B cell engagement with HIV-1 founder virus envelope predicts development of broadly neutralizing antibodies

ABSTRACT All HIV-1-infected individuals develop strain-specific neutralizing antibodies to their infecting virus, which in some cases mature into broadly neutralizing antibodies. Defining the epitopes of strain-specific antibodies that overlap conserved sites of vulnerability might provide mechanistic insights into how broadly neutralizing antibodies arise. We previously described an HIV-1 clade C-infected donor, CAP257, who developed broadly neutralizing plasma antibodies targeting an N276 glycan-dependent epitope in the CD4 binding site. The initial CD4 binding site response potently neutralized the heterologous tier 2 clade B viral strain RHPA, which was used to design resurfaced gp120 antigens for single-B-cell sorting. Here we report the isolation and structural characterization of CAP257-RH1, an N276 glycan-dependent CD4 binding site antibody representative of the early CD4 binding site plasma response in donor CAP257. The cocrystal structure of CAP257-RH1 bound to RHPA gp120 revealed critical interactions with the N276 glycan, loop D, and V5, but not with aspartic acid 368, similarly to HJ16 and 179NC75. The CAP257-RH1 monoclonal antibody was derived from the immunoglobulin-variable IGHV3-33 and IGLV3-10 genes and neutralized RHPA but not the transmitted/founder virus from donor CAP257. Its narrow neutralization breadth was attributed to a binding angle that was incompatible with glycosylated V5 loops present in almost all HIV-1 strains, including the CAP257 transmitted/founder virus. Deep sequencing of autologous CAP257 viruses, however, revealed minority variants early in infection that lacked V5 glycans. These glycan-free V5 loops are unusual holes in the glycan shield that may have been necessary for initiating this N276 glycan-dependent CD4 binding site B-cell lineage. IMPORTANCE The conserved CD4 binding site on gp120 is a major target for HIV-1 vaccine design, but key events in the elicitation and maturation of different antibody lineages to this site remain elusive. Studies have shown that strain-specific antibodies can evolve into broadly neutralizing antibodies or in some cases act as helper lineages. Therefore, characterizing the epitopes of strain-specific antibodies may help to inform the design of HIV-1 immunogens to elicit broadly neutralizing antibodies. In this study, we isolate a narrowly neutralizing N276 glycan-dependent antibody and use X-ray crystallography and viral deep sequencing to describe how gp120 lacking glycans in V5 might have elicited these early glycan-dependent CD4 binding site antibodies. These data highlight how glycan holes can play a role in the elicitation of B-cell lineages targeting the CD4 binding site.

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Limited evidence for a relationship between HIV-1 glycan shield features in early infection and the development of neutralization breadth

Journal of Virology ◽

10.1128/jvi.00797-21 ◽

2021 ◽

Author(s):

Yifan Li ◽

Hongjun Bai ◽

Eric Sanders-Buell ◽

Vincent Dussupt ◽

Samantha Townsley ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Early Infection ◽

Broadly Neutralizing Antibodies ◽

Limited Evidence ◽

Founder Virus ◽

Vaccine Antigens ◽

Acute Hiv ◽

The Relationship ◽

Hiv 1 ◽

Reactive Antibody

Identifying if viral features present in acute HIV-1 infection predetermine the development of neutralization breadth is critical to vaccine design. Incorporating such features in vaccine antigens could initiate cross-reactive antibody responses that could sufficiently protect vaccinees from HIV-1 infection despite the uniqueness of each founder virus. To understand the relationship between Env determinants and the development of neutralization breadth, we focused on 197 individuals enrolled in two cohorts in Thailand and East Africa (RV144 and RV217) and followed since their diagnosis in acute or early HIV-1 infection. We analyzed the distribution of variable loop lengths and glycans as well as the predicted density of the glycan shield and compared these envelope features to the neutralization breadth data obtained three years after infection (n = 121). Our study revealed limited evidence for glycan shield features that associate with the development of neutralization breadth. While the glycan shield tended to be denser in participants who subsequently developed breadth, no significant relationship was found between the size of glycan holes and the development of neutralization breadth. The parallel analysis of 3,000 independent Env sequences showed no evidence of directional evolution of glycan shield features since the beginning of the epidemic. Together, our results highlight that glycan shield features in acute and early HIV-1 infection may not play a role determinant enough to dictate the development of neutralization breadth, and instead suggest that the glycan shield’s reactive properties that are associated with immune evasion may have a greater impact. IMPORTANCE A major goal of HIV-1 vaccine research is to design vaccine candidates that elicit potent broadly neutralizing antibodies (bnAbs). Different viral features have been associated with the development of broadly neutralizing antibodies, including the glycan shield on the surface of the HIV-1 Envelope (Env). Here, we analyzed data from two cohorts of individuals who were followed from early infection to several years after infection spanning multiple HIV-1 subtypes. We compared Env glycan features in HIV-1 sequences obtained in early infection to the potency and breadth of neutralizing antibodies measured one to three years after infection. We found limited evidence of glycan shield properties that associate with the development of neutralization breadth in these cohorts. These results may have important implications for antigen design in future vaccine strategies and emphasize that HIV-1 vaccines will need to rely on a complex set of properties to elicit neutralization breadth.

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192 Computer-aided search for novel anti-HIV-1 agents presenting peptidomimetics of broadly neutralizing antibodies against the virus envelope GP120 V3 loop

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2013.786434 ◽

2013 ◽

Vol 31 (sup1) ◽

pp. 124-125

Author(s):

Alexander M. Andrianov ◽

Ivan A. Kashyn ◽

Alexander V. Tuzikov

Keyword(s):

Neutralizing Antibodies ◽

V3 Loop ◽

Broadly Neutralizing Antibodies ◽

Virus Envelope ◽

Computer Aided ◽

Anti Hiv ◽

Hiv 1 ◽

Envelope Gp120

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Cooperation of B Cell Lineages in Induction of HIV-1-Broadly Neutralizing Antibodies

Cell ◽

10.1016/j.cell.2014.06.022 ◽

2014 ◽

Vol 158 (3) ◽

pp. 481-491 ◽

Cited By ~ 190

Author(s):

Feng Gao ◽

Mattia Bonsignori ◽

Hua-Xin Liao ◽

Amit Kumar ◽

Shi-Mao Xia ◽

...

Keyword(s):

B Cell ◽

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Cell Lineages ◽

Hiv 1

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Structural survey of HIV-1-neutralizing antibodies targeting Env trimer delineates epitope categories and suggests vaccine templates

10.1101/312579 ◽

2018 ◽

Cited By ~ 3

Author(s):

Gwo-Yu Chuang ◽

Jing Zhou ◽

Reda Rawi ◽

Chen-Hsiang Shen ◽

Zizhang Sheng ◽

...

Keyword(s):

B Cell ◽

Binding Site ◽

Neutralizing Antibodies ◽

Vaccine Design ◽

Immune Recognition ◽

Broadly Neutralizing Antibodies ◽

Independent Sequence ◽

Cd4 Binding Site ◽

Hiv 1 ◽

Cell Ontogeny

HIV-1 broadly neutralizing antibodies are desired for their therapeutic potential and as templates for vaccine design. Such antibodies target the HIV-1-envelope (Env) trimer, which is shielded from immune recognition by extraordinary glycosylation and sequence variability. Recognition by broadly neutralizing antibodies thus provides insight into how antibody can bypass these immune-evasion mechanisms. Remarkably, antibodies neutralizing >25% of HIV-1 strains have now been identified that recognize all major exposed surfaces of the prefusion-closed Env trimer. Here we analyzed all 206 broadly neutralizing antibody-HIV-1 Env complexes in the PDB with resolution suitable to define their interaction chemistries. These segregated into 20 antibody classes based on ontogeny and recognition, and into 6 epitope categories (V1V2, glycan-V3, CD4-binding site, silent face center, fusion peptide, and subunit interface) based on recognized Env residues. We measured antibody neutralization on a 208-isolate panel and analyzed features of paratope and B cell ontogeny. The number of protruding loops, CDR H3 length, and level of somatic hypermutation for broadly HIV-1 neutralizing antibodies were significantly higher than for a comparison set of non-HIV-1 antibodies. For epitope, the number of independent sequence segments was higher (P < 0.0001), as well as the glycan component surface area (P = 0.0005). Based on B cell ontogeny, paratope, and breadth, the CD4-binding site antibody IOMA appeared to be a promising candidate for lineage-based vaccine design. In terms of epitope-based vaccine design, antibody VRC34.01 had few epitope segments, low epitope-glycan content, and high epitope-conformational variability, which may explain why VRC34.01-based design is yielding promising vaccine results.

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Anti-HIV-1 B cell responses are dependent on B cell precursor frequency and antigen binding affinity

10.1101/275438 ◽

2018 ◽

Author(s):

Pia Dosenovic ◽

Ervin E. Kara ◽

Anna-Klara Pettersson ◽

Andrew McGuire ◽

Matthew Gray ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Neutralizing Antibodies ◽

Cell Receptor ◽

Broadly Neutralizing Antibodies ◽

Precursor Frequency ◽

The Relationship ◽

Anti Hiv ◽

Hiv 1

AbstractThe discovery that humans can produce potent broadly neutralizing antibodies (bNAbs) to several different epitopes on the HIV-1 spike has reinvigorated efforts to develop an antibody based HIV-1 vaccine. Antibody cloning from single cells revealed that nearly all bNAbs show unusual features that could help explain why it has not been possible to elicit them by traditional vaccination, and instead that it would require a sequence of different immunogens. This idea is supported by experiments with genetically modified immunoglobulin knock-in mice. Sequential immunization with a series of specifically designed immunogens was required to shepherd the development of bNAbs. However, knock-in mice contain super-physiologic numbers of bNAb precursor expressing B cells and therefore how these results can be translated to a more physiologic setting remains to be determined. Here we make use of adoptive transfer experiments using knock-in B cells that carry a synthetic intermediate in the pathway to anti-HIV-1 bNAb development to examine how the relationship between B cell receptor affinity and precursor frequency affects germinal center B cell recrutiment and clonal expansion. Immunization with soluble HIV-1 antigens can recruit bNAb precursor B cells to the germinal center when there are as few as 10 such cells per mouse. However, at low precursor frequencies the extent of clonal expansion is directly proportional to the affinity of the antigen for the B cell receptor, and recruitment to germinal centers is variable and dependent on re-circulation.Significance statementAn essential requirement for an HIV-vaccine is to elicit antibodies to conserved regions of the spike protein (Env) becasue these antibodies can protect against infection. Although broadly neutralizing antibodies develop naturally in rare individuals after prolongued HIV infection, eliciting them by vaccination has only been possible in artificial knock-in mouse models wherein the number of B cells expressing the antibody precursor is super-physiologic. To understand the relationship between precursor frequency, antigen affinity and germinal center recruitment we have performed adoptive transfer experiments in which fixed numbers of precursor cells are engrafted in wild type mice. Our results provide a framework for understanding how precursor frequency and antigen affinity shape humoral immunity to HIV.

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The Role of CXCL13 in Antibody Responses to HIV-1 Infection and Vaccination

Frontiers in Immunology ◽

10.3389/fimmu.2021.638872 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yonas Bekele Feyissa ◽

Francesca Chiodi ◽

Yongjun Sui ◽

Jay A. Berzofsky

Keyword(s):

B Cells ◽

B Cell ◽

Neutralizing Antibodies ◽

Plasma Cells ◽

B Cell Lymphoma ◽

Cell Trafficking ◽

Broadly Neutralizing Antibodies ◽

G Protein Coupled ◽

Hiv 1

CXCL13 signals through the G protein-coupled chemokine receptor CXCR5 to drive development of secondary lymphoid tissue as well as B cell and Tfh cell trafficking to germinal centers (GC), which leads to the differentiation of B cells to plasma cells and memory B cells. CXCL13 has been proposed as a general plasma biomarker for GC activities. In HIV-1 infected individuals, plasma CXCL13 levels have been associated with the rate of disease progression to AIDS. Moreover, CXCL13 production has been reported to be increased in HIV-1-infected lymph nodes, which may drive increased downregulation of CXCR5. In this review, we address the role of CXCL13 in HIV-1 infected individuals with regard to GC formation, generation of broadly neutralizing antibodies after infection and vaccination, and AIDS-related B cell lymphoma.

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