Role of Broadly Neutralizing Antibodies in the Controlling of HIV-1 Infection

An oligomannose patch around the V3 base of HIV-1 envelope glycoprotein (Env) is recognized by multiple classes of broadly neutralizing antibodies (bNAbs). Here, we investigated the bNAb response to the V3 glycan supersite in an HIV-1–infected Chinese donor by Env-specific single B cell sorting, structural and functional studies, and longitudinal analysis of antibody and virus repertoires. Monoclonal antibodies 438-B11 and 438-D5 were isolated that potently neutralize HIV-1 with moderate breadth, are encoded by the VH1-69 germline gene, and have a disulfide-linked long HCDR3 loop. Crystal structures of Env-bound and unbound antibodies revealed heavy chain–mediated recognition of the glycan supersite with a unique angle of approach and a critical role of the intra-HCDR3 disulfide. The mechanism of viral escape was examined via single-genome amplification/sequencing and glycan mutations around the N332 supersite. Our findings further emphasize the V3 glycan supersite as a prominent target for Env-based vaccine design.

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Neutralizing Antibodies Targeting HIV-1 gp41

Viruses ◽

10.3390/v12111210 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1210

Author(s):

Christophe Caillat ◽

Delphine Guilligay ◽

Guidenn Sulbaran ◽

Winfried Weissenhorn

Keyword(s):

Conformational Changes ◽

Neutralizing Antibodies ◽

Somatic Mutations ◽

Heptad Repeat ◽

Broadly Neutralizing Antibodies ◽

Vaccine Research ◽

Membrane Components ◽

And Function ◽

Hiv 1

HIV-1 vaccine research has obtained an enormous boost since the discovery of many broadly neutralizing antibodies (bnAbs) targeting all accessible sites on the HIV-1 envelope glycoprotein (Env). This in turn facilitated high-resolution structures of the Env glycoprotein in complex with bnAbs. Here we focus on gp41, its highly conserved heptad repeat region 1 (HR1), the fusion peptide (FP) and the membrane-proximal external region (MPER). Notably, the broadest neutralizing antibodies target MPER. Both gp41 HR1 and MPER are only fully accessible once receptor-induced conformational changes have taken place, although some studies suggest access to MPER in the close to native Env conformation. We summarize the data on the structure and function of neutralizing antibodies targeting gp41 HR1, FP and MPER and we review their access to Env and their complex formation with gp41 HR1, MPER peptides and FP within native Env. We further discuss MPER bnAb binding to lipids and the role of somatic mutations in recognizing a bipartite epitope composed of the conserved MPER sequence and membrane components. The problematic of gp41 HR1 access and MPER bnAb auto- and polyreactivity is developed in the light of inducing such antibodies by vaccination.

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Complete epitopes for vaccine design derived from a crystal structure of the broadly neutralizing antibodies PGT128 and 8ANC195 in complex with an HIV-1 Env trimer

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s1399004715013917 ◽

2015 ◽

Vol 71 (10) ◽

pp. 2099-2108 ◽

Cited By ~ 48

Author(s):

Leopold Kong ◽

Alba Torrents de la Peña ◽

Marc C. Deller ◽

Fernando Garces ◽

Kwinten Sliepen ◽

...

Keyword(s):

Crystal Structure ◽

Neutralizing Antibodies ◽

Structural Information ◽

Vaccine Design ◽

Cell Entry ◽

Broadly Neutralizing Antibodies ◽

Humoral Immune ◽

Hiv 1 ◽

Gp140 Trimer

The HIV-1 envelope gp160 glycoprotein (Env) is a trimer of gp120 and gp41 heterodimers that mediates cell entry and is the primary target of the humoral immune response. Broadly neutralizing antibodies (bNAbs) to HIV-1 have revealed multiple epitopes or sites of vulnerability, but mapping of most of these sites is incomplete owing to a paucity of structural information on the full epitope in the context of the Env trimer. Here, a crystal structure of the soluble BG505 SOSIP gp140 trimer at 4.6 Å resolution with the bNAbs 8ANC195 and PGT128 reveals additional interactions in comparison to previous antibody–gp120 structures. For 8ANC195, in addition to previously documented interactions with gp120, a substantial interface with gp41 is now elucidated that includes extensive interactions with the N637 glycan. Surprisingly, removal of the N637 glycan did not impact 8ANC195 affinity, suggesting that the antibody has evolved to accommodate this glycan without loss of binding energy. PGT128 indirectly affects the N262 glycan by a domino effect, in which PGT128 binds to the N301 glycan, which in turn interacts with and repositions the N262 glycan, thereby illustrating the important role of neighboring glycans on epitope conformation and stability. Comparisons with other Env trimer and gp120 structures support an induced conformation for glycan N262, suggesting that the glycan shield is allosterically modified upon PGT128 binding. These complete epitopes of two broadly neutralizing antibodies on the Env trimer can now be exploited for HIV-1 vaccine design.

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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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Conserved Role of an N-Linked Glycan on the Surface Antigen of Human Immunodeficiency Virus Type 1 Modulating Virus Sensitivity to Broadly Neutralizing Antibodies against the Receptor and Coreceptor Binding Sites

Journal of Virology ◽

10.1128/jvi.02321-15 ◽

2015 ◽

Vol 90 (2) ◽

pp. 829-841 ◽

Cited By ~ 15

Author(s):

Samantha Townsley ◽

Yun Li ◽

Yury Kozyrev ◽

Brad Cleveland ◽

Shiu-Lok Hu

Keyword(s):

Immune Responses ◽

Binding Site ◽

Surface Antigen ◽

Binding Sites ◽

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Host Immune Responses ◽

Coreceptor Binding ◽

Hiv 1

ABSTRACTHIV-1 establishes persistent infection in part due to its ability to evade host immune responses. Occlusion by glycans contributes to masking conserved sites that are targets for some broadly neutralizing antibodies (bNAbs). Previous work has shown that removal of a highly conserved potential N-linked glycan (PNLG) site at amino acid residue 197 (N7) on the surface antigen gp120 of HIV-1 increases neutralization sensitivity of the mutant virus to CD4 binding site (CD4bs)-directed antibodies compared to its wild-type (WT) counterpart. However, it is not clear if the role of the N7 glycan is conserved among diverse HIV-1 isolates and if other glycans in the conserved regions of HIV-1 Env display similar functions. In this work, we examined the role of PNLGs in the conserved region of HIV-1 Env, particularly the role of the N7 glycan in a panel of HIV-1 strains representing different clades, tissue origins, coreceptor usages, and neutralization sensitivities. We demonstrate that the absence of the N7 glycan increases the sensitivity of diverse HIV-1 isolates to CD4bs- and V3 loop-directed antibodies, indicating that the N7 glycan plays a conserved role masking these conserved epitopes. However, the effect of the N7 glycan on virus sensitivity to neutralizing antibodies directed against the V2 loop epitope is isolate dependent. These findings indicate that the N7 glycan plays an important and conserved role modulating the structure, stability, or accessibility of bNAb epitopes in the CD4bs and coreceptor binding region, thus representing a potential target for the design of immunogens and therapeutics.IMPORTANCEN-linked glycans on the HIV-1 envelope protein have been postulated to contribute to viral escape from host immune responses. However, the role of specific glycans in the conserved regions of HIV-1 Env in modulating epitope recognition by broadly neutralizing antibodies has not been well defined. We show here that a single N-linked glycan plays a unique and conserved role among conserved glycans on HIV-1 gp120 in modulating the exposure or the stability of the receptor and coreceptor binding site without affecting the integrity of the Env in mediating viral infection or the ability of the mutant gp120 to bind to CD4. The observation that the antigenicity of the receptor and coreceptor binding sites can be modulated by a single glycan indicates that select glycan modification offers a potential strategy for the design of HIV-1 vaccine candidates.

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Role of immune mechanisms in induction of HIV-1 broadly neutralizing antibodies

Current Opinion in Immunology ◽

10.1016/j.coi.2011.04.003 ◽

2011 ◽

Vol 23 (3) ◽

pp. 383-390 ◽

Cited By ~ 72

Author(s):

Laurent Verkoczy ◽

Garnett Kelsoe ◽

M Anthony Moody ◽

Barton F Haynes

Keyword(s):

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Immune Mechanisms ◽

Hiv 1

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Unprecedented Role of Hybrid N-Glycans as Ligands for HIV-1 Broadly Neutralizing Antibodies

Journal of the American Chemical Society ◽

10.1021/jacs.8b00896 ◽

2018 ◽

Vol 140 (15) ◽

pp. 5202-5210 ◽

Cited By ~ 22

Author(s):

Vidya S. Shivatare ◽

Sachin S. Shivatare ◽

Chang-Chun David Lee ◽

Chi-Hui Liang ◽

Kuo-Shiang Liao ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Hiv 1

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Mechanisms of HIV-1 evasion to the antiviral activity of chemokine CXCL12 indicate potential links with pathogenesis

PLoS Pathogens ◽

10.1371/journal.ppat.1009526 ◽

2021 ◽

Vol 17 (4) ◽

pp. e1009526

Author(s):

Marie Armani-Tourret ◽

Zhicheng Zhou ◽

Romain Gasser ◽

Isabelle Staropoli ◽

Vincent Cantaloube-Ferrieu ◽

...

Keyword(s):

Chemokine Receptors ◽

Neutralizing Antibodies ◽

Effector Memory ◽

Broadly Neutralizing Antibodies ◽

Treatment Naïve ◽

Chemokine Cxcl12 ◽

Effector Memory Cells ◽

Hiv 1

HIV-1 infects CD4 T lymphocytes (CD4TL) through binding the chemokine receptors CCR5 or CXCR4. CXCR4-using viruses are considered more pathogenic, linked to accelerated depletion of CD4TL and progression to AIDS. However, counterexamples to this paradigm are common, suggesting heterogeneity in the virulence of CXCR4-using viruses. Here, we investigated the role of the CXCR4 chemokine CXCL12 as a driving force behind virus virulence. In vitro, CXCL12 prevents HIV-1 from binding CXCR4 and entering CD4TL, but its role in HIV-1 transmission and propagation remains speculative. Through analysis of thirty envelope glycoproteins (Envs) from patients at different stages of infection, mostly treatment-naïve, we first interrogated whether sensitivity of viruses to inhibition by CXCL12 varies over time in infection. Results show that Envs resistant (RES) to CXCL12 are frequent in patients experiencing low CD4TL levels, most often late in infection, only rarely at the time of primary infection. Sensitivity assays to soluble CD4 or broadly neutralizing antibodies further showed that RES Envs adopt a more closed conformation with distinct antigenicity, compared to CXCL12-sensitive (SENS) Envs. At the level of the host cell, our results suggest that resistance is not due to improved fusion or binding to CD4, but owes to viruses using particular CXCR4 molecules weakly accessible to CXCL12. We finally asked whether the low CD4TL levels in patients are related to increased pathogenicity of RES viruses. Resistance actually provides viruses with an enhanced capacity to enter naive CD4TL when surrounded by CXCL12, which mirrors their situation in lymphoid organs, and to deplete bystander activated effector memory cells. Therefore, RES viruses seem more likely to deregulate CD4TL homeostasis. This work improves our understanding of the pathophysiology and the transmission of HIV-1 and suggests that RES viruses’ receptors could represent new therapeutic targets to help prevent CD4TL depletion in HIV+ patients on cART.

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