title: Viral variants that initiate and drive maturation of V1V2-directed HIV-1 broadly neutralizing antibodies.
abstract: The elicitation of broadly neutralizing antibodies (bNAbs) is likely to be essential for a preventative HIV-1 vaccine, but this has not yet been achieved by immunization. In contrast, some HIV-1-infected individuals naturally mount bNAb responses during chronic infection, suggesting that years of maturation may be required for neutralization breadth. Recent studies have shown that viral diversification precedes the emergence of bNAbs, but the significance of this observation is unknown. Here we delineate the key viral events that drove neutralization breadth within the CAP256-VRC26 family of 33 monoclonal antibodies (mAbs) isolated from a superinfected individual. First, we identified minority viral variants, termed bNAb-initiating envelopes, that were distinct from both of the transmitted/founder (T/F) viruses and that efficiently engaged the bNAb precursor. Second, deep sequencing revealed a pool of diverse epitope variants (immunotypes) that were preferentially neutralized by broader members of the antibody lineage. In contrast, a 'dead-end' antibody sublineage unable to neutralize these immunotypes showed limited evolution and failed to develop breadth. Thus, early viral escape at key antibody-virus contact sites selects for antibody sublineages that can tolerate these changes, thereby providing a mechanism for the generation of neutralization breadth within a developing antibody lineage.
authors.affiliation: Centre for HIV and STIs, National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa.|Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Jinal N
authors.identifier: http://orcid.org/0000-0001-6354-4003
authors.initials: JN
authors.lastname: Bhiman
authors.affiliation: Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Colin
authors.initials: C
authors.lastname: Anthony
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 (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa.
authors.forename: Owen
authors.initials: O
authors.lastname: Karimanzira
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: Centre for HIV and STIs, National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa.
authors.forename: Thandeka
authors.initials: T
authors.lastname: Khoza
authors.affiliation: Centre for HIV and STIs, National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa.
authors.forename: Dale
authors.initials: D
authors.lastname: Kitchin
authors.affiliation: Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Gordon
authors.initials: G
authors.lastname: Botha
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: 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: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban, South Africa.
authors.forename: Salim S
authors.initials: SS
authors.lastname: Abdool Karim
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.|Department of Biochemistry and Systems Biology, Columbia University, New York, New York, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
authors.affiliation: Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.|Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban, South Africa.|National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williamson
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: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: Centre for HIV and STIs, National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa.|Faculty of Health Sciences, 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: Centre for HIV and STIs, National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa.|Faculty of Health Sciences, 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
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000940:Antigenic Variation; D000939:Epitopes / Q000276:immunology*; D005260:Female; D014644:Genetic Variation; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics*; D017423:Sequence Analysis, RNA; D015163:Superinfection / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C059761:HIV envelope protein gp120 (135-148); D010446:Peptide Fragments; D012367:RNA, Viral