Broadly Neutralizing Antibodies for HIV Prevention

2020 ◽  
Vol 71 (1) ◽  
pp. 329-346 ◽  
Author(s):  
Shelly T. Karuna ◽  
Lawrence Corey
Keyword(s):  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Therapeutic Potential ◽  
Broadly Neutralizing Antibodies ◽  
Efficacy Trials ◽  
Preclinical Trials ◽  
Favorable Safety ◽  
Hiv Envelope ◽  
Near Future

In the last decade, over a dozen potent broadly neutralizing antibodies (bnAbs) to several HIV envelope protein epitopes have been identified, and their in vitro neutralization profiles have been defined. Many have demonstrated prevention efficacy in preclinical trials and favorable safety and pharmacokinetic profiles in early human clinical trials. The first human prevention efficacy trials using 10 sequential, every-two-month administrations of a single anti-HIV bnAb are anticipated to conclude in 2020. Combinations of complementary bnAbs and multi-specific bnAbs exhibit improved breadth and potency over most individual antibodies and are entering advanced clinical development. Genetic engineering of the Fc regions has markedly improved bnAb half-life, increased mucosal tissue concentrations of antibodies (especially in the genital tract), and enhanced immunomodulatory and Fc effector functionality, all of which improve antibodies' preventative and therapeutic potential. Human-derived monoclonal antibodies are likely to enter the realm of primary care prevention and therapy for viral infections in the near future.

scholarly journals A glycoside analog of mammalian oligomannose formulated with a TLR4-stimulating adjuvant elicits HIV-1 cross-reactive antibodies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jean-François Bruxelle ◽  
Tess Kirilenko ◽  
Nino Trattnig ◽  
Yiqiu Yang ◽  
Matteo Cattin ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Envelope Protein ◽  
Protein Sequence ◽  
Neutralizing Antibodies ◽  
Human Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Specific Antibodies ◽  
Strong Binding ◽  
Hiv Envelope ◽  
Hiv 1

AbstractThe occurrence of oligomannose-specific broadly neutralizing antibodies (bnAbs) has spurred efforts to develop immunogens that can elicit similar antibodies. Here, we report on the antigenicity and immunogenicity of a CRM197-conjugate of a previously reported oligomannose mimetic. Oligomannose-specific bnAbs that are less dependent on interactions with the HIV envelope protein sequence showed strong binding to the glycoconjugates, with affinities approximating those reported for their cognate epitope. The glycoconjugate is also recognized by inferred germline precursors of oligomannose-specific bnAbs, albeit with the expected low avidity, supporting its potential as an immunogen. Immunization of human-antibody transgenic mice revealed that only a TLR4-stimulating adjuvant formulation resulted in antibodies able to bind a panel of recombinant HIV trimers. These antibodies bound at relatively modest levels, possibly explaining their inability to neutralize HIV infectivity. Nevertheless, these findings contribute further to understanding conditions for eliciting HIV-cross-reactive oligomannose-specific antibodies and inform on next steps for improving on the elicited response.

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 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.

Blocking α4β7 integrin delays viral rebound in SHIVSF162P3-infected macaques treated with anti-HIV broadly neutralizing antibodies

2021 ◽  
Vol 13 (607) ◽  
pp. eabf7201
Author(s):  
Ines Frank ◽  
Mariasole Cigoli ◽  
Muhammad S. Arif ◽  
Marissa D. Fahlberg ◽  
Stephanie Maldonado ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Therapeutic Potential ◽  
Rhesus Macaques ◽  
Antibody Therapy ◽  
Control Treatment ◽  
Viral Rebound ◽  
Broadly Neutralizing Antibodies ◽  
Hiv Antibodies ◽  
Virologic Control ◽  
Anti Hiv

Anti-HIV broadly neutralizing antibodies (bNAbs) may favor development of antiviral immunity by engaging the immune system during immunotherapy. Targeting integrin α4β7 with an anti-α4β7 monoclonal antibody (Rh-α4β7) affects immune responses in SIV/SHIV-infected macaques. To explore the therapeutic potential of combining bNAbs with α4β7 integrin blockade, SHIVSF162P3-infected, viremic rhesus macaques were treated with bNAbs only (VRC07-523LS and PGT128 anti-HIV antibodies) or a combination of bNAbs and Rh-α4β7 or were left untreated as a control. Treatment with bNAbs alone decreased viremia below 200 copies/ml in all macaques, but seven of eight macaques (87.5%) in the bNAbs-only group rebounded within a median of 3 weeks (95% CI: 2 to 9). In contrast, three of six macaques treated with a combination of Rh-α4β7 and bNAbs (50%) maintained a viremia below 200 copies/ml until the end of the follow-up period; viremia in the other three macaques rebounded within a median of 6 weeks (95% CI: 5 to 11). Thus, there was a modest delay in viral rebound in the macaques treated with the combination antibody therapy compared to bNAbs alone. Our study suggests that α4β7 integrin blockade may prolong virologic control by bNAbs in SHIVSF162P3-infected macaques.

scholarly journals Virus-Like Particle Based Vaccines Elicit Neutralizing Antibodies against the HIV-1 Fusion Peptide

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 765
Author(s):  
Alemu Tekewe Mogus ◽  
Lihong Liu ◽  
Manxue Jia ◽  
Diane T. Ajayi ◽  
Kai Xu ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccination Strategy ◽  
Fusion Peptide ◽  
Linear Epitope ◽  
Broadly Neutralizing Antibodies ◽  
Virus Like Particle ◽  
Boost Immunization ◽  
Potential Vaccine ◽  
Hiv Envelope ◽  
Hiv 1

Broadly neutralizing antibodies (bnAbs) isolated from HIV-infected individuals delineate vulnerable sites on the HIV envelope glycoprotein that are potential vaccine targets. A linear epitope within the N-terminal region of the HIV-1 fusion peptide (FP8) is the primary target of VRC34.01, a bnAb that neutralizes ~50% of primary HIV isolates. FP8 has attracted attention as a potential HIV vaccine target because it is a simple linear epitope. Here, platform technologies based on RNA bacteriophage virus-like particles (VLPs) were used to develop multivalent vaccines targeting the FP8 epitope. Both recombinant MS2 VLPs displaying the FP8 peptide and Qβ VLPs displaying chemically conjugated FP8 peptide induced high titers of FP8-specific antibodies in mice. Moreover, a heterologous prime-boost-boost regimen employing the two FP8-VLP vaccines and native envelope trimer was the most effective approach for eliciting HIV-1 neutralizing antibodies. Given the potent immunogenicity of VLP-based vaccines, this vaccination strategy—inspired by bnAb-guided epitope mapping, VLP bioengineering, and prime-boost immunization approaches—may be a useful strategy for eliciting bnAb responses against HIV.

scholarly journals Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies

2019 ◽  
Vol 216 (2) ◽  
pp. 304-316 ◽  
Author(s):  
Ivan Kosik ◽  
Davide Angeletti ◽  
James S. Gibbs ◽  
Matthew Angel ◽  
Kazuyo Takeda ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Influenza A ◽  
Cell Activation ◽  
Immune Cell ◽  
Broadly Neutralizing Antibodies ◽  
Neutralization Activity ◽  
Immune Cell Activation ◽  
Influenza Virus Hemagglutinin ◽  
Infected Cells

Broadly neutralizing antibodies (Abs) that bind the influenza virus hemagglutinin (HA) stem may enable universal influenza vaccination. Here, we show that anti-stem Abs sterically inhibit viral neuraminidase (NA) activity against large substrates, with activity inversely proportional to the length of the fibrous NA stalk that supports the enzymatic domain. By modulating NA stalk length in recombinant IAVs, we show that anti-stem Abs inhibit virus release from infected cells by blocking NA, accounting for their in vitro neutralization activity. NA inhibition contributes to anti-stem Ab protection in influenza-infected mice, likely due at least in part to NA-mediated inhibition of FcγR-dependent activation of innate immune cells by Ab bound to virions. Food and Drug Administration–approved NA inhibitors enhance anti-stem–based Fc-dependent immune cell activation, raising the possibility of therapeutic synergy between NA inhibitors and anti-stem mAb treatment in humans.

Expression of HIV-1 broadly neutralizing antibodies mediated by recombinant adeno-associated virus 8 in vitro and in vivo

2016 ◽  
Vol 80 ◽  
pp. 68-77
Author(s):  
Yongjiao Yu ◽  
Lu Fu ◽  
Xiaoyu Jiang ◽  
Shanshan Guan ◽  
Ziyu Kuai ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Broadly Neutralizing Antibodies ◽  
Adeno Associated Virus ◽  
Hiv 1

scholarly journals Broadly neutralizing antibodies for therapy of viral infections

2016 ◽  
pp. 1 ◽  
Author(s):  
Raghavan Varadarajan ◽  
Sankaranarayanan Srinivasan ◽  
Sunit Maity ◽  
Maloy Ghosh
Keyword(s):  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Broadly Neutralizing Antibodies

scholarly journals A narrative review of herbal preparations against RNA viruses

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Eghbal Jasemi ◽  
Saeideh Momtaz ◽  
Reza Ghaffarzadegan ◽  
Amir Hossein Abdolghaffari ◽  
Mohammad Abdollahi
Keyword(s):  
Infectious Diseases ◽  
Viral Infections ◽  
Therapeutic Potential ◽  
Synthetic Compound ◽  
Novel Approach ◽  
Plant Families ◽  
Approved Drugs ◽  
Almost All

Background: Throughout history, the plant kingdom has been a source of medicine in almost all cultures. Nowadays, ensuring the safety, quality, and effectiveness of medicinal herbs and their products has become an essential issue in industrialized and developing countries. Phytochemicals are usually involved in pharmacological actions and are used worldwide for various purposes, including the treatment of infectious diseases. Objectives: Although several therapeutics were designed to control infectious diseases, viral infections are still fatal. Currently, evidence extracted from in vivo, in vitro, and silico studies support the antiviral activity of many herbs scientifically; however, the therapeutic potential of many other herbs is still unknown. Plants and their products may potentially control the propagation of viruses in a variety of conditions. Methods: Data were extracted from PubMed, Scopus, Google Scholar, and Science Direct from 1983-2020. We gathered a list of plant extracts, phytochemicals, and herbal formulations that can inhibit RNA viral infections, mainly those are originated from the coronaviruses family. We also provided an overview of their inhibitory mechanism of actions. Results: Plant families, including Lamiaceae, Asteraceae, and Myrtaceae, contain the highest number of species with anti-coronaviruses activities, respectively. Conclusion: It can be suggested that the combination of these antiviral ingredients with each other, any synthetic compound, or already approved drugs or inhibitors can be a novel approach for antiviral therapies.  

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.

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