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

Townsley, Samantha; Li, Yun; Kozyrev, Yury; Cleveland, Brad; Hu, Shiu Lok

doi:10.1128/jvi.02321-15

Cited by 21 publications

(30 citation statements)

References 100 publications

(99 reference statements)

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“…Specifically, we used a replication-competent vaccinia virus vector for priming and two clade B Envs (JR-FL or PVO.4) for boosting. These Envs differ in multiple parameters, including tissue origin, neutralization sensitivity, and presence of the N7 glycan, which modulates the exposure of variable loop 3 (V3) and CD4 binding sites (CD4bs) on Env (17,(21)(22)(23). Using this prime-boost immunization regimen, we were able to induce cross-reactive binding antibodies against V1/V2 fusion proteins and neutralizing responses against heterologous tier 2 isolates.…”

mentioning

confidence: 88%

“…To determine if antibody responses elicited by a poxvirus prime-gp120 protein boost strategy are affected by the choice of the Env immunogen used, we studied two clade B Envs (JR-FL and PVO.4) that differ in multiple parameters, including tissue origin, neutralization sensitivity, and presence of the N7 glycan previously shown to modulate the exposure of the CD4 and coreceptor binding sites on Env (17,(21)(22)(23). JR-FL is a brain isolate that lacks the N7 glycan sequon (22) and shows tier 2 neutralization sensitivity, whereas PVO.4 is a blood isolate that retains the highly conserved N7 glycan sequon and shows a tier 3 neutralization-resistant phenotype (21,23,50).…”

Section: Immunogens and Immunization Regimenmentioning

confidence: 99%

“…JR-FL is a brain isolate that lacks the N7 glycan sequon (22) and shows tier 2 neutralization sensitivity, whereas PVO.4 is a blood isolate that retains the highly conserved N7 glycan sequon and shows a tier 3 neutralization-resistant phenotype (21,23,50).…”

Section: Immunogens and Immunization Regimenmentioning

confidence: 99%

“…Mutations in an epitope(s) targeted by a panel of broadly neutralizing monoclonal antibodies (bNMAb) were introduced into the CE1176_A3 env gene using the QuikChange mutagenesis kit (Stratagene) (21). The epitopes targeted and the specific mutations introduced were as follows: (i) CD4bs epitopes, N280D and G458Y; (ii) V2 epitopes, N160K; (iii) V3 epitopes, N332A; (iv) membrane-proximal external region (MPER) epitopes, W672A; and (v) gp120/gp41 epitopes, N611A and N625A.…”

Section: Recombinant Vaccinia Virus (Rvv)mentioning

confidence: 99%

“…This study was based on a single isolate, 89.6. Since the N7 glycan and its effect on Env antigenicity are highly conserved (17)(18)(19)(20)(21), it is of interest to determine if the effects of the N7 glycan on Env immunogenicity can be observed in isolates other than 89. 6.…”

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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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mentioning

confidence: 88%

Section: Immunogens and Immunization Regimenmentioning

confidence: 99%

Section: Immunogens and Immunization Regimenmentioning

confidence: 99%

Section: Recombinant Vaccinia Virus (Rvv)mentioning

confidence: 99%

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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Composition and Antigenic Effects of Individual Glycan Sites of a Trimeric HIV-1 Envelope Glycoprotein

et al. 2016

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SummaryThe HIV-1 envelope glycoprotein trimer is covered by an array of N-linked glycans that shield it from immune surveillance. The high density of glycans on the trimer surface imposes steric constraints limiting the actions of glycan-processing enzymes, so that multiple under-processed structures remain on specific areas. These oligomannose glycans are recognized by broadly neutralizing antibodies (bNAbs) that are not thwarted by the glycan shield but, paradoxically, target it. Our site-specific glycosylation analysis of a soluble, recombinant trimer (BG505 SOSIP.664) maps the extremes of simplicity and diversity of glycan processing at individual sites and reveals a mosaic of dense clusters of oligomannose glycans on the outer domain. Although individual sites usually minimally affect the global integrity of the glycan shield, we identify examples of how deleting some glycans can subtly influence neutralization by bNAbs that bind at distant sites. The network of bNAb-targeted glycans should be preserved on vaccine antigens.

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Targeted Elimination of Immunodominant B Cells Drives the Germinal Center Reaction toward Subdominant Epitopes

et al. 2017

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SUMMARYRapidly evolving pathogens such as HIV or influenza can quickly mutate their antigenic profiles, reducing the efficacy of conventional vaccines. Despite this challenge, functionally required epitopes are highly conserved among heterologous viral strains and represent a key vulnerability that could be targeted during vaccine development. As the antigenicity of these conserved epitopes is frequently subdominant, there is a critical need for innovative vaccination strategies designed to target these neutralizing epitopes. Here, we immunized mice with antigens containing discrete immunodominant and subdominant moieties and show that treatment with soluble heterologous antigen bearing only the immunodominant epitope selectively suppresses these germinal center (GC) B cells. By exploiting this intrinsic tolerance mechanism, we promote the expansion of subdominant B cells in the GC and the subsequent long-lived components of the humoral response. We propose that this strategy may be applied to elicit preferential expansion of subdominant B cells that recognize weakly immunogenic epitopes on microbial pathogens.

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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

Cited by 21 publications

References 100 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

Composition and Antigenic Effects of Individual Glycan Sites of a Trimeric HIV-1 Envelope Glycoprotein

Targeted Elimination of Immunodominant B Cells Drives the Germinal Center Reaction toward Subdominant Epitopes

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