title: New Member of the V1V2-Directed CAP256-VRC26 Lineage That Shows Increased Breadth and Exceptional Potency.
abstract: 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.
  
  
  OBJECTIVE
  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. 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.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Doria-Rose
authors.affiliation: Centre for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Services, Johannesburg, South Africa University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Jinal N
authors.initials: JN
authors.lastname: Bhiman
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Roark
authors.affiliation: Department of Biochemistry and Systems Biology, Columbia University, New York, New York, USA.
authors.forename: Chaim A
authors.initials: CA
authors.lastname: Schramm
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gorman
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Gwo-Yu
authors.initials: GY
authors.lastname: Chuang
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Pancera
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Evan M
authors.initials: EM
authors.lastname: Cale
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ernandes
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Louder
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Mangaiarkarasi
authors.initials: M
authors.lastname: Asokan
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Bailer
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Aliaksandr
authors.initials: A
authors.lastname: Druz
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Isabella R
authors.initials: IR
authors.lastname: Fraschilla
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban, South Africa.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Garrett
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Marissa
authors.initials: M
authors.lastname: Jarosinski
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Lynch
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Krisha
authors.initials: K
authors.lastname: McKee
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Sijy
authors.initials: S
authors.lastname: O'Dell
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Amarendra
authors.initials: A
authors.lastname: Pegu
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Schmidt
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Staupe
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Sutton
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Keyun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Centre for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Services, Johannesburg, South Africa University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Constantinos Kurt
authors.initials: CK
authors.lastname: Wibmer
authors.affiliation: Duke University School of Medicine and Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery at Duke University, Durham, North Carolina, USA.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban, South Africa Department of Epidemiology, Columbia University, New York, New York, USA.
authors.forename: Salim
authors.initials: S
authors.lastname: Abdool-Karim
authors.affiliation: Department of Biochemistry and Systems Biology, Columbia University, New York, New York, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: Centre for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Services, Johannesburg, South Africa University of the Witwatersrand, Johannesburg, South Africa Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban, South Africa.
authors.forename: Penny L
authors.initials: PL
authors.lastname: Moore
authors.affiliation: Centre for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Services, Johannesburg, South Africa University of the Witwatersrand, Johannesburg, South Africa Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban, South Africa.
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA jmascola@nih.gov.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
mesh_terms: D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D003429:Cross Reactions; D018604:Epitope Mapping; D005260:Female; D015483:HIV Antibodies / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1