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Immunoglobulin gene insertions and deletions in the affinity maturation of HIV-1 broadly reactive neutralizing antibodies. Cell host & microbe Kepler, T. B., Liao, H., Alam, S. M., Bhaskarabhatla, R., Zhang, R., Yandava, C., Stewart, S., Anasti, K., Kelsoe, G., Parks, R., Lloyd, K. E., Stolarchuk, C., Pritchett, J., Solomon, E., Friberg, E., Morris, L., Karim, S. S., Cohen, M. S., Walter, E., Moody, M. A., Wu, X., Altae-Tran, H. R., Georgiev, I. S., Kwong, P. D., Boyd, S. D., Fire, A. Z., Mascola, J. R., Haynes, B. F. 2014; 16 (3): 304-313

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.

View details for DOI 10.1016/j.chom.2014.08.006

View details for PubMedID 25211073

View details for PubMedCentralID PMC4163498