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Title: New Member of the V1V2-Directed CAP256-VRC26 Lineage That Shows Increased Breadth and Exceptional Potency

Journal Article · · Journal of Virology
DOI:https://doi.org/10.1128/JVI.01791-15· OSTI ID:1242300
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  1. National Inst. of Health (NIH), Bethesda, MD (United States)
  2. National Inst. for Communicable Diseases of the National Health Lab. Services, Johannesburg (South Africa); Univ. of Witwatersrand, Johannesburg (South Africa)
  3. Columbia Univ., New York, NY (United States)
  4. Univ. of KwaZulu Natal, Durban (South Africa)
  5. Duke Univ., Durham, NC (United States)
  6. Univ. of KwaZulu Natal, Durban (South Africa); Columbia Univ., New York, NY (United States)
  7. National Inst. for Communicable Diseases of the National Health Lab. Services, Johannesburg (South Africa); Univ. of Witwatersrand, Johannesburg (South Africa); Univ. of KwaZulu Natal, Durban (South Africa)
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The epitopes defined by HIV-1 broadly neutralizing antibodies (bNAbs) are valuable templates for vaccine design, and studies of the immunological development of these antibodies are providing insights for vaccination strategies. In addition, the most potent and broadly reactive of these bNAbs have potential for clinical use. We previously described a family of 12 V1V2-directed neutralizing antibodies, CAP256-VRC26, isolated from an HIV-1 clade C-infected donor at years 1, 2, and 4 of infection (N. A. Doria-Rose et al., Nature 509:55–62, 2014, http://dx.doi.org/10.1038/nature13036). Here, we report on the isolation and characterization of new members of the family mostly obtained at time points of peak serum neutralization breadth and potency. Thirteen antibodies were isolated from B cell culture, and eight were isolated using trimeric envelope probes for differential single B cell sorting. One of the new antibodies displayed a 10-fold greater neutralization potency than previously published lineage members. This antibody, CAP256-VRC26.25, neutralized 57% of diverse clade viral isolates and 70% of clade C isolates with remarkable potency. Among the viruses neutralized, the median 50% inhibitory concentration was 0.001 μg/ml. All 33 lineage members targeted a quaternary epitope focused on V2. While all known bNAbs targeting the V1V2 region interact with the N160 glycan, the CAP256-VRC26 antibodies showed an inverse correlation of neutralization potency with dependence on this glycan. Overall, our results highlight the ongoing evolution within a single antibody lineage and describe more potent and broadly neutralizing members with potential clinical utility, particularly in areas where clade C is prevalent. Studies of HIV-1 broadly neutralizing antibodies (bNAbs) provide valuable information for vaccine design, and the most potent and broadly reactive of these bNAbs have potential for clinical use. We previously described a family of V1V2-directed neutralizing antibodies from an HIV-1 clade C-infected donor. Here, we report on the isolation and characterization of new members of the family mostly obtained at time points of peak serum neutralization breadth and potency. One of the new antibodies, CAP256-VRC26.25, displayed a 10-fold greater neutralization potency than previously described lineage members. It neutralized 57% of diverse clade viral isolates and 70% of clade C isolates with remarkable potency: the median 50% inhibitory concentration was 0.001 μg/ml. Furthermore, our results highlight the ongoing evolution within a single antibody lineage and describe more potent and broadly neutralizing members with potential clinical utility, particularly in areas where clade C is prevalent.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Health; South African Medical Research Council; Wellcome Trust
Grant/Contract Number:
W-31-109-Eng-38; AI116086-01; D1407250-01; 089933/Z/09/Z; U19 AI51794; 5 D43TW000231
OSTI ID:
1242300
Journal Information:
Journal of Virology, Vol. 90, Issue 1; ISSN 0022-538X
Publisher:
American Society for MicrobiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 160 works
Citation information provided by
Web of Science

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Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design journal December 2015
Antibody responses to viral infections: a structural perspective across three different enveloped viruses journal March 2019
Strategies for inducing effective neutralizing antibody responses against HIV-1 journal November 2019
Native-like Env trimers as a platform for HIV-1 vaccine design journal January 2017
The HIV-1 envelope glycoprotein structure: nailing down a moving target journal January 2017
Antibody-virus co-evolution in HIV infection: paths for HIV vaccine development journal January 2017
Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody journal May 2016
Positive Selection at Key Residues in the HIV Envelope Distinguishes Broad and Strain-Specific Plasma Neutralizing Antibodies journal December 2018
Molecular Basis of Unusually High Neutralization Resistance in Tier 3 HIV-1 Strain 253-11 journal April 2018
A Bispecific Antibody That Simultaneously Recognizes the V2- and V3-Glycan Epitopes of the HIV-1 Envelope Glycoprotein Is Broader and More Potent than Its Parental Antibodies journal January 2020
Unique binding modes for the broad neutralizing activity of single-chain variable fragments (scFv) targeting CD4-induced epitopes journal September 2017
Broadly neutralizing antibodies: What is needed to move from a rare event in HIV-1 infection to vaccine efficacy? journal July 2018
Engineering and characterising a novel, highly potent bispecific antibody iMab-CAP256 that targets HIV-1 journal November 2019
Glycoengineering HIV-1 Env creates ‘supercharged’ and ‘hybrid’ glycans to increase neutralizing antibody potency, breadth and saturation journal May 2018
IgG3 enhances neutralization potency and Fc effector function of an HIV V2-specific broadly neutralizing antibody journal December 2019
Beyond Hot Spots: Biases in Antibody Somatic Hypermutation and Implications for Vaccine Design journal August 2018
Impact of HIV-1 Diversity on Its Sensitivity to Neutralization journal July 2019
Sequencing HIV-neutralizing antibody exons and introns reveals detailed aspects of lineage maturation journal October 2018
Recent progress in broadly neutralizing antibodies to HIV journal October 2018
Use of broadly neutralizing antibodies for HIV-1 prevention journal January 2017
Tfh cells and HIV bnAbs, an immunodominance model of the HIV neutralizing antibody generation problem journal January 2017
Neutralization Breadth and Potency of Single-Chain Variable Fragments Derived from Broadly Neutralizing Antibodies Targeting Multiple Epitopes on the HIV-1 Envelope journal October 2019
HIV-1 Glycan Density Drives the Persistence of the Mannose Patch within an Infected Individual journal October 2016
Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections journal March 2018
Somatic hypermutation to counter a globally rare viral immunotype drove off-track antibodies in the CAP256-VRC26 HIV-1 V2-directed bNAb lineage journal September 2019
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Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies journal January 2020
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Broadly neutralizing antibodies: What is needed to move from a rare event in HIV-1 infection to vaccine efficacy? text January 2018
Phenotypic deficits in the HIV-1 envelope are associated with the maturation of a V2-directed broadly neutralizing antibody lineage journal January 2018

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