title: Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection.
abstract: HIV-1-neutralizing antibodies develop in most HIV-1-infected individuals, although highly effective antibodies are generally observed only after years of chronic infection. Here, we characterize the rate of maturation and extent of diversity for the lineage that produced the broadly neutralizing antibody VRC01 through longitudinal sampling of peripheral B cell transcripts over 15 years and co-crystal structures of lineage members. Next-generation sequencing identified VRC01-lineage transcripts, which encompassed diverse antibodies organized into distinct phylogenetic clades. Prevalent clades maintained characteristic features of antigen recognition, though each evolved binding loops and disulfides that formed distinct recognition surfaces. Over the course of the study period, VRC01-lineage clades showed continuous evolution, with rates of ∼2 substitutions per 100 nucleotides per year, comparable to that of HIV-1 evolution. This high rate of antibody evolution provides a mechanism by which antibody lineages can achieve extraordinary diversity and, over years of chronic infection, develop effective HIV-1 neutralization.
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY 10016, USA.
authors: Xueling
authors: X
authors: Wu
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics and Department of Systems Biology, Columbia University, New York, NY 10032, USA; State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors: Zhenhai
authors: Z
authors: Zhang
authors: Department of Biochemistry and Molecular Biophysics and Department of Systems Biology, Columbia University, New York, NY 10032, USA.
authors: Chaim A
authors: CA
authors: Schramm
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: M Gordon
authors: MG
authors: Joyce
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Young Do
authors: YD
authors: Kwon
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Tongqing
authors: T
authors: Zhou
authors: Department of Biochemistry and Molecular Biophysics and Department of Systems Biology, Columbia University, New York, NY 10032, USA.
authors: Zizhang
authors: Z
authors: Sheng
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Baoshan
authors: B
authors: Zhang
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Sijy
authors: S
authors: O'Dell
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Krisha
authors: K
authors: McKee
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Ivelin S
authors: IS
authors: Georgiev
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Gwo-Yu
authors: GY
authors: Chuang
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Nancy S
authors: NS
authors: Longo
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Rebecca M
authors: RM
authors: Lynch
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Kevin O
authors: KO
authors: Saunders
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Cinque
authors: C
authors: Soto
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Sanjay
authors: S
authors: Srivatsan
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Yongping
authors: Y
authors: Yang
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Robert T
authors: RT
authors: Bailer
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Mark K
authors: MK
authors: Louder
authors: NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: James C
authors: JC
authors: Mullikin
authors: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Mark
authors: M
authors: Connors
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: pdkwong@nih.gov.
authors: Peter D
authors: PD
authors: Kwong
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jmascola@nih.gov.
authors: John R
authors: JR
authors: Mascola
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics and Department of Systems Biology, Columbia University, New York, NY 10032, USA. Electronic address: lss8@columbia.edu.
authors: Lawrence
authors: L
authors: Shapiro
mesh_terms: D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D000916:Antibody Diversity; D001402:B-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D019143:Evolution, Molecular; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment
chemical_list: D057134:Antibodies, Neutralizing