HIV-1 Envelope gp41 Broadly Neutralizing Antibodies: Hurdles for Vaccine Development

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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Reverse Immunology Approach to Define a New HIV-gp41-Neutralizing Epitope

Journal of Immunology Research ◽

10.1155/2019/9804584 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Karim Dorgham ◽

Nicolas Pietrancosta ◽

Amel Affoune ◽

Olivier Lucar ◽

Tahar Bouceba ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Molecular Design ◽

Docking Studies ◽

Viral Envelope ◽

Broadly Neutralizing Antibodies ◽

Immunodeficiency Virus ◽

Surface Envelope ◽

Hiv 1

The design of immunogens susceptible to elicit potent and broadly neutralizing antibodies against the human immunodeficiency virus type 1 (HIV-1) remains a veritable challenge in the course of vaccine development. Viral envelope proteins adopt different conformational states during the entry process, allowing the presentation of transient neutralizing epitopes. We focused on the highly conserved 3S motif of gp41, which is exposed to the surface envelope in its trimeric prefusion state. Vaccination with a W614A-modified 3S peptide induces in animals neutralizing anti-HIV-1 antibodies among which we selected clone F8. We used F8 as bait to select for W614A-3S phage-peptide mimics. Binding and molecular docking studies revealed that F8 interacts similarly with W614A-3S and a Mim_F8-1 mimotope, despite their lack of sequence homology, suggesting structural mimicry. Finally, vaccination of mice with the purified Mim_F8-1 phage elicited HIV-1-neutralizing antibodies that bound to the cognate W614A-3S motif. Collectively, our findings provide new insights into the molecular design of immunogens to elicit antibodies with neutralizing properties.

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Development of a Norovirus P Particle Platform for Eliciting Neutralizing Antibody Responses to the Membrane Proximal External Region of Human Immunodeficiency Virus Type 1 Envelope

Protein and Peptide Letters ◽

10.2174/0929866521666140616120955 ◽

2014 ◽

Vol 21 (12) ◽

pp. 1230-1239

Author(s):

Yang Zang ◽

Jinpeng Bi ◽

Dongchuan Du ◽

Xintao Liu ◽

Yan Zhang ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Broadly Neutralizing Antibodies ◽

External Region ◽

Membrane Proximal External Region ◽

Immunodeficiency Virus ◽

Hiv 1

Eliciting efficient broadly neutralizing antibodies (BnAbs) is an important goal that has yet to be achieved for human immunodeficiency type 1 (HIV-1) vaccine development, although they are rarely produced in virus-infected individuals. In particular, inducing specific neutralizing antibodies to the gp41 membrane proximal external region (MPER) has proven a difficult task. In this study, we introduce Norovirus P particles as a new platform to display the MPER epitope of HIV-1 as a vaccine with the aim of enhancing immune responses. The results showed that HIV-1 chimeric P particles were capable of inducing MPER-specific antibody responses in immunized guinea pigs, although only weakly neutralizing activity could be detected. These findings are consistent with other previous studies which have also focused on the well-studied 2F5 and 4E10 BnAbs. Our findings provide an alternate strategy for design of vaccines against HIV-1. However, great challenges remain in the effort to develop vaccines that can induce efficient HIV-1 neutralizing antibodies.

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Augmenting Neutralization breadth against Diverse HIV-1 by increasing the Ab-Ag interface on V2

10.1101/2021.08.07.455519 ◽

2021 ◽

Author(s):

Nan Gao ◽

Yanxin Gai ◽

Lina Meng ◽

Chu Wang ◽

Wei Wang ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Rhesus Macaques ◽

Broadly Neutralizing Antibodies ◽

Binding Surface ◽

Monomeric Gp120 ◽

Chinese Rhesus Macaques ◽

Shiv Infection ◽

Hiv 1 ◽

Trimeric Envelope

Understanding maturation pathways of broadly neutralizing antibodies (bnAbs) against HIV-1 in non-human primates can be highly informative for HIV-1 vaccine development. We now obtained a lineage of J038 from Chinese rhesus macaques after 7-years of SHIV infection. J038 has short complementary determining loops and neutralizes 54% of global circulating HIV-1 strains. Its binding induces a unique 'up' conformation for one of the V2 loops in the trimeric envelope glycoprotein (Env) and is heavily dependent on glycan, which provides nearly half of the binding surface. The unmutated common ancestor of the J038 lineage antibodies binds monomeric gp120 and neutralizes the autologous virus. Continuous maturation enhances neutralization potency and breadth of J038 lineage antibodies via expanding antibody-Env contact areas surrounding the core region contacted by germline-encoded residues. Developmental details and recognition features of J038 lineage antibodies revealed here provide a new pathway for maturation elicitation of V2-targeting bnAbs.

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Multiple Antibody Lineages in One Donor Target the Glycan-V3 Supersite of the HIV-1 Envelope Glycoprotein and Display a Preference for Quaternary Binding

Journal of Virology ◽

10.1128/jvi.01012-16 ◽

2016 ◽

Vol 90 (23) ◽

pp. 10574-10586 ◽

Cited By ~ 16

Author(s):

Nancy S. Longo ◽

Matthew S. Sutton ◽

Andrea R. Shiakolas ◽

Javier Guenaga ◽

Marissa C. Jarosinski ◽

...

Keyword(s):

Envelope Glycoprotein ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Culture Method ◽

High Serum ◽

Broadly Neutralizing Antibodies ◽

Monomeric Gp120 ◽

Antibody Specificities ◽

V3 Region ◽

Hiv 1

ABSTRACT One of the goals of HIV-1 vaccine development is the elicitation of neutralizing antibodies against vulnerable regions on the envelope glycoprotein (Env) viral spike. Broadly neutralizing antibodies targeting the Env glycan-V3 region (also called the N332 glycan supersite) have been described previously, with several single lineages each derived from different individual donors. We used a high-throughput B-cell culture method to isolate neutralizing antibodies from an HIV-1-infected donor with high serum neutralization breadth. Clonal relatives from three distinct antibody lineages were isolated. Each of these antibody lineages displayed modest breadth and potency but shared several characteristics with the well-characterized glycan-V3 antibodies, including dependence on glycans N332 and N301, VH4 family gene utilization, a heavy chain complementarity-determining region 2 (CDRH2) insertion, and a longer-than-average CDRH3. In contrast to previously described glycan-V3 antibodies, these antibodies preferentially recognized the native Env trimer compared to monomeric gp120. These data indicate the diversity of antibody specificities that target the glycan-V3 site. The quaternary binding preference of these antibodies suggests that that their elicitation likely requires the presentation of a native-like trimeric Env immunogen. IMPORTANCE Broadly neutralizing antibodies targeting the HIV-1 glycan-V3 region with single lineages from individual donors have been described previously. Here we describe three lineages from a single donor, each of which targets glycan-V3. Unlike previously described glycan-V3 antibodies, these mature antibodies bind preferentially to the native Env trimer and weakly to the gp120 monomer. These data extend our knowledge of the immune response recognition of the N332 supersite region and suggest that the mode of epitope recognition is more complex than previously anticipated.

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Cooperation between Strain-Specific and Broadly Neutralizing Responses Limited Viral Escape and Prolonged the Exposure of the Broadly Neutralizing Epitope

Journal of Virology ◽

10.1128/jvi.00828-17 ◽

2017 ◽

Vol 91 (18) ◽

Cited By ~ 21

Author(s):

Colin Anthony ◽

Talita York ◽

Valerie Bekker ◽

David Matten ◽

Philippe Selhorst ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Prolonged Exposure ◽

Vaccine Development ◽

Viral Evolution ◽

Neutralizing Antibody ◽

Viral Escape ◽

Broadly Neutralizing Antibodies ◽

Immunogen Design ◽

Early Strain ◽

Hiv 1

ABSTRACT V3-glycan-targeting broadly neutralizing antibodies (bNAbs) are a focus of HIV-1 vaccine development. Understanding the viral dynamics that stimulate the development of these antibodies can provide insights for immunogen design. We used a deep-sequencing approach, together with neutralization phenotyping, to investigate the rate and complexity of escape from V3-glycan-directed bNAbs compared to overlapping early strain-specific neutralizing antibody (ssNAb) responses to the V3/C3 region in donor CAP177. Escape from the ssNAb response occurred rapidly via an N334-to-N332 glycan switch, which took just 7.5 weeks to reach >50% frequency. In contrast, escape from the bNAbs was mediated via multiple pathways and took longer, with escape first occurring through an increase in V1 loop length, which took 46 weeks to reach 50% frequency, followed by an N332-to-N334 reversion, which took 66 weeks. Importantly, bNAb escape was incomplete, with contemporaneous neutralization observed up to 3 years postinfection. Both the ssNAb response and the bNAb response were modulated by the presence/absence of the N332 glycan, indicating an overlap between the two epitopes. Thus, selective pressure by ssNAbs to maintain the N332 glycan may have constrained the bNAb escape pathway. This slower and incomplete viral escape resulted in prolonged exposure of the bNAb epitope, which may in turn have aided the maturation of the bNAb lineage. IMPORTANCE The development of an HIV-1 vaccine is of paramount importance, and broadly neutralizing antibodies are likely to be a key component of a protective vaccine. The V3-glycan-targeting bNAb responses are among the most promising vaccine targets, as they are commonly elicited during infection. Understanding the interplay between viral evolution and the development of these antibodies provides insights that may guide immunogen design. Our work contrasted the dynamics of the early strain-specific antibodies and the later broadly neutralizing responses to a common Env target (V3C3), showing slower and more complex escape from bNAbs. Constrained bNAb escape, together with evidence of contemporaneous autologous virus neutralization, supports the proposal that prolonged exposure of the bNAb epitope enabled the maturation of the bNAb lineage.

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Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds

Journal of Virology ◽

10.1128/jvi.03211-15 ◽

2016 ◽

Vol 90 (10) ◽

pp. 5031-5046 ◽

Cited By ~ 21

Author(s):

Navid Madani ◽

Amy M. Princiotto ◽

David Easterhoff ◽

Todd Bradley ◽

Kan Luo ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Small Molecule ◽

Conformational Changes ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Protective Efficacy ◽

Effective Vaccine ◽

Broadly Neutralizing Antibodies ◽

Variable Regions ◽

Hiv 1

ABSTRACTThe human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines.IMPORTANCEPreventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.

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Plasma neutralizing antibodies in an infant with interclade HIV-1 superinfection preferentially neutralize superinfecting HIV-1 strains

10.1101/2020.12.10.420703 ◽

2020 ◽

Author(s):

Nitesh Mishra ◽

Shaifali Sharma ◽

Ayushman Dobhal ◽

Sanjeev Kumar ◽

Himanshi Chawla ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Broadly Neutralizing Antibodies ◽

Infected Infant ◽

Polyvalent Vaccine ◽

Clade C ◽

Sequential Infection ◽

Hiv 1

AbstractHIV-1 superinfection is defined as infection by an unrelated second strain of HIV-1 after seroconversion due to primary infecting strain and has been associated with development of breadth in the neutralizing antibody (nAb) response, altered disease progression and efficacy of antiretrovirals; though conflicting observations have also been reported. Superinfection has been reported in HIV-1 infected adults. Recently we observed that multivariant infection in infants was associated with early induction of plasma broadly neutralizing antibodies (bnAbs) targeting diverse autologous viruses, however, there is paucity of information on infants with HIV-1 superinfection. Furthermore, the mechanisms by which superinfection in an infant, after priming by an initial infection, potentiate the evolution of a bnAb response have not been evaluated. Herein, we performed a longitudinal analysis and observed evolution of nAb responses in an antiretroviral naïve perinatally HIV-1 infected infant, with interclade superinfection (clade C followed by a unique A1C recombinant). The nAb responses broadened rapidly after superinfection targeted an undefined glycan-dependent epitope on the superinfecting variant, while no enrichment of nAb response against the primary infecting strain occurred. Defining virological features in infants with sequential infection with highly divergent circulating viruses that improve nAb responses will contribute information that could be leveraged for optimization of multicomponent candidate vaccines.ImportanceHIV-1 infected infants develop bnAbs rapidly suggesting factors governing bnAb induction in infants are distinct from adults. HIV-1 superinfection is more common in adults whereas the stringent genetic bottleneck for transmission in infants often leads to infection by a single transmitted/founder HIV-1 strain. Longitudinal studies in infants with HIV-1 superinfection can provide key information on the viral factors that induce a bnAb response towards development of a polyvalent vaccine. Herein, we show that in infant who was sequentially infected with two HIV-1 strains from different clades, antibody responses were primarily generated against the superinfecting, second strain of HIV-1.These antibody responses were dependent on glycans, and targeted an undefined epitope in the C3V4 region of HIV-1 Env. A better understanding of how neutralizing antibody responses develop during natural HIV-1 superinfection in infants will provide information relevant to HIV Env vaccine development and evaluation.

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Differential Antibody Responses to Conserved HIV-1 Neutralizing Epitopes in the Context of Multivalent Scaffolds and Native-Like gp140 Trimers

mBio ◽

10.1128/mbio.00036-17 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 14

Author(s):

Charles D. Morris ◽

Parisa Azadnia ◽

Natalia de Val ◽

Nemil Vora ◽

Andrew Honda ◽

...

Keyword(s):

Mouse Model ◽

Antibody Response ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Vaccine Design ◽

Viral Envelope ◽

Antibody Responses ◽

Broadly Neutralizing Antibodies ◽

Systematic Effort ◽

Hiv 1

ABSTRACT Broadly neutralizing antibodies (bNAbs) have provided valuable insights into the humoral immune response to HIV-1. While rationally designed epitope scaffolds and well-folded gp140 trimers have been proposed as vaccine antigens, a comparative understanding of their antibody responses has not yet been established. In this study, we probed antibody responses to the N332 supersite and the membrane-proximal external region (MPER) in the context of heterologous protein scaffolds and native-like gp140 trimers. Ferritin nanoparticles and fragment crystallizable (Fc) regions were utilized as multivalent carriers to display scaffold antigens with grafted N332 and MPER epitopes, respectively. Trimeric scaffolds were also identified to stabilize the MPER-containing BG505 gp140.681 trimer in a native-like conformation. Following structural and antigenic evaluation, a subset of scaffold and trimer antigens was selected for immunization in BALB/c mice. Serum binding revealed distinct patterns of antibody responses to these two bNAb targets presented in different structural contexts. For example, the N332 nanoparticles elicited glycan epitope-specific antibody responses that could also recognize the native trimer, while a scaffolded BG505 gp140.681 trimer generated a stronger and more rapid antibody response to the trimer apex than its parent gp140.664 trimer. Furthermore, next-generation sequencing (NGS) of mouse splenic B cells revealed expansion of antibody lineages with long heavy-chain complementarity-determining region 3 (HCDR3) loops upon activation by MPER scaffolds, in contrast to the steady repertoires primed by N332 nanoparticles and a soluble gp140.664 trimer. These findings will facilitate the future development of a coherent vaccination strategy that combines both epitope-focused and trimer-based approaches. IMPORTANCE Both epitope-focused and trimer-based strategies are currently being explored in HIV-1 vaccine development, which aims to elicit broadly neutralizing antibodies (bNAbs) targeting conserved epitopes on the viral envelope (Env). However, little is known about the differences in antibody response to these bNAb targets presented by foreign scaffolds and native Env. In this study, a systematic effort was undertaken to design multivalent epitope scaffolds and soluble gp140.681 trimers with a complete antigenic surface, and to comparatively analyze the antibody responses elicited by these antigens to the N332 supersite and MPER in a mouse model. This study will inform both epitope-focused and trimer-based vaccine design and will facilitate integration of the two vaccine strategies. IMPORTANCE Both epitope-focused and trimer-based strategies are currently being explored in HIV-1 vaccine development, which aims to elicit broadly neutralizing antibodies (bNAbs) targeting conserved epitopes on the viral envelope (Env). However, little is known about the differences in antibody response to these bNAb targets presented by foreign scaffolds and native Env. In this study, a systematic effort was undertaken to design multivalent epitope scaffolds and soluble gp140.681 trimers with a complete antigenic surface, and to comparatively analyze the antibody responses elicited by these antigens to the N332 supersite and MPER in a mouse model. This study will inform both epitope-focused and trimer-based vaccine design and will facilitate integration of the two vaccine strategies.

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Functional Stability of HIV-1 Envelope Trimer Affects Accessibility to Broadly Neutralizing Antibodies at Its Apex

Journal of Virology ◽

10.1128/jvi.01216-17 ◽

2017 ◽

Vol 91 (24) ◽

Cited By ~ 5

Author(s):

Syna Kuriakose Gift ◽

Daniel P. Leaman ◽

Lei Zhang ◽

Arthur S. Kim ◽

Michael B. Zwick

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Inverse Correlation ◽

Functional Stability ◽

Broadly Neutralizing Antibodies ◽

Antibody Recognition ◽

Partial Neutralization ◽

The Stability ◽

Hiv 1 ◽

Trimeric Envelope

ABSTRACT The trimeric envelope glycoprotein spike (Env) of HIV-1 is the target of vaccine development to elicit broadly neutralizing antibodies (bnAbs). Env trimer instability and heterogeneity in principle make subunit interfaces inconsistent targets for the immune response. Here, we investigate how functional stability of Env relates to neutralization sensitivity to V2 bnAbs and V3 crown antibodies that engage subunit interfaces upon binding to unliganded Env. Env heterogeneity was inferred when antibodies neutralized a mutant Env with a plateau of less than 100% neutralization. A statistically significant correlation was found between the stability of mutant Envs and the MPN of V2 bnAb, PG9, as well as an inverse correlation between stability of Env and neutralization by V3 crown antibody, 447-52D. A number of Env-stabilizing mutations and V2 bnAb-enhancing mutations were identified in Env, but they did not always overlap, indicating distinct requirements of functional stabilization versus antibody recognition. Blocking complex glycosylation of Env affected V2 bnAb recognition, as previously described, but also notably increased functional stability of Env. This study shows how instability and heterogeneity affect antibody sensitivity of HIV-1 Env, which is relevant to vaccine design involving its dynamic apex. IMPORTANCE The Env trimer is the only viral protein on the surface of HIV-1 and is the target of neutralizing antibodies that reduce viral infectivity. Quaternary epitopes at the apex of the spike are recognized by some of the most potent and broadly neutralizing antibodies to date. Being that their glycan-protein hybrid epitopes are at subunit interfaces, the resulting heterogeneity can lead to partial neutralization. Here, we screened for mutations in Env that allowed for complete neutralization by the bnAbs. We found that when mutations outside V2 increased V2 bnAb recognition, they often also increased Env stability-of-function and decreased binding by narrowly neutralizing antibodies to the V3 crown. Three mutations together increased neutralization by V2 bnAb and eliminated binding by V3 crown antibodies. These results may aid the design of immunogens that elicit antibodies to the trimer apex.

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