Characterization of MPER broad neutralizing antibodies in a person living with HIV-1 9202

Abstract Description Eliciting broadly neutralizing antibodies (bNAbs) remains a key goal in HIV-1 vaccine research. bNAbs targeting the membrane proximal external region (MPER) on the HIV-1 Envelope are highly cross-reactive and are templates for vaccine design. Prior studies defined early events in MPER bNAb development, however, later stages of development need further investigation. Participant 40512 from the RV217 actue-infection longitudinal cohort was followed 4+ years after detection of viral RNA. From this participant, the VRC42 MPER-directed bNAb lineage was isolated and characterized at day 646. Notably, VRC42 was highly similar to bNAbs isolated from several unrelated individuals, suggesting common pathways exist that elicit MPER bNAbs. In this study, 30 new VRC42 lineage bNAbs were isolated from days 1142-1427 via fluorescent-activated cell sorting with MPER probes, followed by rapid amplification, transfection, and production of immunoglobulins (RATP-Ig); and assessed for neutralization activity. Sequence analysis revealed expansion of the VRC42 lineage, somatic hypermutation rates of 10-18%, and multiple amino acid changes in the heavy chain (HC) and light chain genes. Site-directed mutagenesis of the HC, followed by neutralization testing, identified that changes in the CDRH1, CDRH2, and CDRH3, in different sublineages, increased neutralization potency against auto- and heterologous strains. Understanding the fine details of bNAb development will aid in vaccine design for bNAbs. Topic Categories Vaccines and Immunotherapy (VAC)