to induce in vaccines but are generated in some HIV-infected individuals. Understanding the cellular and molecular mechanisms of host control of bnAb induction is critical for vaccine design. Using Systems Immunology approaches, we have identified a predictive blood signature associated with HIV bnAbs, indicative of strong CD4 T follicular helper responses and reduced tolerance constraints. To this end, we will discuss methods and techniques applied to overcome the challenges involved in patient cohorts with limited cell numbers, lack of tissue samples, and data scarcity. These include high-dimensional spectral flow cytometry (38+colours), curtailed in vitro functional assays, and non-human primate models to provide mechanistic insight. Together, these findings suggest mechanistic targets for regulating HIV-1 bnAb responses that could be modulated in vaccine platforms.