Rapid Identification of Antigen-Specific Monoclonal Antibodies from HIV-1 Elite Controllers Using the Beacon Single-Cell Platform

Elite controllers (ECs) are rare human immunodeficiency virus (HIV) infected individuals who manage viral replication without antiretroviral therapy. While their cellular immunity is well-characterized, humoral responses remain limited. Using single-cell functional screening, this study aimed to isolate and characterize HIV-1 envelope (Env) specific monoclonal antibodies (mAbs) from an EC. The Beacon® platform helped in enrichment, activation, and screening of cluster of differentiation 27+ (CD27⁺) memory B cells. Out of ~12,000 single B cells, we identified 40 Env-specific IgG-secreting cells. Although 18 mAbs were recovered, six showed high-affinity binding to multiple Env trimers (average EC50 < 100 ng/mL). Notably, one mAb (2#) neutralized 15 of 17 pseudoviruses with a geometric mean half maximal inhibitory concentration (IC50) of 46.53 μg/mL. Sequence analysis revealed a predominant usage of IGHV1-69 and varied somatic hypermutation levels. However, the high binding affinity could not consistently predict neutralization potency. This study demonstrated the utility of integrated single-cell screening for rapid antibody discovery from rare donors. It also highlighted the need for functional assessment in HIV-1 antibody development and identifying an mAb candidate with moderate breadth and potency for potential therapeutic or vaccine applications.