scholarly journals New Connections: Cell-to-Cell HIV-1 Transmission, Resistance to Broadly Neutralizing Antibodies, and an Envelope Sorting Motif

2017 ◽  
Vol 91 (9) ◽  
Author(s):  
S. Abigail Smith ◽  
Cynthia A. Derdeyn
Keyword(s):  
Neutralizing Antibodies ◽  
Differential Susceptibility ◽  
Neutralizing Antibody ◽  
Dependent Manner ◽  
Broadly Neutralizing Antibodies ◽  
Cell Infection ◽  
Viral Spread ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1

ABSTRACT HIV-1 infection from cell-to-cell may provide an efficient mode of viral spread in vivo and could therefore present a significant challenge for preventative or therapeutic strategies based on broadly neutralizing antibodies. Indeed, Li et al. (H. Li, C. Zony, P. Chen, and B. K. Chen, J. Virol. 91:e02425-16, 2017, https://doi.org/10.1128/JVI.02425-16 ) showed that the potency and magnitude of multiple HIV-1 broadly neutralizing antibody classes are decreased during cell-to-cell infection in a context-dependent manner. A functional motif in gp41 appears to contribute to this differential susceptibility by modulating exposure of neutralization epitopes.

scholarly journals Validation of a Triplex Pharmacokinetic Assay for Simultaneous Quantitation of HIV-1 Broadly Neutralizing Antibodies PGT121, PGDM1400, and VRC07-523-LS

2021 ◽  
Vol 12 ◽  
Author(s):  
Martina S. Wesley ◽  
Kelvin T. Chiong ◽  
Kelly E. Seaton ◽  
Christine A. Arocena ◽  
Sheetal Sawant ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Testing Method ◽  
Cd4 Binding Site ◽  
Broadly Neutralizing Antibody ◽  
Effective Doses ◽  
Pharmacokinetic Assay ◽  
Hiv 1

The outcome of the recent Antibody Mediated Prevention (AMP) trials that tested infusion of the broadly neutralizing antibody (bnAb) VRC01 provides proof of concept for blocking infection from sensitive HIV-1 strains. These results also open up the possibility that triple combinations of bnAbs such as PGT121, PGDM1400, as well as long-lasting LS variants such as VRC07-523 LS, have immunoprophylactic potential. PGT121 and PGDM1400 target the HIV-1 V3 and V2 glycan regions of the gp120 envelope protein, respectively, while VRC07-523LS targets the HIV-1 CD4 binding site. These bnAbs demonstrate neutralization potency and complementary breadth of HIV-1 strain coverage. An important clinical trial outcome is the accurate measurement of in vivo concentrations of passively infused bnAbs to determine effective doses for therapy and/or prevention. Standardization and validation of this testing method is a key element for clinical studies as is the ability to simultaneously detect multiple bnAbs in a specific manner. Here we report the development of a sensitive, specific, accurate, and precise multiplexed microsphere-based assay that simultaneously quantifies the respective physiological concentrations of passively infused bnAbs in human serum to ultimately define the threshold needed for protection from HIV-1 infection.

scholarly journals Vaccines and Broadly Neutralizing Antibodies for HIV-1 Prevention

2020 ◽  
Vol 38 (1) ◽  
pp. 673-703 ◽  
Author(s):  
Kathryn E. Stephenson ◽  
Kshitij Wagh ◽  
Bette Korber ◽  
Dan H. Barouch
Keyword(s):  
Clinical Trials ◽  
Neutralizing Antibodies ◽  
Passive Immunization ◽  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Aids Pandemic ◽  
Broadly Neutralizing Antibody ◽  
Early Phase Clinical Trials ◽  
Hiv 1 ◽  
Review Current

Development of improved approaches for HIV-1 prevention will likely be required for a durable end to the global AIDS pandemic. Recent advances in preclinical studies and early phase clinical trials offer renewed promise for immunologic strategies for blocking acquisition of HIV-1 infection. Clinical trials are currently underway to evaluate the efficacy of two vaccine candidates and a broadly neutralizing antibody (bNAb) to prevent HIV-1 infection in humans. However, the vast diversity of HIV-1 is a major challenge for both active and passive immunization. Here we review current immunologic strategies for HIV-1 prevention, with a focus on current and next-generation vaccines and bNAbs.

scholarly journals Trimeric Glycosylphosphatidylinositol-Anchored HCDR3 of Broadly Neutralizing Antibody PG16 Is a Potent HIV-1 Entry Inhibitor

2012 ◽  
Vol 87 (3) ◽  
pp. 1899-1905 ◽  
Author(s):  
Lihong Liu ◽  
Weiming Wang ◽  
Lifei Yang ◽  
Huanhuan Ren ◽  
Jason T. Kimata ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Lipid Rafts ◽  
Neutralizing Antibodies ◽  
Quaternary Structure ◽  
Neutralizing Antibody ◽  
Entry Inhibitor ◽  
Broadly Neutralizing Antibodies ◽  
Broadly Neutralizing Antibody ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTPG9 and PG16 are two quaternary-structure-specific broadly neutralizing antibodies with unique HCDR3 subdomains. Previously, we showed that glycosylphosphatidylinositol (GPI)-anchored HCDR3 subdomains (GPI-HCDR3) can be targeted to lipid rafts of the plasma membrane, bind to the epitope recognized by HCDR3 of PG16, and neutralize diverse HIV-1 isolates. In this study, we further developed trimeric GPI-HCDR3s and demonstrated that trimeric GPI-HCDR3 (PG16) dramatically improves anti-HIV-1 neutralization, suggesting that a stoichiometry of recognition of 3 or 2 HCDR3 molecules (PG16) to 1 viral spike is possible.

scholarly journals Predicting in vivo escape dynamics of HIV-1 from a broadly neutralizing antibody

2021 ◽  
Vol 118 (30) ◽  
pp. e2104651118
Author(s):  
Matthijs Meijers ◽  
Kanika Vanshylla ◽  
Henning Gruell ◽  
Florian Klein ◽  
Michael Lässig
Keyword(s):  
Viral Load ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Antibody Treatment ◽  
Trade Off ◽  
Escape Dynamics ◽  
Resistance Evolution ◽  
Hiv 1

Broadly neutralizing antibodies are promising candidates for treatment and prevention of HIV-1 infections. Such antibodies can temporarily suppress viral load in infected individuals; however, the virus often rebounds by escape mutants that have evolved resistance. In this paper, we map a fitness model of HIV-1 interacting with broadly neutralizing antibodies using in vivo data from a recent clinical trial. We identify two fitness factors, antibody dosage and viral load, that determine viral reproduction rates reproducibly across different hosts. The model successfully predicts the escape dynamics of HIV-1 in the course of an antibody treatment, including a characteristic frequency turnover between sensitive and resistant strains. This turnover is governed by a dosage-dependent fitness ranking, resulting from an evolutionary trade-off between antibody resistance and its collateral cost in drug-free growth. Our analysis suggests resistance–cost trade-off curves as a measure of antibody performance in the presence of resistance evolution.

scholarly journals HIV-1 hijacks the cell extracellular matrix to spread collectively and efficiently between T lymphocytes

2021 ◽  
Author(s):  
Catherine Inizan ◽  
Marina Caillet ◽  
Alexandra Desrames ◽  
Perrine Bomme ◽  
Adeline MALLET ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
T Lymphocytes ◽  
Neutralizing Antibodies ◽  
Antiretroviral Treatment ◽  
Broadly Neutralizing Antibodies ◽  
Viral Dissemination ◽  
Viral Spread ◽  
Viral Particles ◽  
Hiv 1

Collective transmission via structures containing several virions has recently emerged as a highly efficient mode of viral spread. Here, we demonstrate that HIV-1 spreads between T lymphocytes in the form of viral particles colonies that are concentrated and sheltered in an extracellular matrix (ECM) lattice enabling their collective transmission upon cell contacts. Intrinsically, ECM-clustered viruses infect T lymphocytes more efficiently than individual viral particles. They preserve HIV-1 transmission from antiretroviral treatment (ArT) and potent broadly neutralizing antibodies. We also show that collagen induced by HIV-1 infection controls the clustering of virions and their collective spread, thereby enhancing infectivity. CD4+ T cells from HIV-1-infected patients produce and transmit ECM-virus clusters, supporting that they could be involved in vivo. This study provides new insights into modes of HIV-1 transmission and identifies a novel fundamental role for collagen in this process. HIV-1 spread via ECM-virus clusters may have important implications for viral dissemination and persistence, including during therapy.

scholarly journals Predicting in vivo escape dynamics of HIV-1 from a broadly neutralizing antibody

2020 ◽  
Author(s):  
Matthijs Meijers ◽  
Kanika Vanshylla ◽  
Henning Gruell ◽  
Florian Klein ◽  
Michael Lässig
Keyword(s):  
Viral Load ◽  
Neutralizing Antibodies ◽  
Fitness Landscape ◽  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Antibody Treatment ◽  
Escape Dynamics ◽  
Resistance Evolution ◽  
Hiv 1

ABSTRACTBroadly neutralizing antibodies are promising candidates for treatment and prevention of HIV-1 infections. Such antibodies can temporarily suppress viral load in infected individuals; however, the virus often rebounds by escape mutants that have evolved resistance. In this paper, we map an in vivo fitness landscape of HIV-1 interacting with broadly neutralizing antibodies, using data from a recent clinical trial. We identify two fitness factors, antibody dosage and viral load, that determine viral reproduction rates reproducibly across different hosts. The model successfully predicts the escape dynamics of HIV-1 in the course of an antibody treatment, including a characteristic frequency turnover between sensitive and resistant strains. This turnover is governed by a dosage-dependent fitness ranking, resulting from an evolutionary tradeoff between antibody resistance and its collateral cost in drug-free growth. Our analysis suggests resistance-cost tradeoff curves as a measure of antibody performance in the presence of resistance evolution.

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 Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo

Science ◽  
2016 ◽  
Vol 352 (6288) ◽  
pp. 1001-1004 ◽  
Author(s):  
C.-L. Lu ◽  
D. K. Murakowski ◽  
S. Bournazos ◽  
T. Schoofs ◽  
D. Sarkar ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Broadly Neutralizing Antibodies ◽  
Infected Cells ◽  
Hiv 1

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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