Structural Constraints of Vaccine-Induced Tier-2 Autologous HIV Neutralizing Antibodies Targeting the Receptor-Binding Site

Bradley, Todd; Fera, Daniela; Eslamizar, Leila; Lu, Xiaozhi; Anasti, Kara; Zhang, Ruijung; Sutherland, Laura L.; Scearce, Richard M.; Bowman, Cindy; Stolarchuk, Christina; Lloyd, Krissey E.; Parks, Robert; Eaton, Amanda; Foulger, Andrew; Nie, Xin; Karim, Salim Safurdeen. Abdool; Barnett, Susan W.; Kepler, Thomas B.; Alam, S. Munir; Montefiori, David C.; Moody, M. Anthony; Liao, Hua‐Xin; Morris, Lynn; Santra, Sampa; Haynes, Barton F.

doi:10.1016/j.celrep.2015.12.017

Cited by 45 publications

(56 citation statements)

References 55 publications

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“…Several recent studies have succeeded in demonstrating vaccine-induced NAb against autologous tier 2 virus or a panel of mutated tier 2 isolates with increased CD4 or V3 epitope exposure (12)(13)(14)21). Our finding of neutralizing responses against heterologous tier 2 global isolates, albeit of modest potency and breadth, point to the possibility of generating such responses through the prime-boost immunization platform.…”

Section: Discussionmentioning

confidence: 73%

“…Despite many attempts (12)(13)(14)(78)(79)(80), generation of bNAb against tier 2 HIV-1 primary isolates by vaccination remains an unmet goal. Several recent studies have succeeded in demonstrating vaccine-induced NAb against autologous tier 2 virus or a panel of mutated tier 2 isolates with increased CD4 or V3 epitope exposure (12)(13)(14)21).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies described vaccine-induced tier 2 virus NAb in immunized animals; however, these responses are limited, sporadic, and primarily against the autologous tier 2 isolates (12)(13)(14). Novel immunogens are being examined in the hope that they may elicit cross-reactive tier 2 NAb (1, 2, 15, 16).…”

mentioning

confidence: 99%

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Induction of Heterologous Tier 2 HIV-1-Neutralizing and Cross-Reactive V1/V2-Specific Antibodies in Rabbits by Prime-Boost Immunization

Townsley

Mohamed²,

Guo

et al. 2016

J Virol

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Poxvirus prime-protein boost used in the RV144 trial remains the only immunization strategy shown to elicit a modest level of protection against HIV-1 acquisition in humans. Although neutralizing antibodies (NAb) were generated, they were against sensitive viruses, not the more resistant "tier 2" isolates that dominate circulating strains. Instead, risk reduction correlated with antibodies recognizing epitopes in the V1/V2 region of HIV-1 envelope glycoprotein (Env). Here, we examined whether tier 2 virus NAb and V1/V2-specific non-NAb could be elicited by a poxvirus prime-gp120 boost strategy in a rabbit model. We studied two clade B Envs that differ in multiple parameters, including tissue origin, neutralization sensitivity, and presence of the N197 (N7) glycan that was previously shown to modulate the exposure of conserved epitopes on Env. We demonstrate that immunized rabbits generated cross-reactive neutralizing activities against >50% of the tier 2 global HIV-1 isolates tested. Some of these activities were directed against the CD4 binding site (CD4bs). These rabbits also generated antibodies that recognized protein scaffolds bearing V1/V2 sequences from diverse HIV-1 isolates and mediated antibody-dependent cellular cytotoxicity. However, there are subtle differences in the specificities and the response rates of V1/V2-specific antibodies between animals immunized with different Envs, with or without the N7 glycan. These findings demonstrate that antibody responses that have been correlated with protection against HIV-1 acquisition in humans can be elicited in a preclinical model by a poxvirus prime-gp120 boost strategy and that improvements may be achievable by optimizing the nature of the priming and boosting immunogens. IMPORTANCEThe only vaccine approach shown to elicit any protective efficacy against HIV-1 acquisition is based on a poxvirus prime-protein boost regimen (RV144 Thai trial). Reduction of risk was associated with nonneutralizing antibodies targeting the V1/V2 loops of the envelope protein gp120. However, the modest efficacy (31.2%) achieved in this trial highlights the need to examine approaches and factors that may improve vaccine-induced responses, including cross-reactive neutralizing activities. We show here that rabbits immunized with a novel recombinant vaccinia virus prime-gp120 protein boost regimen generated antibodies that recognize protein scaffolds bearing V1/V2 sequences from diverse HIV-1 isolates and mediated antibody-dependent cellular cytotoxicity. Importantly, immunized rabbits also showed neutralizing activities against heterologous tier 2 HIV-1 isolates. These findings may inform the design of prime-boost immunization approaches and help improve the protective efficacy of candidate HIV-1 vaccines.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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Induction of Heterologous Tier 2 HIV-1-Neutralizing and Cross-Reactive V1/V2-Specific Antibodies in Rabbits by Prime-Boost Immunization

Townsley

Mohamed²,

Guo

et al. 2016

J Virol

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“…Until recently, very few immunization studies had induced even Tier‐2 autologous neutralization, let alone a broad response 90, 91, 92, 93. Post‐immune neutralization titers are lower than those seen in elite neutralizer bnAb donors, thus neutralizing Abs may be less frequent among the post‐immunization B‐cell population.…”

Section: Discussionmentioning

confidence: 99%

Identification and specificity of broadly neutralizing antibodies against HIV

McCoy

Burton

2017

Immunological Reviews

210

193

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SummaryBeginning in 2009, studies of the humoral responses of HIV‐positive individuals have led to the identification of scores, if not hundreds, of antibodies that are both broadly reactive and potently neutralizing. This development has provided renewed impetus toward an HIV vaccine and led directly to the development of novel immunogens. Advances in identification of donors with the most potent and broad anti‐HIV serum neutralizing responses were crucial in this effort. Equally, development of methods for the rapid generation of human antibodies from these donors was pivotal. Primarily these methods comprise single B‐cell culture coupled to high‐throughput neutralization screening and flow cytometry‐based sorting of single B cells using HIV envelope protein baits. In this review, the advantages and disadvantages of these methodologies are discussed in the context of the specificities targeted by individual antibodies and the need for further improvements to evaluate HIV vaccine candidates.

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“…Despite the extensive genetic diversity that exists among circulating HIV-1 variants, broadly neutralizing antibodies (bNAbs) capable of neutralizing a diverse panel of viral isolates have been identified in rare HIV-infected individuals. Elicitation of such bNAbs is thought to be a critical requirement for an effective HIV-1 vaccine (2, 3), but to date, HIV vaccine efforts have resulted in limited, narrow neutralization activity and have failed to elicit bNAbs (4)(5)(6)(7).…”

mentioning

confidence: 99%

Changes in Structure and Antigenicity of HIV-1 Env Trimers Resulting from Removal of a Conserved CD4 Binding Site-Proximal Glycan

Liang

Guttman

Williams

et al. 2016

J Virol

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The envelope glycoprotein (Env) is the major target for HIV-1 broadly neutralizing antibodies (bNAbs). One of the mechanisms that HIV has evolved to escape the host's immune response is to mask conserved epitopes on Env with dense glycosylation. Previous studies have shown that the removal of a particular conserved glycan at N197 increases the neutralization sensitivity of the virus to antibodies targeting the CD4 binding site (CD4bs), making it a site of significant interest from the perspective of vaccine design. At present, the structural consequences that result from the removal of the N197 glycan have not been characterized. Using native-like SOSIP trimers, we examine the effects on antigenicity and local structural dynamics resulting from the removal of this glycan. A large increase in the binding of CD4bs and V3-targeting antibodies is observed for the N197Q mutant in trimeric Env, while no changes are observed with monomeric gp120. While the overall structure and thermostability are not altered, a subtle increase in the flexibility of the variable loops at the trimeric interface of adjacent protomers is evident in the N197Q mutant by hydrogen-deuterium exchange mass spectrometry. Structural modeling of the glycan chains suggests that the spatial occupancy of the N197 glycan leads to steric clashes with CD4bs antibodies in the Env trimer but not monomeric gp120. Our results indicate that the removal of the N197 glycan enhances the exposure of relevant bNAb epitopes on Env with a minimal impact on the overall trimeric structure. These findings present a simple modification for enhancing trimeric Env immunogens in vaccines. IMPORTANCEThe HIV-1 Env glycoprotein presents a dense patchwork of host cell-derived N-linked glycans. This so-called glycan shield is considered to be a major protective mechanism against immune recognition. While the positions of many N-linked glycans are isolate specific, some are highly conserved and are believed to play key functional roles. In this study, we examine the conserved, CD4 binding site-proximal N197 glycan and demonstrate that its removal both facilitates neutralizing antibody access to the CD4 binding site and modestly impacts the structural dynamics at the trimer crown without drastically altering global Env trimer stability. This indicates that surgical glycosylation site modification may be an effective way of sculpting epitope presentation in Env-based vaccines.T he trimeric HIV-1 envelope glycoprotein (Env), a trimer composed of gp120/gp41 heterodimers, is the primary antigenic feature on the virus and the sole target for neutralizing antibodies (1). Despite the extensive genetic diversity that exists among circulating HIV-1 variants, broadly neutralizing antibodies (bNAbs) capable of neutralizing a diverse panel of viral isolates have been identified in rare HIV-infected individuals. Elicitation of such bNAbs is thought to be a critical requirement for an effective HIV-1 vaccine (2, 3), but to date, HIV vaccine efforts have resulted in limited, narrow neu...

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Structural Constraints of Vaccine-Induced Tier-2 Autologous HIV Neutralizing Antibodies Targeting the Receptor-Binding Site

Cited by 45 publications

References 55 publications

Induction of Heterologous Tier 2 HIV-1-Neutralizing and Cross-Reactive V1/V2-Specific Antibodies in Rabbits by Prime-Boost Immunization

Induction of Heterologous Tier 2 HIV-1-Neutralizing and Cross-Reactive V1/V2-Specific Antibodies in Rabbits by Prime-Boost Immunization

Identification and specificity of broadly neutralizing antibodies against HIV

Changes in Structure and Antigenicity of HIV-1 Env Trimers Resulting from Removal of a Conserved CD4 Binding Site-Proximal Glycan

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