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

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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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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HIV-1 Envelope Glycosylation and the Signal Peptide

Vaccines ◽

10.3390/vaccines9020176 ◽

2021 ◽

Vol 9 (2) ◽

pp. 176

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

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Broadly Neutralizing Antibodies (BNAbs): templates for HIV-1 vaccine design

Journal of Medical Discovery ◽

10.24262/jmd.2.4.17039 ◽

2017 ◽

Vol 2 (4) ◽

Cited By ~ 1

Author(s):

Lixin Yan ◽

◽

Lihong Liu ◽

Yilin Wang ◽

Xi Huang ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Design ◽

Broadly Neutralizing Antibodies ◽

Hiv 1

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A VH1-69 antibody lineage from an infected Chinese donor potently neutralizes HIV-1 by targeting the V3 glycan supersite

Science Advances ◽

10.1126/sciadv.abb1328 ◽

2020 ◽

Vol 6 (38) ◽

pp. eabb1328 ◽

Cited By ~ 1

Author(s):

Sonu Kumar ◽

Bin Ju ◽

Benjamin Shapero ◽

Xiaohe Lin ◽

Li Ren ◽

...

Keyword(s):

Cell Sorting ◽

Neutralizing Antibodies ◽

Critical Role ◽

Viral Escape ◽

Germline Gene ◽

Broadly Neutralizing Antibodies ◽

Functional Studies ◽

Single Genome ◽

Hiv 1

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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Broadly neutralizing antibodies and vaccine design against HIV-1 infection

Frontiers of Medicine ◽

10.1007/s11684-019-0721-9 ◽

2019 ◽

Vol 14 (1) ◽

pp. 30-42 ◽

Cited By ~ 5

Author(s):

Qian Wang ◽

Linqi Zhang

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Vaccine Design ◽

Therapeutic Interventions ◽

Type I ◽

Broadly Neutralizing Antibodies ◽

Dynamic Studies ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Remarkable Progress

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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An HIV-1 broadly neutralizing antibody from a clade C infected pediatric elite neutralizer potently neutralizes the contemporaneous and autologous evolving viruses

10.1101/403469 ◽

2018 ◽

Cited By ~ 1

Author(s):

Sanjeev Kumar ◽

Harekrushna Panda ◽

Muzamil Ashraf Makhdoomi ◽

Nitesh Mishra ◽

Haaris Ahsan Safdari ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Structural Information ◽

Vaccine Design ◽

Neutralizing Antibody ◽

Elite Controller ◽

Effective Vaccine ◽

Protective Effects ◽

Isolation And Characterization ◽

Clade C ◽

Hiv 1

AbstractBroadly neutralizing antibodies (bNAbs) have demonstrated protective effects against HIV-1 in primate studies and recent human clinical trials. Elite-neutralizers are potential candidates for isolation of HIV-1 bNAbs and coexistence of bNAbs such as BG18 with neutralization susceptible autologous viruses in an HIV-1 infected adult elite controller has been suggested to control viremia. Disease progression is faster in HIV-1 infected children than adults. Plasma bNAbs with multiple epitope specificities are developed in HIV-1 chronically infected children with more potency and breadth than in adults. Therefore, we evaluated the specificity of plasma neutralizing antibodies of an antiretroviral naïve HIV-1 clade C chronically infected pediatric elite neutralizer AIIMS_330. The plasma antibodies showed broad and potent HIV-1 neutralizing activity with >87% (29/33) breadth, median inhibitory dilution (ID50) value of 1246 and presence of N160 and N332-supersite dependent HIV-1 bNAbs. The sorting of BG505.SOSIP.664.C2 T332N gp140 HIV-1 antigen-specific single B cells of AIIMS_330 resulted in the isolation of an HIV-1 N332-supersite dependent bNAb AIIMS-P01. The AIIMS-P01 neutralized 67% of HIV-1 cross-clade viruses; exhibited substantial indels despite limited somatic hypermutations; interacted with native-like HIV-1 trimer as observed in negative stain electron microscopy and demonstrated high binding affinity. In addition, AIIMS-P01 potently neutralized the coexisting and evolving autologous viruses suggesting the coexistence of vulnerable autologous viruses and HIV-1 bNAbs in AIIMS_330 pediatric elite neutralizer. Further studies on such pediatric elite-neutralizers and isolation of novel HIV-1 pediatric bNAbs may provide newer insights to guide vaccine design.ImportanceMore than 50% of the HIV-1 infections globally are caused by clade C viruses. Till date, there is no effective vaccine to prevent HIV-1 infection. Based on the structural information of the currently available HIV-1 bNAbs, attempts are underway to design immunogens that can elicit correlates of protection upon vaccination. Here we report the isolation and characterization of an HIV-1 N332-supersite dependent bNAb AIIMS-P01 from a clade C chronically infected pediatric elite neutralizer. The N332-supersite is an important epitope and is one of the current HIV-1 vaccine targets. AIIMS-P01 potently neutralized the contemporaneous and autologous evolving viruses and exhibits substantial indels despite low somatic hypermutations. Taken together with the information on infant bNAbs, further isolation of bNAbs contributing to the plasma breadth in HIV-1 infected children may help to better understand their development and characteristics, which in turn may guide 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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