Large-scale analysis of human heavy chain V(D)J recombination patterns

Volpe, Joseph M.; Kepler, Thomas B.

doi:10.1186/1745-7580-4-3

Cited by 43 publications

(46 citation statements)

References 44 publications

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“…The mean CDRH3 length in healthy donor human memory B cells (29,(48)(49)(50)) is 14 to 16 aa, while a length of 24 aa is 2 standard deviations above the mean (51). Strikingly, the other known glycan-V3 bNAbs have CDRH3 lengths of 18 to 24 aa, and the glycan-V3 antibodies reported here have lengths of 19, 20, or 26 aa (Table 1).…”

Section: Discussionmentioning

confidence: 75%

Multiple Antibody Lineages in One Donor Target the Glycan-V3 Supersite of the HIV-1 Envelope Glycoprotein and Display a Preference for Quaternary Binding

Longo

Sutton

Shiakolas

et al. 2016

J Virol

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One of the goals of HIV-1 vaccine development is the elicitation of neutralizing antibodies against vulnerable regions on the envelope glycoprotein (Env) viral spike. Broadly neutralizing antibodies targeting the Env glycan-V3 region (also called the N332 glycan supersite) have been described previously, with several single lineages each derived from different individual donors. We used a high-throughput B-cell culture method to isolate neutralizing antibodies from an HIV-1-infected donor with high serum neutralization breadth. Clonal relatives from three distinct antibody lineages were isolated. Each of these antibody lineages displayed modest breadth and potency but shared several characteristics with the well-characterized glycan-V3 antibodies, including dependence on glycans N332 and N301, VH4 family gene utilization, a heavy chain complementarity-determining region 2 (CDRH2) insertion, and a longer-than-average CDRH3. In contrast to previously described glycan-V3 antibodies, these antibodies preferentially recognized the native Env trimer compared to monomeric gp120. These data indicate the diversity of antibody specificities that target the glycan-V3 site. The quaternary binding preference of these antibodies suggests that that their elicitation likely requires the presentation of a native-like trimeric Env immunogen. IMPORTANCEBroadly neutralizing antibodies targeting the HIV-1 glycan-V3 region with single lineages from individual donors have been described previously. Here we describe three lineages from a single donor, each of which targets glycan-V3. Unlike previously described glycan-V3 antibodies, these mature antibodies bind preferentially to the native Env trimer and weakly to the gp120 monomer. These data extend our knowledge of the immune response recognition of the N332 supersite region and suggest that the mode of epitope recognition is more complex than previously anticipated. During the course of natural human immunodeficiency virus type 1 (HIV-1) infection, most individuals generate neutralizing antibodies (NAbs) to the infecting viral strain, but viral evolution and escape allow persistent viral replication despite this antibody (Ab) response (1-3). As HIV-1 infection progresses over months to years, the neutralizing antibody response often broadens, and it is estimated that sera from about 50% of HIV-1-infected donors can neutralize about 50% of diverse HIV-1 strains (4, 5). This observation leads to some optimism that a fuller understanding of the characteristics and evolution of such NAbs could provide insights for the design of vaccine immunogens and immunization strategies that would elicit such cross-reactive NAbs.The most potent and broadly reactive neutralizing monoclonal antibodies (bNAbs) were isolated from highly selected donors whose sera had unusually potent or broad neutralizing activity. These antibodies form the basis for our current understanding of the major neutralization epitopes on the HIV-1 envelope glycoprotein (Env). Most of these antibodies can be grouped in...

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Section: Discussionmentioning

confidence: 75%

Multiple Antibody Lineages in One Donor Target the Glycan-V3 Supersite of the HIV-1 Envelope Glycoprotein and Display a Preference for Quaternary Binding

Longo

Sutton

Shiakolas

et al. 2016

J Virol

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“…These 6 residues include Val106 and Asp107, which together make the most critical contacts within the sialic-acid pocket. The predicted nontemplated nucleotide additions are somewhat fewer than average at the V-D junction and somewhat greater than average at the D-J junction (13).…”

Section: Resultsmentioning

confidence: 81%

“…It has contributions from V H 1∼2, D H 1∼1, and J H 6 and from Vκ3∼21 and Jκ2 (Table S3). The 19-residue heavy-chain CDR3 is of roughly average length (13). Its sequence in the mature antibody is the same as in the UCA.…”

Section: Resultsmentioning

confidence: 99%

Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin

Whittle

Zhang

Khurana

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

411

489

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Seasonal antigenic drift of circulating influenza virus leads to a requirement for frequent changes in vaccine composition, because exposure or vaccination elicits human antibodies with limited cross-neutralization of drifted strains. We describe a human monoclonal antibody, CH65, obtained by isolating rearranged heavy- and light-chain genes from sorted single plasma cells, coming from a subject immunized with the 2007 trivalent influenza vaccine. The crystal structure of a complex of the hemagglutinin (HA) from H1N1 strain A/Solomon Islands/3/2006 with the Fab of CH65 shows that the tip of the CH65 heavy-chain complementarity determining region 3 (CDR3) inserts into the receptor binding pocket on HA1, mimicking in many respects the interaction of the physiological receptor, sialic acid. CH65 neutralizes infectivity of 30 out of 36 H1N1 strains tested. The resistant strains have a single-residue insertion near the rim of the sialic-acid pocket. We conclude that broad neutralization of influenza virus can be achieved by antibodies with contacts that mimic those of the receptor.

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“…On comparing the prevalence of specific IGHV, D and J gene families in B-ALL and BL with that in previously published studies on PBLs, [15][16][17] no statistically significant difference was found. In addition, the frequencies of IGHD and IGHJ gene segments were not significantly different between complete and incomplete rearrangements.…”

Section: Features Of Igh and Igk Rearrangementsmentioning

confidence: 69%

“…22 In addition, the frequencies of specific gene families were similar to those reported for normal PBLs. [15][16][17][18][19] The prevalence of specific IGHD and IGHJ gene segments was significantly different from that reported for BCP-ALL. 8 The remarkable predominance of incomplete rearrangements involving IGHD genes from the more upstream part of the IGHD region and the most downstream IGHJ6 segment Ig-based MRD assay in B-NHL/B-ALL F Lovisa et al suggests that, in BCP-ALL, most IGHD-J rearrangements likely represent secondary recombinations, deleting pre-existing D-J joinings.…”

Section: Discussionmentioning

confidence: 91%

IGH and IGK gene rearrangements as PCR targets for pediatric Burkitt's lymphoma and mature B-ALL MRD analysis

Lovisa

Mussolin

Corral

et al. 2009

Laboratory Investigation

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We recently reported that minimal residual disease (MRD) and minimal disseminated disease (MDD), assessed by longdistance PCR (LD-PCR) for t (8;14), are negative prognostic factors in mature B-cell acute lymphoblastic leukemia (B-ALL) and in Burkitt's lymphoma (BL). However, t(8;14) is detectable in only about 70% of patients, thus preventing MRD studies by this approach in the remaining patients. At present, no molecular assays have been reported for MRD and MDD analysis in t(8;14)-negative patients. The aim of our study was to evaluate the characteristics of patient-specific immunoglobulin (Ig) gene rearrangements as RQ-PCR targets for MRD analysis, in order to extend MRD studies to those patients who are not eligible for the LD-PCR assay. The study was performed according to the guidelines of the European Study Group on MRD detection in ALL (ESG-MRD-ALL). Overall, 36 B-ALL and 19 BL cases were analyzed. Multiple PCR reactions were performed for each sample to identify heavy and kappa light-chain rearrangements. A total of 97 RQ-PCR targets (62 for B-ALL, 35 for BL) were analyzed for sensitivity. The rearrangement pattern identified was similar to that reported for normal peripheral blood lymphocytes. In 88% of the targets, a sensitivity of at least 10 À4 was achieved. In 87% of patients (84% of B-ALLs, 95% of BLs) at least one sensitive target was available. All PCR targets identified at diagnosis were preserved at relapse. Our results suggest that MDD and MRD can be successfully studied using a single sensitive Ig target in the great majority of B-ALL and BL cases. The combination of LD-PCR and Ig-based assays will allow MRD analysis in virtually all of the patients. KEYWORDS: B-cell acute lymphoblastic leukemia; Burkitt's lymphoma; child; clonality; immunoglobulin rearrangement; minimal residual disease Mature B-cell lymphoblastic leukemia (B-ALL) and Burkitt's lymphoma (BL) of childhood are often considered to be different manifestations of BL rather than different diseases. 1 Both are characterized by the expression of mature B-cell surface markers, including CD19, CD20 and immunoglobulin (Ig)M. 2 The chromosomal translocation t(8;14)(q24;q32) can be identified in about 70% of B-ALL and 70-75% of BL cases. 3,4 The amplification by long-distance PCR (LD-PCR) of this translocation breakpoint is currently used to monitor minimal residual disease (MRD) in patients enrolled in the Italian Association of Pediatric Hematology-Oncology (AIEOP) national protocol NHL-97. Using this approach, we have recently reported that minimal disseminated disease (MDD) in BL has a negative prognostic impact on the outcome, being often associated with advanced stage disease and high levels of serum LDH. 5 In addition, using multivariate analysis, we demonstrated that MRD was predictive of higher risk of failure in children with mature B-ALL. 6 All together, these data suggest that, similar to other subtypes of ALL, a MRD-based risk group classification could be conceived for BL and mature B-ALL, and that this information might b...

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Large-scale analysis of human heavy chain V(D)J recombination patterns

Cited by 43 publications

References 44 publications

Multiple Antibody Lineages in One Donor Target the Glycan-V3 Supersite of the HIV-1 Envelope Glycoprotein and Display a Preference for Quaternary Binding

Multiple Antibody Lineages in One Donor Target the Glycan-V3 Supersite of the HIV-1 Envelope Glycoprotein and Display a Preference for Quaternary Binding

Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin

IGH and IGK gene rearrangements as PCR targets for pediatric Burkitt's lymphoma and mature B-ALL MRD analysis

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