scholarly journals Rapid selection of HIV envelopes that bind to neutralizing antibody B cell lineage members with functional improbable mutations

2021 ◽  
Author(s):  
Olivia Swanson ◽  
Brianna Rhodes ◽  
Avivah Wang ◽  
Shi-Mao Xia ◽  
Robert Parks ◽  
...  
Keyword(s):  
B Cell ◽  
Neutralizing Antibodies ◽  
Cell Lineage ◽  
Neutralizing Antibody ◽  
Developmental Pathways ◽  
Broadly Neutralizing Antibodies ◽  
Minimal Subset ◽  
Functional Features ◽  
Selection Of

SummaryElicitation of broadly neutralizing antibodies (bnAbs) by an HIV vaccine will involve priming the immune system to activate antibody precursors, followed by boosting immunizations to select for antibodies with functional features required for neutralization breadth. The higher the number of mutations necessary for function, the more convoluted are the antibody developmental pathways. HIV bnAbs acquire a large number of somatic mutations, but not all mutations are functionally important. Here we identified a minimal subset of mutations sufficient for the function of the V3-glycan bnAb DH270.6. Using antibody library screening, candidate envelope immunogens that interacted with DH270.6-like antibodies containing this set of key mutations were identified and selected in vitro. Our results demonstrate that less complex B cell evolutionary pathways than those naturally observed exist for the induction of HIV bnAbs by vaccination, and establish rational approaches to identify boosting sequential envelope candidate immunogens.

scholarly journals Rapid selection of HIV envelopes that bind to neutralizing antibody B cell lineage members with functional improbable mutations

Cell Reports ◽  
2021 ◽  
Vol 36 (7) ◽  
pp. 109561
Author(s):  
Olivia Swanson ◽  
Brianna Rhodes ◽  
Avivah Wang ◽  
Shi-Mao Xia ◽  
Robert Parks ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lineage ◽  
Neutralizing Antibody ◽  
Selection Of

scholarly journals The Neutralizing Antibody Response to the HIV-1 Env Protein

2018 ◽  
Vol 16 (1) ◽  
pp. 21-28 ◽  
Author(s):  
Penny L. Moore
Keyword(s):  
Neutralizing Antibodies ◽  
Passive Immunization ◽  
Neutralizing Antibody ◽  
Developmental Pathways ◽  
Broadly Neutralizing Antibodies ◽  
Infected People ◽  
B Cell Maturation ◽  
Public Health Challenge ◽  
Env Protein ◽  
Hiv 1

Background: A vaccine able to elicit broadly neutralizing antibodies capable of blocking infection by global viruses has not been achieved, and remains a key public health challenge.Objective: During infection, a robust strain-specific neutralizing response develops in most people, but only a subset of infected people develop broadly neutralizing antibodies. Understanding how and why these broadly neutralizing antibodies develop has been a focus of the HIV-1 vaccine field for many years, and has generated extraordinary insights into the neutralizing response to HIV-1 infection.Results: This review describes the features, targets and developmental pathways of early strainspecific antibodies and later broadly neutralizing antibodies, and explores the reasons such broad antibodies are not more commonly elicited during infection.Conclusion: The insights from these studies have been harnessed for the development of pioneering new vaccine approaches that seek to drive B cell maturation towards breadth. Overall, this review describes how findings from infected donors have impacted on active and passive immunization approaches that seek to prevent HIV-1 infection.

scholarly journals ­­­­Rapid Selection of HIV Envelopes that Bind to Neutralizing Antibody B Cell Lineage Members with Functional Improbable Mutations

2021 ◽  
Author(s):  
Olivia Swanson ◽  
Brianna Rhodes ◽  
Avivah Wang ◽  
Shi-Mao Xia ◽  
Melissa Cooper ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lineage ◽  
Neutralizing Antibody ◽  
Selection Of

scholarly journals In vitro affinity maturation of broader and more-potent variants of the HIV-1–neutralizing antibody CAP256-VRC26.25

2021 ◽  
Vol 118 (29) ◽  
pp. e2106203118
Author(s):  
Yiming Yin ◽  
Brian D. Quinlan ◽  
Tianling Ou ◽  
Yan Guo ◽  
Wenhui He ◽  
...  
Keyword(s):  
B Cell ◽  
Posttranslational Modifications ◽  
Neutralizing Antibodies ◽  
Cytidine Deaminase ◽  
Neutralizing Antibody ◽  
Affinity Maturation ◽  
Homology Directed Repair ◽  
Activation Induced Cytidine Deaminase ◽  
Hiv 1

Three variable 2 (V2) loops of HIV-1 envelope glycoprotein (Env) trimer converge at the Env apex to form the epitope of an important classes of HIV-1 broadly neutralizing antibodies (bNAbs). These V2-glycan/apex antibodies are exceptionally potent but less broad (∼60 to 75%) than many other bNAbs. Their CDRH3 regions are typically long, acidic, and tyrosine sulfated. Tyrosine sulfation complicates efforts to improve these antibodies through techniques such as phage or yeast display. To improve the breadth of CAP256-VRC26.25 (VRC26.25), a very potent apex antibody, we adapted and extended a B cell display approach. Specifically, we used CRISPR/Cas12a to introduce VRC26.25 heavy- and light-chain genes into their respective loci in a B cell line, ensuring that each cell expresses a single VRC26.25 variant. We then diversified these loci through activation-induced cytidine deaminase–mediated hypermutation and homology-directed repair using randomized CDRH3 sequences as templates. Iterative sorting with soluble Env trimers and further randomization selected VRC26.25 variants with successively improving affinities. Three mutations in the CDRH3 region largely accounted for this improved affinity, and VRC26.25 modified with these mutations exhibited greater breadth and potency than the original antibody. Our data describe a broader and more-potent form of VRC26.25 as well as an approach useful for improving the breadth and potency of antibodies with functionally important posttranslational modifications.

scholarly journals Virus-Neutralizing Monoclonal Antibody Expressed in Milk of Transgenic Mice Provides Full Protection against Virus-Induced Encephalitis

2001 ◽  
Vol 75 (6) ◽  
pp. 2803-2809 ◽  
Author(s):  
Andreas F. Kolb ◽  
Lecia Pewe ◽  
John Webster ◽  
Stanley Perlman ◽  
C. Bruce A. Whitelaw ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Neutralizing Antibodies ◽  
Defense Mechanism ◽  
Viral Infections ◽  
Hepatitis Virus ◽  
Recombinant Antibody ◽  
Lethal Dose ◽  
Neutralizing Antibody ◽  
Murine Hepatitis Virus

ABSTRACT Neutralizing antibodies represent a major host defense mechanism against viral infections. In mammals, passive immunity is provided by neutralizing antibodies passed to the offspring via the placenta or the milk as immunoglobulin G and secreted immunoglobulin A. With the long-term goal of producing virus-resistant livestock, we have generated mice carrying transgenes that encode the light and heavy chains of an antibody that is able to neutralize the neurotropic JHM strain of murine hepatitis virus (MHV-JHM). MHV-JHM causes acute encephalitis and acute and chronic demyelination in susceptible strains of mice and rats. Transgene expression was targeted to the lactating mammary gland by using the ovine β-lactoglobulin promoter. Milk from these transgenic mice contained up to 0.7 mg of recombinant antibody/ml. In vitro analysis of milk derived from different transgenic lines revealed a linear correlation between antibody expression and virus-neutralizing activity, indicating that the recombinant antibody is the major determinant of MHV-JHM neutralization in murine milk. Offspring of transgenic and control mice were challenged with a lethal dose of MHV-JHM. Litters suckling nontransgenic dams succumbed to fatal encephalitis, whereas litters suckling transgenic dams were fully protected against challenge, irrespective of whether they were transgenic. This demonstrates that a single neutralizing antibody expressed in the milk of transgenic mice is sufficient to completely protect suckling offspring against MHV-JHM-induced encephalitis.

scholarly journals A public broadly neutralizing antibody class targets a membrane-proximal anchor epitope of influenza virus hemagglutinin

2021 ◽  
Author(s):  
Jenna J. Guthmiller ◽  
Julianna Han ◽  
Henry A. Utset ◽  
Lei Li ◽  
Linda Yu-Ling Lan ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Human Memory ◽  
Influenza Virus Vaccine ◽  
Virus Infections ◽  
Broadly Neutralizing Antibodies ◽  
Cell Repertoire ◽  
Influenza Virus Hemagglutinin

SummaryBroadly neutralizing antibodies against influenza virus hemagglutinin (HA) have the potential to provide universal protection against influenza virus infections. Here, we report a distinct class of broadly neutralizing antibodies targeting an epitope toward the bottom of the HA stalk domain where HA is “anchored” to the viral membrane. Antibodies targeting this membrane-proximal anchor epitope utilized a highly restricted repertoire, which encode for two conserved motifs responsible for HA binding. Anchor targeting B cells were common in the human memory B cell repertoire across subjects, indicating pre-existing immunity against this epitope. Antibodies against the anchor epitope at both the serological and monoclonal antibody levels were potently induced in humans by a chimeric HA vaccine, a potential universal influenza virus vaccine. Altogether, this study reveals an underappreciated class of broadly neutralizing antibodies against H1-expressing viruses that can be robustly recalled by a candidate universal influenza virus vaccine.

scholarly journals An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Andrew I Flyak ◽  
Stormy E Ruiz ◽  
Jordan Salas ◽  
Semi Rho ◽  
Justin R Bailey ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Disulfide Bond ◽  
Chronic Infection ◽  
Neutralizing Antibodies ◽  
Infected Individual ◽  
Structural Plasticity ◽  
Neutralizing Antibody ◽  
Single Individual ◽  
Broadly Neutralizing Antibodies ◽  
E2 Glycoprotein

A vaccine protective against diverse HCV variants is needed to control the HCV epidemic. Structures of E2 complexes with front layer-specific broadly neutralizing antibodies (bNAbs) isolated from HCV-infected individuals, revealed a disulfide bond-containing CDRH3 that adopts straight (individuals who clear infection) or bent (individuals with chronic infection) conformation. To investigate whether a straight versus bent disulfide bond-containing CDRH3 is specific to particular HCV-infected individuals, we solved a crystal structure of the HCV E2 ectodomain in complex with AR3X, a bNAb with an unusually long CDRH2 that was isolated from the chronically-infected individual from whom the bent CDRH3 bNAbs were derived. The structure revealed that AR3X utilizes both its ultralong CDRH2 and a disulfide motif-containing straight CDRH3 to recognize the E2 front layer. These results demonstrate that both the straight and bent CDRH3 classes of HCV bNAb can be elicited in a single individual, revealing a structural plasticity of VH1-69-derived bNAbs.

scholarly journals Functional development of a V3/glycan-specific broadly neutralizing antibody isolated from a case of HIV superinfection

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Mackenzie M Shipley ◽  
Vidya Mangala Prasad ◽  
Laura E Doepker ◽  
Adam S Dingens ◽  
Duncan K Ralph ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Viral Escape ◽  
Single Infection ◽  
Structural Studies ◽  
Broadly Neutralizing Antibodies ◽  
Hiv Vaccines ◽  
Functional Development ◽  
Broadly Neutralizing Antibody

Stimulating broadly neutralizing antibodies (bnAbs) directly from germline remains a barrier for HIV vaccines. HIV superinfection elicits bnAbs more frequently than single infection, providing clues of how to elicit such responses. We used longitudinal antibody sequencing and structural studies to characterize bnAb development from a superinfection case. BnAb QA013.2 bound initial and superinfecting viral Env, despite its probable naïve progenitor only recognizing the superinfecting strain, suggesting both viruses influenced this lineage. A 4.15 Å cryo-EM structure of QA013.2 bound to native-like trimer showed recognition of V3 signatures (N301/N332 and GDIR). QA013.2 relies less on CDRH3 and more on framework and CDRH1 for affinity and breadth compared to other V3/glycan-specific bnAbs. Antigenic profiling revealed that viral escape was achieved by changes in the structurally-defined epitope and by mutations in V1. These results highlight shared and novel properties of QA013.2 relative to other V3/glycan-specific bnAbs in the setting of sequential, diverse antigens.

scholarly journals Evaluation of HIV-1 latency reversal and antibody-dependent viral clearance by quantification of singly spliced HIV-1 vpu/env mRNA

2021 ◽  
Author(s):  
Hongbo Gao ◽  
Ayşe N. Ozantürk ◽  
Qiankun Wang ◽  
Gray H. Harlan ◽  
Aaron J. Schmitz ◽  
...  
Keyword(s):  
T Cells ◽  
Neutralizing Antibodies ◽  
Ex Vivo ◽  
Viral Envelope ◽  
Latent Reservoir ◽  
Broadly Neutralizing Antibodies ◽  
Major Barrier ◽  
Hiv 1 ◽  
Reversing Agents

The latent reservoir of HIV-1 is a major barrier for viral eradication. Potent HIV-1 broadly neutralizing antibodies (bNabs) have been used to prevent and treat HIV-1 infections in animal models and clinical trials. Combination of bNabs and latency-reversing agents (LRAs) is considered a promising approach for HIV-1 eradication. PCR-based assays that can rapidly and specifically measure singly spliced HIV-1 vpu/env mRNA are needed to evaluate the induction of the viral envelope production at the transcription level and bNab-mediated reservoir clearance. Here we reported a PCR-based method to accurately quantify the production of intracellular HIV-1 vpu/env mRNA. With the vpu/env assay, we determined the LRA combinations that could effectively induce vpu/env mRNA production in CD4+ T cells from ART-treated individuals. None of the tested LRAs were effective alone. A comparison between the quantitative viral outgrowth assay (Q-VOA) and the vpu/env assay showed that vpu/env mRNA production was closely associated with the reactivation of replication-competent HIV-1, suggesting that vpu/env mRNA was mainly produced by intact viruses. Finally, antibody-mediated in vitro killing in HIV-1-infected humanized mice demonstrated that the vpu/env assay could be used to measure the reduction of infected cells in tissues and was more accurate than the commonly used gag-based PCR assay which measured unspliced viral genomic RNA. In conclusion, the vpu/env assay allows convenient and accurate assessment of HIV-1 latency reversal and bNab-mediated therapeutic strategies. Importance HIV-1 persists in individuals on antiretroviral therapy (ART) due to the long-lived cellular reservoirs that contain dormant viruses. Recent discoveries of HIV-1-specific broadly neutralizing antibodies (bNabs) targeting HIV-1 Env protein rekindled the interest in antibody-mediated elimination of latent HIV-1. Latency-reversing agents (LRAs) together with HIV-1 bNabs is a possible strategy to clear residual viral reservoirs, which makes the evaluation of HIV-1 Env expression upon LRA treatment critical. We developed a PCR-based assay to quantify the production of intracellular HIV-1 vpu/env mRNA. Using patient CD4+ T cells, we found that induction of HIV-1 vpu/env mRNA required a combination of different LRAs. Using in vitro, ex vivo and humanized mouse models, we showed that the vpu/env assay could be used to measure antibody efficacy in clearing HIV-1 infection. These results suggest that the vpu/env assay can accurately evaluate HIV-1 reactivation and bNab-based therapeutic interventions.

scholarly journals Nanoparticle Vaccines for Inducing HIV-1 Neutralizing Antibodies

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 76 ◽  
Author(s):  
Mitch Brinkkemper ◽  
Kwinten Sliepen
Keyword(s):  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Critical Role ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Broadly Neutralizing Antibodies ◽  
Viral Membrane ◽  
Immunodeficiency Virus ◽  
Hiv 1

The enormous sequence diversity between human immunodeficiency virus type 1 (HIV-1) strains poses a major roadblock for generating a broadly protective vaccine. Many experimental HIV-1 vaccine efforts are therefore aimed at eliciting broadly neutralizing antibodies (bNAbs) that are capable of neutralizing the majority of circulating HIV-1 strains. The envelope glycoprotein (Env) trimer on the viral membrane is the sole target of bNAbs and the key component of vaccination approaches aimed at eliciting bNAbs. Multimeric presentation of Env on nanoparticles often plays a critical role in these strategies. Here, we will discuss the different aspects of nanoparticles in Env vaccination, including recent insights in immunological processes underlying their perceived advantages, the different nanoparticle platforms and the various immunogenicity studies that employed nanoparticles to improve (neutralizing) antibody responses against Env.

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