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

Immunity. 2016 May 17;44(5):1215-26. doi: 10.1016/j.immuni.2016.04.016.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS Vaccines / immunology*
  • Africa South of the Sahara
  • Antibodies, Neutralizing / immunology*
  • Antibody Diversity / genetics
  • B-Lymphocytes / immunology*
  • Biological Evolution
  • Cell Differentiation
  • Complementarity Determining Regions / genetics
  • HIV Antibodies / immunology*
  • HIV Infections / immunology*
  • HIV-1 / immunology*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunodominant Epitopes / immunology
  • Lymphocyte Activation
  • Mannose / immunology
  • Mannose / metabolism
  • env Gene Products, Human Immunodeficiency Virus / immunology
  • env Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • AIDS Vaccines
  • Antibodies, Neutralizing
  • Complementarity Determining Regions
  • HIV Antibodies
  • Immunodominant Epitopes
  • env Gene Products, Human Immunodeficiency Virus
  • Mannose