title: Ability to develop broadly neutralizing HIV-1 antibodies is not restricted by the germline Ig gene repertoire.
abstract: The human Ig repertoire is vast, producing billions of unique Abs from a limited number of germline Ig genes. The IgH V region (IGHV) is central to Ag binding and consists of 48 functional genes. In this study, we analyzed whether HIV-1-infected individuals who develop broadly neutralizing Abs show a distinctive germline IGHV profile. Using both 454 and Illumina technologies, we sequenced the IGHV repertoire of 28 HIV-infected South African women from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 002 and 004 cohorts, 13 of whom developed broadly neutralizing Abs. Of the 259 IGHV alleles identified in this study, approximately half were not found in the International Immunogenetics Database (IMGT). This included 85 entirely novel alleles and 38 alleles that matched rearranged sequences in non-IMGT databases. Analysis of the rearranged H chain V region genes of mAbs isolated from seven of these women, as well as previously isolated broadly neutralizing Abs from other donors, provided evidence that at least eight novel or non-IMGT alleles contributed to functional Abs. Importantly, we found that, despite a wide range in the number of IGHV alleles in each individual, including alleles used by known broadly neutralizing Abs, there were no significant differences in germline IGHV repertoires between individuals who do and do not develop broadly neutralizing Abs. This study reports novel IGHV repertoires and highlights the importance of a fully comprehensive Ig database for germline gene usage prediction. Furthermore, these data suggest a lack of genetic bias in broadly neutralizing Ab development in HIV-1 infection, with positive implications for HIV vaccine design.
authors.affiliation: Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Division of Virology and Communicable Disease Surveillance, School of Pathology, University of the Witwatersrand, Johannesburg 2050, South Africa;
authors.forename: Cathrine
authors.initials: C
authors.lastname: Scheepers
authors.affiliation: South African National Bioinformatics Institute, South African Medical Research Council Bioinformatics Unit, University of the Western Cape, Bellville 7535, South Africa;
authors.forename: Ram K
authors.initials: RK
authors.lastname: Shrestha
authors.affiliation: Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Division of Virology and Communicable Disease Surveillance, School of Pathology, University of the Witwatersrand, Johannesburg 2050, South Africa;
authors.forename: Bronwen E
authors.initials: BE
authors.lastname: Lambson
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia; Department of Pathology, School of Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Katherine J L
authors.initials: KJ
authors.lastname: Jackson
authors.affiliation: South African National Bioinformatics Institute, South African Medical Research Council Bioinformatics Unit, University of the Western Cape, Bellville 7535, South Africa;
authors.forename: Imogen A
authors.initials: IA
authors.lastname: Wright
authors.affiliation: Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa;
authors.forename: Dshanta
authors.initials: D
authors.lastname: Naicker
authors.affiliation: Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa;
authors.forename: Mark
authors.initials: M
authors.lastname: Goosen
authors.affiliation: Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa;
authors.forename: Leigh
authors.initials: L
authors.lastname: Berrie
authors.affiliation: Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa;
authors.forename: Arshad
authors.initials: A
authors.lastname: Ismail
authors.affiliation: Centre for the AIDS Programme of Research in South Africa, KwaZulu-Natal 4013, South Africa; Department of Infectious Diseases, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, 4041 Durban, South Africa; and.
authors.forename: Nigel
authors.initials: N
authors.lastname: Garrett
authors.affiliation: Centre for the AIDS Programme of Research in South Africa, KwaZulu-Natal 4013, South Africa; Department of Epidemiology, Columbia University, New York, NY 10032.
authors.forename: Quarraisha
authors.initials: Q
authors.lastname: Abdool Karim
authors.affiliation: Centre for the AIDS Programme of Research in South Africa, KwaZulu-Natal 4013, South Africa; Department of Epidemiology, Columbia University, New York, NY 10032.
authors.forename: Salim S
authors.initials: SS
authors.lastname: Abdool Karim
authors.affiliation: Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Division of Virology and Communicable Disease Surveillance, School of Pathology, University of the Witwatersrand, Johannesburg 2050, South Africa; Centre for the AIDS Programme of Research in South Africa, KwaZulu-Natal 4013, South Africa;
authors.forename: Penny L
authors.initials: PL
authors.lastname: Moore
authors.affiliation: South African National Bioinformatics Institute, South African Medical Research Council Bioinformatics Unit, University of the Western Cape, Bellville 7535, South Africa;
authors.forename: Simon A
authors.initials: SA
authors.lastname: Travers
authors.affiliation: Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Division of Virology and Communicable Disease Surveillance, School of Pathology, University of the Witwatersrand, Johannesburg 2050, South Africa; Centre for the AIDS Programme of Research in South Africa, KwaZulu-Natal 4013, South Africa; lynnm@nicd.ac.za.
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
mesh_terms: D000328:Adult; D000483:Alleles; D057134:Antibodies, Neutralizing; D044383:Black People / Q000235:genetics; D005260:Female; D005803:Genes, Immunoglobulin; D005854:Germ Cells / Q000378:metabolism*; D015483:HIV Antibodies / Q000235:genetics* / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D010802:Phylogeny; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region
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