scholarly journals HIV-1 gp120 Vaccine Induces Affinity Maturation in both New and Persistent Antibody Clonal Lineages

2012 ◽  
Vol 86 (14) ◽  
pp. 7496-7507 ◽  
Author(s):  
M. A. Moody ◽  
N. L. Yates ◽  
J. D. Amos ◽  
M. S. Drinker ◽  
J. A. Eudailey ◽  
...  
Keyword(s):  
Affinity Maturation ◽  
Hiv 1 ◽  
Gp120 Vaccine

scholarly journals Conditional antibody expression to avoid central B cell deletion in humanized HIV-1 vaccine mouse models

2020 ◽  
Vol 117 (14) ◽  
pp. 7929-7940
Author(s):  
Ming Tian ◽  
Kelly McGovern ◽  
Hwei-Ling Cheng ◽  
Peyton Waddicor ◽  
Lisa Rieble ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Mouse Models ◽  
Negative Selection ◽  
Cell Development ◽  
B Cell Development ◽  
Affinity Maturation ◽  
Variable Regions ◽  
Conditional Expression ◽  
Hiv 1

HIV-1 vaccine development aims to elicit broadly neutralizing antibodies (bnAbs) against diverse viral strains. In some HIV-1–infected individuals, bnAbs evolved from precursor antibodies through affinity maturation. To induce bnAbs, a vaccine must mediate a similar antibody maturation process. One way to test a vaccine is to immunize mouse models that express human bnAb precursors and assess whether the vaccine can convert precursor antibodies into bnAbs. A major problem with such mouse models is that bnAb expression often hinders B cell development. Such developmental blocks may be attributed to the unusual properties of bnAb variable regions, such as poly-reactivity and long antigen-binding loops, which are usually under negative selection during primary B cell development. To address this problem, we devised a method to circumvent such B cell developmental blocks by expressing bnAbs conditionally in mature B cells. We validated this method by expressing the unmutated common ancestor (UCA) of the human VRC26 bnAb in transgenic mice. Constitutive expression of the VRC26UCA led to developmental arrest of B cell progenitors in bone marrow; poly-reactivity of the VRC26UCA and poor pairing of the VRC26UCA heavy chain with the mouse surrogate light chain may contribute to this phenotype. The conditional expression strategy bypassed the impediment to VRC26UCA B cell development, enabling the expression of VRC26UCA in mature B cells. This approach should be generally applicable for expressing other bnAbs that are under negative selection during B cell development.

scholarly journals Distinct clonal evolution of B-cells in HIV controllers with neutralizing antibody breadth

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Deniz Cizmeci ◽  
Giuseppe Lofano ◽  
Evan Rossignol ◽  
Anne-Sophie Dugast ◽  
Dongkyoon Kim ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Clonal Evolution ◽  
Neutralizing Antibody ◽  
Affinity Maturation ◽  
Gene Repertoire ◽  
Immunoglobulin Gene ◽  
Hiv Controllers ◽  
Hiv 1

A minor subset of individuals infected with HIV-1 develop antibody neutralization breadth during the natural course of the infection, often linked to chronic, high-level viremia. Despite significant efforts, vaccination strategies have been unable to induce similar neutralization breadth and the mechanisms underlying neutralizing antibody induction remain largely elusive. Broadly neutralizing antibody responses can also be found in individuals who control HIV to low and even undetectable plasma levels in the absence of antiretroviral therapy, suggesting that high antigen exposure is not a strict requirement for neutralization breadth. We therefore performed an analysis of paired heavy and light chain B-cell receptor (BCR) repertoires in 12,591 HIV-1 envelope-specific single memory B-cells to determine alterations in the BCR immunoglobulin gene repertoire and B-cell clonal expansions that associate with neutralizing antibody breadth in 22 HIV controllers. We found that the frequency of genomic mutations in IGHV and IGLV was directly correlated with serum neutralization breadth. The repertoire of the most mutated antibodies was dominated by a small number of large clones with evolutionary signatures suggesting that these clones had reached peak affinity maturation. These data demonstrate that even in the setting of low plasma HIV antigenemia, similar to what a vaccine can potentially achieve, BCR selection for extended somatic hypermutation and clonal evolution can occur in some individuals suggesting that host-specific factors might be involved that could be targeted with future vaccine strategies.

scholarly journals IDLV-HIV-1 Env vaccination in non-human primates induces affinity maturation of antigen-specific memory B cells

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Maria Blasi ◽  
Donatella Negri ◽  
Celia LaBranche ◽  
S. Munir Alam ◽  
Erich J. Baker ◽  
...  
Keyword(s):  
B Cells ◽  
Affinity Maturation ◽  
Memory B Cells ◽  
Specific Memory ◽  
Hiv 1

CDR Walking Mutagenesis for the Affinity Maturation of a Potent Human Anti-HIV-1 Antibody into the Picomolar Range

1995 ◽  
Vol 254 (3) ◽  
pp. 392-403 ◽  
Author(s):  
Wei-Ping Yang ◽  
Kimberly Green ◽  
Sally Pinz-Sweeney ◽  
Amelia T. Briones ◽  
Dennis R. Burton ◽  
...  
Keyword(s):  
Affinity Maturation ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals Increased Epitope Complexity Correlated with Antibody Affinity Maturation and a Novel Binding Mode Revealed by Structures of Rabbit Antibodies against the Third Variable Loop (V3) of HIV-1 gp120

2018 ◽  
Vol 92 (7) ◽  
Author(s):  
Ruimin Pan ◽  
Yali Qin ◽  
Marisa Banasik ◽  
William Lees ◽  
Adrian J. Shepherd ◽  
...  
Keyword(s):  
Animal Model ◽  
Crystal Structures ◽  
Germ Line ◽  
Binding Mode ◽  
Affinity Maturation ◽  
V3 Loop ◽  
Vaccine Candidates ◽  
The Third ◽  
Hiv 1 ◽  
Human Vaccine

ABSTRACT The third variable (V3) loop of HIV-1 gp120 is an immunodominant region targeted by neutralizing antibodies (nAbs). Despite limited breadth, better characterization of the structural details of the interactions between these nAbs and their target epitopes would enhance our understanding of the mechanism of neutralization and facilitate designing better immunogens to induce nAbs with greater breadth. Recently, we isolated two anti-V3 neutralizing monoclonal antibodies (MAbs), 10A3 and 10A37, from a rabbit immunized with gp120 of the M group consensus sequence. In this study, crystal structures of these MAbs bound to target epitopes were determined. 10A3 binds to the V3 crown ( 303 TRKSIHIGPGRAF 317 ) using the cradle binding mode, similar to human V3 MAbs encoded by IGHV5-51 germ line genes, and its epitope structure resembles that bound to the human antibodies. In contrast, 10A37, which exhibits greater breadth and potency than 10A3, binds the V3 crown and the succeeding stem region ( 308 HIGPGRAFYTTGEI 323 ). Unexpectedly, the 315 RAFYTT 320 portion of the epitope existed as helical turns, a V3 structure that has not been observed previously. Its main chain-dominated antigen-antibody interactions not only explain the broad neutralization of 10A37 but also show that its epitope is a potential vaccine target to be further evaluated. In conclusion, our study provides novel insights about neutralization-susceptible epitope structures of the V3 loop of HIV-1 gp120 and demonstrates that, despite low amino acid sequence similarity to human antibody germ line genes, rabbits can serve as a useful animal model to evaluate human vaccine candidates. IMPORTANCE The apex crown of V3 of HIV-1 gp120 is the most immunogenic region of the surface glycoprotein, and many MAbs targeting this region have been developed. Structural understanding of V3 crown MAbs not only can help understand how antibody responses target this unique region but also contribute to immunogen design for vaccine development. We present here crystal structures of two neutralizing V3 MAbs, 10A3 and 10A37, developed from a rabbit immunized with gp120. Our analysis of 10A3 in complex with V3 provided a detailed example of how epitope complexity can evolve with affinity maturation, while that of 10A37 revealed a novel V3 binding mode targeting the C-terminal side of the V3 crown and showed that this region can form a helical structure. Our study provides novel insights about neutralization-susceptible V3 epitope structures and demonstrates that rabbits can serve as a useful animal model to evaluate human vaccine candidates.

scholarly journals Structural Comparison of Human Anti-HIV-1 gp120 V3 Monoclonal Antibodies of the Same Gene Usage Induced by Vaccination and Chronic Infection

2018 ◽  
Vol 92 (18) ◽  
Author(s):  
Kun-Wei Chan ◽  
Ruimin Pan ◽  
Matthew Costa ◽  
Miroslaw K. Gorny ◽  
Shixia Wang ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Chronic Infection ◽  
Germ Line ◽  
Affinity Maturation ◽  
Hiv Vaccine ◽  
Structural Basis ◽  
Antigen Binding ◽  
Gene Usage ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTElucidating the structural basis of antibody (Ab) gene usage and affinity maturation of vaccine-induced Abs can inform the design of immunogens for inducing desired Ab responses in HIV vaccine development. Analyses of monoclonal Abs (MAbs) encoded by the same immunoglobulin genes at different stages of maturation can help to elucidate the maturation process. We have analyzed four human anti-V3 MAbs with the same VH1-3*01 and VL3-10*01 gene usage. Two MAbs, TA6 and TA7, were developed from a vaccinee in the HIV vaccine phase I trial DP6-001 with a polyvalent DNA prime/protein boost regimen, and two others, 311-11D and 1334, were developed from HIV-infected patients. The somatic hypermutation (SHM) rates in VH of vaccine-induced MAbs are lower than in chronic HIV infection-induced MAbs, while those in VL are comparable. Crystal structures of the antigen-binding fragments (Fabs) in complex with V3 peptides show that these MAbs bind the V3 epitope with a new cradle-binding mode and that the V3 β-hairpin lies along the antigen-binding groove, which consists of residues from both heavy and light chains. Residues conserved from the germ line sequences form specific binding pockets accommodating conserved structural elements of the V3 crown hairpin, predetermining the Ab gene selection, while somatically mutated residues create additional hydrogen bonds, electrostatic interactions, and van der Waals contacts, correlating with an increased binding affinity. Our data provide a unique example of germ line sequences determining the primordial antigen-binding sites and SHMs correlating with affinity maturation of Abs induced by vaccine and natural HIV infection.IMPORTANCEUnderstanding the structural basis of gene usage and affinity maturation for anti-HIV-1 antibodies may help vaccine design and development. Antibodies targeting the highly immunogenic third variable loop (V3) of HIV-1 gp120 provide a unique opportunity for detailed structural investigations. By comparing the sequences and structures of four anti-V3 MAbs at different stages of affinity maturation but of the same V gene usage, two induced by vaccination and another two by chronic infection, we provide a fine example of how germ line sequence determines the essential elements for epitope recognition and how affinity maturation improves the antibody's recognition of its epitope.

scholarly journals Immunoglobulin Gene Insertions and Deletions in the Affinity Maturation of HIV-1 Broadly Reactive Neutralizing Antibodies

2014 ◽  
Vol 16 (3) ◽  
pp. 304-313 ◽  
Author(s):  
Thomas B. Kepler ◽  
Hua-Xin Liao ◽  
S. Munir Alam ◽  
Rekha Bhaskarabhatla ◽  
Ruijun Zhang ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Affinity Maturation ◽  
Immunoglobulin Gene ◽  
Insertions And Deletions ◽  
Hiv 1
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