Diverse Recombinant HIV-1 Envs Fail To Activate B Cells Expressing the Germline B Cell Receptors of the Broadly Neutralizing Anti-HIV-1 Antibodies PG9 and 447-52D

McGuire, Andrew T.; Glenn, Jolene A.; Lippy, Adriana; Stamatatos, Leonidas

doi:10.1128/jvi.03228-13

Cited by 69 publications

(71 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As seen for other families of bnAbs, no HIV reactivity for the predicted germ line antibody was detected on the 6-virus panel (Fig. 2B), and no binding to the corresponding recombinant gp120 glycoprotein was observed in an enzyme-linked immunosorbent assay (ELISA) (data not shown) (31)(32)(33)(34)(35). Within the PGT128 branch, the least mutated predicted intermediate 95H 71L (12% mutated in the nucleotide sequence of the heavy-and light-chain V-and J-gene segments) was able to neutralize all 6 viruses albeit at a slightly lower potency than that of the fully mutated PGT128 (16%).…”

Section: Resultsmentioning

confidence: 99%

Two Classes of Broadly Neutralizing Antibodies within a Single Lineage Directed to the High-Mannose Patch of HIV Envelope

Doores

Kong

Krumm

et al. 2015

J Virol

114

View full text Add to dashboard Cite

The high-mannose patch of human immunodeficiency virus (HIV) envelope (Env) elicits broadly neutralizing antibodies (bnAbs) during natural infection relatively frequently, and consequently, this region has become a major target of vaccine design. However, it has also become clear that antibody recognition of the region is complex due, at least in part, to variability in neighboring loops and glycans critical to the epitopes. bnAbs against this region have some shared features and some distinguishing features that are crucial to understand in order to design optimal immunogens that can induce different classes of bnAbs against this region. Here, we compare two branches of a single antibody lineage, in which all members recognize the highmannose patch. One branch (prototype bnAb PGT128) has a 6-amino-acid insertion in CDRH2 that is crucial for broad neutralization. Antibodies in this branch appear to favor a glycan site at N332 on gp120, and somatic hypermutation is required to accommodate the neighboring V1 loop glycans and glycan heterogeneity. The other branch (prototype bnAb PGT130) lacks the CDRH2 insertion. Antibodies in this branch are noticeably effective at neutralizing viruses with an alternate N334 glycan site but are less able to accommodate glycan heterogeneity. We identify a new somatic variant within this branch that is predominantly dependent on N334. The crystal structure of PGT130 offers insight into differences from PGT128. We conclude that different immunogens may be required to elicit bnAbs that have the optimal characteristics of the two branches of the lineage described. IMPORTANCEDevelopment of an HIV vaccine is of vital importance for prevention of new infections, and it is thought that elicitation of HIV bnAbs will be an important component of an effective vaccine. Increasingly, bnAbs that bind to the cluster of high-mannose glycans on the HIV envelope glycoprotein, gp120, are being highlighted as important templates for vaccine design. In particular, bnAbs from IAVI donor 36 (PGT125 to PGT131) have been shown to be extremely broad and potent. Combination of these bnAbs enhanced neutralization breadth considerably, suggesting that an optimal immunogen should elicit several antibodies from this family. Here we study the evolution of this antibody family to inform immunogen design. We identify two classes of bnAbs that differ in their recognition of the high-mannose patch and show that different immunogens may be required to elicit these different classes.

show abstract

Section: Resultsmentioning

confidence: 99%

Two Classes of Broadly Neutralizing Antibodies within a Single Lineage Directed to the High-Mannose Patch of HIV Envelope

Doores

Kong

Krumm

et al. 2015

J Virol

114

View full text Add to dashboard Cite

show abstract

“…To determine if the enhanced in vivo immunogenicity of “sparse” NPs was due to more efficient stimulation of individual B cells, we performed in vitro experiments using a human B cell line (DG75) that was transfected to express B cell receptors (BCRs) specific for HIV-1 Env (or HA) [15, 17]. To do this, DG75 cells were transiently transfected with BCR expression plasmids corresponding to (i) wild-type NIH45-46, a high affinity (3.66nM) broadly neutralizing antibody specific for recombinant 426c HIV-1 Env used in our experiments [17], (ii) a germline reverted derivative of the NIH45-46 BCR, which has low (693nM) affinity for 426c Env [17], and (iii) FI6, a high affinity antibody specific for IAV HA.…”

Section: Resultsmentioning

confidence: 99%

“…We then tested the effect of antigen density on the generation of antigen-specific humoral and cellular immune responses using both in vitro and in vivo approaches. Antigen-decorated NPs were evaluated for their ability to stimulate the activation of antigen specific B cell lines in vitro (as assessed by calcium flux) [15, 16]. Additionally, BALB/c mice were immunized with antigen-decorated NPs at multiple densities and the resulting serologic and cellular response was evaluated using a number of approaches that evaluate B cell signaling, priming of follicular helper cell and germinal responses, production of serum antibody and development of antibody secreting cells.…”

Section: Introductionmentioning

confidence: 99%

Nanoparticles decorated with viral antigens are more immunogenic at low surface density

Brewer

DiPiazza

Acklin

et al. 2017

Vaccine

View full text Add to dashboard Cite

There is an urgent need to develop protective vaccines for high priority viral pathogens. One approach known to enhance immune responses to viral proteins is to display them on a nanoparticle (NP) scaffold. However, little is known about the effect of protein density on the B cell response to antigens displayed on NPs. To address this question HIV-1 Envelope (Env) and influenza hemagglutinin (HA) were displayed on a polystyrene-based NP scaffold at various densities - corresponding to mean antigen distances that span the range encountered on naturally occurring virions. Our studies revealed that NPs displaying lower densities of Env or HA more efficiently stimulated antigen-specific B cells in vitro, as measured by calcium flux, than did NPs displaying higher antigen densities. Similarly, NPs displaying a low density of Env or HA also elicited higher titers of antigen-specific serum IgG in immunized BALB/c mice (including elevated titers of hemagglutination-inhibiting antibodies), as well as an increased frequency of antigen-specific antibody secreting cells in the lymph node, spleen and bone marrow. Importantly, our studies showed that the enhanced B cell response elicited by the lower density NPs is likely secondary to more efficient development of follicular helper CD4 T cells and germinal center B cells. These findings demonstrate that the density of antigen on a NP scaffold is a critical determinant of the humoral immune response elicited, and that high density display does not always result in an optimal response

show abstract

“…It is unknown whether a vaccine can promote adequate affinity maturation during the course of an immunization regimen to elicit protective Abs, primarily because it is not known to what extent germline B cell receptors (BCRs) influence affinity maturation and selection of B cells giving rise to bNAbs in GCs. Recent studies suggest these events may be rare (67), and only a few Env mutations confer high affinity germline binding which may indicate the stochastic nature of these mutations occurring during chronic infection (67,68). Nonetheless, all subjects who seroconvert develop ANAbs, despite exposure to Envs from T/F that are rarely identical among subjects.…”

Section: Discussionmentioning

confidence: 99%

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

Hessell

Malherbe

Pissani

et al. 2016

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Advancement in immunogen selection and vaccine design that will rapidly elicit a protective Ab response is considered critical for HIV vaccine protective efficacy. Vaccine-elicited Ab responses must therefore have the capacity to prevent infection by neutralization-resistant phenotypes of transmitted/founder (T/F) viruses that establish infection in humans. Most vaccine candidates to date have been ineffective at generating Abs that neutralize T/F or early variants. In this study, we report that coimmunizing rhesus macaques with HIV-1 gp160 DNA and gp140 trimeric protein selected from native envelope gene sequences (envs) induced neutralizing Abs against Tier 2 autologous viruses expressing cognate envelope (Env). The Env immunogens were selected from envs emerging during the earliest stages of neutralization breadth developing within the first 2 years of infection in two clade B–infected human subjects. Moreover, the IgG responses in macaques emulated the targeting to specific regions of Env known to be associated with autologous and heterologous neutralizing Abs developed within the human subjects. Furthermore, we measured increasing affinity of macaque polyclonal IgG responses over the course of the immunization regimen that correlated with Tier 1 neutralization. In addition, we report firm correlations between Tier 2 autologous neutralization and Tier 1 heterologous neutralization, as well as overall TZM-bl breadth scores. Additionally, the activation of Env-specific follicular helper CD4 T cells in lymphocytes isolated from inguinal lymph nodes of vaccinated macaques correlated with Tier 2 autologous neutralization. These results demonstrate the potential for native Env derived from subjects at the time of neutralization broadening as effective HIV vaccine elements.

show abstract

Diverse Recombinant HIV-1 Envs Fail To Activate B Cells Expressing the Germline B Cell Receptors of the Broadly Neutralizing Anti-HIV-1 Antibodies PG9 and 447-52D

Cited by 69 publications

References 78 publications

Two Classes of Broadly Neutralizing Antibodies within a Single Lineage Directed to the High-Mannose Patch of HIV Envelope

Two Classes of Broadly Neutralizing Antibodies within a Single Lineage Directed to the High-Mannose Patch of HIV Envelope

Nanoparticles decorated with viral antigens are more immunogenic at low surface density

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

Contact Info

Product

Resources

About