Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design

AbstractRemarkable progress has been achieved for prophylactic and therapeutic interventions against human immunodeficiency virus type I (HIV-1) through antiretroviral therapy. However, vaccine development has remained challenging. Recent discoveries in broadly neutralizing monoclonal antibodies (bNAbs) has led to the development of multiple novel vaccine approaches for inducing bNAbs-like antibody response. Structural and dynamic studies revealed several vulnerable sites and states of the HIV-1 envelop glycoprotein (Env) during infection. Our review aims to highlight these discoveries and rejuvenate our endeavor in HIV-1 vaccine design and development.

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Anti-V3/Glycan and Anti-MPER Neutralizing Antibodies, but Not Anti-V2/Glycan Site Antibodies, Are Strongly Associated with Greater Anti-HIV-1 Neutralization Breadth and Potency

Journal of Virology ◽

10.1128/jvi.00129-15 ◽

2015 ◽

Vol 89 (10) ◽

pp. 5264-5275 ◽

Cited By ~ 23

Author(s):

Rajesh Abraham Jacob ◽

Thandeka Moyo ◽

Michael Schomaker ◽

Fatima Abrahams ◽

Berta Grau Pujol ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Prediction Interval ◽

Vaccine Design ◽

Broadly Neutralizing Antibodies ◽

External Region ◽

Membrane Proximal External Region ◽

Site Recognition ◽

Anti Hiv ◽

Glycan Site ◽

Hiv 1

ABSTRACTThe membrane-proximal external region (MPER), the V2/glycan site (initially defined by PG9 and PG16 antibodies), and the V3/glycans (initially defined by PGT121–128 antibodies) are targets of broadly neutralizing antibodies and potential targets for anti-HIV-1 antibody-based vaccines. Recent evidence shows that antibodies with moderate neutralization breadth are frequently attainable, with 50% of sera from chronically infected individuals neutralizing ≥50% of a large, diverse set of viruses. Nonetheless, there is little systematic information addressing which specificities are preferentially targeted among such commonly found, moderately broadly neutralizing sera. We explored associations between neutralization breadth and potency and the presence of neutralizing antibodies targeting the MPER, V2/glycan site, and V3/glycans in sera from 177 antiretroviral-naive HIV-1-infected (>1 year) individuals. Recognition of both MPER and V3/glycans was associated with increased breadth and potency. MPER-recognizing sera neutralized 4.62 more panel viruses than MPER-negative sera (95% prediction interval [95% PI], 4.41 to 5.20), and V3/glycan-recognizing sera neutralized 3.24 more panel viruses than V3/glycan-negative sera (95% PI, 3.15 to 3.52). In contrast, V2/glycan site-recognizing sera neutralized only 0.38 more panel viruses (95% PI, 0.20 to 0.45) than V2/glycan site-negative sera and no association between V2/glycan site recognition and breadth or potency was observed. Despite autoreactivity of many neutralizing antibodies recognizing MPER and V3/glycans, antibodies to these sites are major contributors to neutralization breadth and potency in this cohort. It may therefore be appropriate to focus on developing immunogens based upon the MPER and V3/glycans.IMPORTANCEPrevious candidate HIV vaccines have failed either to induce wide-coverage neutralizing antibodies or to substantially protect vaccinees. Therefore, current efforts focus on novel approaches never before successfully used in vaccine design, including modeling epitopes. Candidate immunogen models identified by broadly neutralizing antibodies include the membrane-proximal external region (MPER), V3/glycans, and the V2/glycan site. Autoreactivity and polyreactivity of anti-MPER and anti-V3/glycan antibodies are thought to pose both direct and indirect barriers to achieving neutralization breadth. We found that antibodies to the MPER and the V3/glycans contribute substantially to neutralization breadth and potency. In contrast, antibodies to the V2/glycan site were not associated with neutralization breadth/potency. This suggests that the autoreactivity effect is not critical and that the MPER and the V3/glycans should remain high-priority vaccine candidates. The V2/glycan site result is surprising because broadly neutralizing antibodies to this site have been repeatedly observed. Vaccine design priorities should shift toward the MPER and V3/glycans.

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HIV-1 Envelope Glycosylation and the Signal Peptide

10.20944/preprints202102.0210.v1 ◽

2021 ◽

Author(s):

Gregory S. Lambert ◽

Chitra Upadhyay

Keyword(s):

Signal Peptide ◽

Neutralizing Antibodies ◽

Vaccine Trial ◽

Vaccine Design ◽

Antibody Responses ◽

Broadly Neutralizing Antibodies ◽

Structural Determinants ◽

Humoral Immune ◽

Env Protein ◽

Hiv 1

The RV144 trial represents the only vaccine trial to demonstrate any protective effect against HIV-1 infection. While the reason(s) for this protection are still being evaluated, it serves as justification for widespread efforts aimed at developing new, more effective HIV-1 vaccines. Advances in our knowledge of HIV-1 immunogens and host antibody responses to these immunogens are crucial to informing vaccine design. While the envelope (Env) protein is the only viral protein present on the surface of virions, it exists in a complex trimeric conformation and is decorated with an array of variable N-linked glycans, making it an important but difficult target for vaccine design. Thus far, efforts to elicit a protective humoral immune response using structural mimics of native Env trimers have been unsuccessful. Notably, the aforementioned N-linked glycans serve as a component of many of the epitopes crucial for the induction of potentially protective broadly neutralizing antibodies (bnAbs). Thus, a greater understanding of Env structural determinants, most critically Env glycosylation, will no doubt be of importance in generating effective immunogens. Recent studies have identified the HIV-1 Env signal peptide (SP) as an important contributor to Env glycosylation. Further investigation into the mechanisms by which the SP directs glycosylation will be important, both in the context of understanding HIV-1 biology and in order to inform HIV-1 vaccine design.

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A Structural Update of Neutralizing Epitopes on the HIV Envelope, a Moving Target

Viruses ◽

10.3390/v13091774 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1774

Author(s):

Emma Parker Miller ◽

Maxwell T. Finkelstein ◽

Molly C. Erdman ◽

Paul C. Seth ◽

Daniela Fera

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Design ◽

Moving Target ◽

Resistance Mutations ◽

Broadly Neutralizing Antibodies ◽

Spike Analysis ◽

Hiv Envelope ◽

Structural Characterizations ◽

Hiv 1 ◽

Neutralizing Epitopes

Antibodies that can neutralize diverse HIV-1 strains develop in ~10–20% of HIV-1 infected individuals, and their elicitation is a goal of vaccine design. Such antibodies can also serve as therapeutics for those who have already been infected with the virus. Structural characterizations of broadly reactive antibodies in complex with the HIV-1 spike indicate that there are a limited number of sites of vulnerability on the spike. Analysis of their structures can help reveal commonalities that would be useful in vaccine design and provide insights on combinations of antibodies that can be used to minimize the incidence of viral resistance mutations. In this review, we give an update on recent structures determined of the spike in complex with broadly neutralizing antibodies in the context of all epitopes on the HIV-1 spike identified to date.

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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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Correction: Minimally Mutated HIV-1 Broadly Neutralizing Antibodies to Guide Reductionist Vaccine Design

PLoS Pathogens ◽

10.1371/journal.ppat.1005905 ◽

2016 ◽

Vol 12 (9) ◽

pp. e1005905

Author(s):

Joseph G. Jardine ◽

Devin Sok ◽

Jean-Philippe Julien ◽

Bryan Briney ◽

Anita Sarkar ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Design ◽

Broadly Neutralizing Antibodies ◽

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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A site of vulnerability at V3 crown defined by HIV-1 bNAb M4008_N1

Nature Communications ◽

10.1038/s41467-021-26846-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Kun-Wei Chan ◽

Christina C. Luo ◽

Hong Lu ◽

Xueling Wu ◽

Xiang-Peng Kong

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Design ◽

Tier 2 ◽

Broadly Neutralizing Antibodies ◽

Closed Conformation ◽

Immunogen Design ◽

A Site ◽

Β Sheet ◽

Hiv 1

AbstractIdentification of vulnerable sites defined by broadly neutralizing antibodies (bNAbs) on HIV-1 envelope (Env) is crucial for vaccine design, and we present here a vulnerable site defined by bNAb M4008_N1, which neutralizes about 40% of a tier-2 virus panel. A 3.2 Å resolution cryo-EM structure of M4008_N1 in complex with BG505 DS-SOSIP reveals a large, shallow protein epitope surface centered at the V3 crown of gp120 and surrounded by key glycans. M4008_N1 interacts with gp120 primarily through its hammerhead CDR H3 to form a β-sheet interaction with the V3 crown hairpin. This makes M4008_N1 compatible with the closed conformation of the prefusion Env trimer, and thus distinct from other known V3 crown mAbs. This mode of bNAb approaching the immunogenic V3 crown in the native Env trimer suggests a strategy for immunogen design targeting this site of vulnerability.

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