Immunoglobulin gene insertions and deletions in the affinity maturation of HIV-1 broadly reactive neutralizing antibodies.

Published

Journal Article

Induction of HIV-1 broad neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development but has remained challenging partially due to unusual traits of bnAbs, including high somatic hypermutation (SHM) frequencies and in-frame insertions and deletions (indels). Here we examined the propensity and functional requirement for indels within HIV-1 bnAbs. High-throughput sequencing of the immunoglobulin (Ig) VHDJH genes in HIV-1 infected and uninfected individuals revealed that the indel frequency was elevated among HIV-1-infected subjects, with no unique properties attributable to bnAb-producing individuals. This increased indel occurrence depended only on the frequency of SHM point mutations. Indel-encoded regions were generally proximal to antigen binding sites. Additionally, reconstruction of a HIV-1 CD4-binding site bnAb clonal lineage revealed that a large compound VHDJH indel was required for bnAb activity. Thus, vaccine development should focus on designing regimens targeted at sustained activation of bnAb lineages to achieve the required SHM and indel events.

Full Text

Duke Authors

Cited Authors

  • Kepler, TB; Liao, H-X; Alam, SM; Bhaskarabhatla, R; Zhang, R; Yandava, C; Stewart, S; Anasti, K; Kelsoe, G; Parks, R; Lloyd, KE; Stolarchuk, C; Pritchett, J; Solomon, E; Friberg, E; Morris, L; Karim, SSA; Cohen, MS; Walter, E; Moody, MA; Wu, X; Altae-Tran, HR; Georgiev, IS; Kwong, PD; Boyd, SD; Fire, AZ; Mascola, JR; Haynes, BF

Published Date

  • September 10, 2014

Published In

Volume / Issue

  • 16 / 3

Start / End Page

  • 304 - 313

PubMed ID

  • 25211073

Pubmed Central ID

  • 25211073

Electronic International Standard Serial Number (EISSN)

  • 1934-6069

Digital Object Identifier (DOI)

  • 10.1016/j.chom.2014.08.006

Language

  • eng

Conference Location

  • United States