title: Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort.
abstract: Broadly neutralizing antibodies (bnAbs) are thought to be a critical component of a protective HIV vaccine. However, designing vaccines immunogens able to elicit bnAbs has proven unsuccessful to date. Understanding the correlates and immunological mechanisms leading to the development of bnAb responses during natural HIV infection is thus critical to the design of a protective vaccine. The IAVI Protocol C program investigates a large longitudinal cohort of primary HIV-1 infection in Eastern and South Africa. Development of neutralization was evaluated in 439 donors using a 6 cross-clade pseudo-virus panel predictive of neutralization breadth on larger panels. About 15% of individuals developed bnAb responses, essentially between year 2 and year 4 of infection. Statistical analyses revealed no influence of gender, age or geographical origin on the development of neutralization breadth. However, cross-clade neutralization strongly correlated with high viral load as well as with low CD4 T cell counts, subtype-C infection and HLA-A*03(-) genotype. A correlation with high overall plasma IgG levels and anti-Env IgG binding titers was also found. The latter appeared not associated with higher affinity, suggesting a greater diversity of the anti-Env responses in broad neutralizers. Broadly neutralizing activity targeting glycan-dependent epitopes, largely the N332-glycan epitope region, was detected in nearly half of the broad neutralizers while CD4bs and gp41-MPER bnAb responses were only detected in very few individuals. Together the findings suggest that both viral and host factors are critical for the development of bnAbs and that the HIV Env N332-glycan supersite may be a favorable target for vaccine design.
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, La Jolla, California, United States of America.
authors.forename: Elise
authors.initials: E
authors.lastname: Landais
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Xiayu
authors.initials: X
authors.lastname: Huang
authors.affiliation: La Jolla Institute for Allergy and Immunology (LIAI), La Jolla, California, United States of America.|Department of Medicine, University of California San Diego, San Diego, California, United States of America.
authors.forename: Colin
authors.initials: C
authors.lastname: Havenar-Daughton
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, California, United States of America.
authors.forename: Ben
authors.initials: B
authors.lastname: Murrell
authors.affiliation: IAVI Medical Affairs, New York, New York, United States of America.|University of California San Francisco Department of Epidemiology and Biostatistics, San Francisco, California, United States of America.
authors.forename: Matt A
authors.initials: MA
authors.lastname: Price
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, La Jolla, California, United States of America.
authors.forename: Lalinda
authors.initials: L
authors.lastname: Wickramasinghe
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, La Jolla, California, United States of America.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Ramos
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, La Jolla, California, United States of America.
authors.forename: Charoan B
authors.initials: CB
authors.lastname: Bian
authors.affiliation: IAVI Medical Affairs, New York, New York, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Simek
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia, United States of America.|Rwanda-Zambia HIV Research Group, Lusaka & Ndola, Zambia.
authors.forename: Susan
authors.initials: S
authors.lastname: Allen
authors.affiliation: Rwanda-Zambia HIV Research Group, Project San Francisco, Kigali, Rwanda.
authors.forename: Etienne
authors.initials: E
authors.lastname: Karita
authors.affiliation: Rwanda-Zambia HIV Research Group, Lusaka & Ndola, Zambia.
authors.forename: William
authors.initials: W
authors.lastname: Kilembe
authors.affiliation: Rwanda-Zambia HIV Research Group, Lusaka & Ndola, Zambia.
authors.forename: Shabir
authors.initials: S
authors.lastname: Lakhi
authors.affiliation: Rwanda-Zambia HIV Research Group, Lusaka & Ndola, Zambia.
authors.forename: Mubiana
authors.initials: M
authors.lastname: Inambao
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, Masaka & Entebbe, Uganda.
authors.forename: Anatoli
authors.initials: A
authors.lastname: Kamali
authors.affiliation: Centre for Geographic Medicine-Coast, Kenya Medical Research Institute, Kilifi, Kenya.|Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Eduard J
authors.initials: EJ
authors.lastname: Sanders
authors.affiliation: Kenya AIDS Vaccine Initiative, Nairobi, Kenya.
authors.forename: Omu
authors.initials: O
authors.lastname: Anzala
authors.affiliation: The Aurum Institute, Parktown, Johannesburg, South Africa.
authors.forename: Vinodh
authors.initials: V
authors.lastname: Edward
authors.affiliation: Desmond Tutu HIV Center, University of Cape Town, Cape Town, South Africa.
authors.forename: Linda-Gail
authors.initials: LG
authors.lastname: Bekker
authors.affiliation: University of Alabama Birmingham, Department of Epidemiology and Department of Medicine, Birmingham, Alabama, United States of America.
authors.forename: Jianming
authors.initials: J
authors.lastname: Tang
authors.affiliation: IAVI Human Immunology Laboratory, Imperial College of Science Technology and Medicine, Chelsea & Westminster Hospital, London, United Kingdom.
authors.forename: Jill
authors.initials: J
authors.lastname: Gilmour
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, California, United States of America.
authors.forename: Sergei L
authors.initials: SL
authors.lastname: Kosakovsky-Pond
authors.affiliation: Monogram Biosciences, Laboratory Corporation of America® Holdings, San Francisco California, United States of America.
authors.forename: Pham
authors.initials: P
authors.lastname: Phung
authors.affiliation: Monogram Biosciences, Laboratory Corporation of America® Holdings, San Francisco California, United States of America.
authors.forename: Terri
authors.initials: T
authors.lastname: Wrin
authors.affiliation: La Jolla Institute for Allergy and Immunology (LIAI), La Jolla, California, United States of America.|Department of Medicine, University of California San Diego, San Diego, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), La Jolla, California, United States of America.
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), La Jolla, California, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Godzik
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, La Jolla, California, United States of America.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Pascal
authors.initials: P
authors.lastname: Poignard
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000328:Adult; D017954:Africa South of the Sahara; D057134:Antibodies, Neutralizing / Q000276:immunology*; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D005260:Female; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D018985:Epitopes, B-Lymphocyte; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus