title: Immunoglobulin gene insertions and deletions in the affinity maturation of HIV-1 broadly reactive neutralizing antibodies.
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.
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Department of Mathematics & Statistics, Boston University, Boston, MA 02118, USA. Electronic address: tbkepler@bu.edu.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Kepler
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Department of Mathematics & Statistics, Boston University, Boston, MA 02118, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Bhaskarabhatla
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Ruijun
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Department of Mathematics & Statistics, Boston University, Boston, MA 02118, USA.
authors.forename: Chandri
authors.initials: C
authors.lastname: Yandava
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Shelley
authors.initials: S
authors.lastname: Stewart
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Anasti
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA; Department of Immunology, Durham, NC 27710, USA.
authors.forename: Garnett
authors.initials: G
authors.lastname: Kelsoe
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Parks
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Krissey E
authors.initials: KE
authors.lastname: Lloyd
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Stolarchuk
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Pritchett
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Solomon
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Friberg
authors.affiliation: 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.
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
authors.affiliation: Center for AIDS Program of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Congella, 4013, South Africa.
authors.forename: Salim S Abdool
authors.initials: SS
authors.lastname: Karim
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Myron S
authors.initials: MS
authors.lastname: Cohen
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA; Department of Pediatrics, Durham, NC 27710, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Walter
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA; Department of Pediatrics, Durham, NC 27710, USA.
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Moody
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Xueling
authors.initials: X
authors.lastname: Wu
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Han R
authors.initials: HR
authors.lastname: Altae-Tran
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Ivelin S
authors.initials: IS
authors.lastname: Georgiev
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: Stanford University Medical Center, Stanford, CA 94305, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Boyd
authors.affiliation: Stanford University Medical Center, Stanford, CA 94305, USA.
authors.forename: Andrew Z
authors.initials: AZ
authors.lastname: Fire
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: Duke University Human Vaccine Institute, Durham, NC 27710, USA; Department of Immunology, Durham, NC 27710, USA; Department of Medicine, Durham, NC 27710, USA.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D015483:HIV Antibodies / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000276:immunology*; D006801:Humans; D054643:INDEL Mutation; D007136:Immunoglobulins / Q000235:genetics* / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D007136:Immunoglobulins