Early Antibody Lineage Diversification and Independent Limb Maturation Lead to Broad HIV-1 Neutralization Targeting the Env High-Mannose Patch

Abstract

SUMMARY The high-mannose patch on HIV Env is a preferred target for broadly neutralizing antibodies (bnAbs), but to date, no vaccination regimen has elicited bnAbs against this region. Here, we present the development of a bnAb lineage targeting the high-mannose patch in an HIV-1 subtype-C-infected donor from sub-Saharan Africa. The Abs first acquired autologous neutralization, then gradually matured to achieve breadth. One Ab neutralized >47% of HIV-1 strains with only ~11% somatic hypermutation and no insertions or deletions. By sequencing autologous env, we determined key residues that triggered the lineage and participated in Ab-Env coevolution. Next-generation sequencing of the Ab repertoire showed an early expansive diversification of the lineage followed by independent maturation of individual limbs, several of them developing notable breadth and potency. Overall, the findings are encouraging from a vaccine standpoint and suggest immunization strategies mimicking the evolution of the entire high-mannose patch and promoting maturation of multiple diverse Ab pathways.

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

“…The development of V3-glycan bnAb B cell lineages over time and the co-evolution with autologous TF virus have been recently elucidated by three independent groups in different individuals: chronically HIV-1 infected adult individuals PC76 (20) and CH848 (Bonsignori M. et al, submitted), and an infant who became infected during the first 4 months after birth, likely through breastfeeding (28). …”

“…MacLeod and colleagues isolated a V3-glycan bnAb lineage (the PCDN lineage ) with moderate neutralization breadth and potency (20). PCDN neutralization was sensitive to the H330A mutation (50, 59), depended more on the presence of glycans at positions N156, N301 and N332 and less on integrity of the GDIR motif; it also appeared to require interactions with hybrid glycans (20). …”

“…The PCDN V3-glycan bnAb B cell lineage evolved from the very early phases of development into multiple divergent phylogenetic branches that matured in parallel (20). Approximately 2.3 years post-transmission the autologous virus quasispecies lost the N332 glycosylation site, which likely represented the definitive route of escape from PCDN lineage neutralization and only few PCDN lineage branches kept evolving beyond this time point.…”

“…Approximately 2.3 years post-transmission the autologous virus quasispecies lost the N332 glycosylation site, which likely represented the definitive route of escape from PCDN lineage neutralization and only few PCDN lineage branches kept evolving beyond this time point. While heterologous neutralizing antibodies could be identified in multiple branches, the broadest and most mutated ones arose from the few that survived the virus-induced lineage sieving and kept evolving beyond 2.3 years (20). The trajectory of somatic mutations that accumulated in the PCDN lineage suggest a more prominent role of AID-dependent intrinsic mutability during the early phases of clonal maturation and a progressively higher prevalence of mutations, including nucleotide reversion mutations at previously mutated sites, controlled by strong selective pressure during the later phases (20).…”

“…Notably, the PCDN B cell lineage UCA did not bind or neutralized any of the isolated autologous viruses (20). Rather, analysis of the autologous virus quasispecies neutralization suggested that the PCDN lineage was triggered by a virus variant that emerged in-between 5 and 10 months post-transmission after removal of the N-linked glycosylation site at position 335 and a E328K mutation (20), suggesting the early presence of cooperating lineages (18).…”