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Cell Host Microbe. 2014 Sep 10;16(3):304-13. doi: 10.1016/j.chom.2014.08.006.

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

Author information

1
Department of Microbiology, Boston University School of Medicine, Department of Mathematics & Statistics, Boston University, Boston, MA 02118, USA. Electronic address: tbkepler@bu.edu.
2
Duke University Human Vaccine Institute, Durham, NC 27710, USA.
3
Department of Microbiology, Boston University School of Medicine, Department of Mathematics & Statistics, Boston University, Boston, MA 02118, USA.
4
Duke University Human Vaccine Institute, Durham, NC 27710, USA; Department of Immunology, Durham, NC 27710, USA.
5
Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg 2131, South Africa; Center for AIDS Program of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Congella, 4013, South Africa.
6
Center for AIDS Program of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Congella, 4013, South Africa.
7
University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
8
Duke University Human Vaccine Institute, Durham, NC 27710, USA; Department of Pediatrics, Durham, NC 27710, USA.
9
Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
10
Stanford University Medical Center, Stanford, CA 94305, USA.
11
Duke University Human Vaccine Institute, Durham, NC 27710, USA; Department of Immunology, Durham, NC 27710, USA; Department of Medicine, Durham, NC 27710, USA.

Abstract

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.

PMID:
25211073
PMCID:
PMC4163498
DOI:
10.1016/j.chom.2014.08.006
[Indexed for MEDLINE]
Free PMC Article
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