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Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV broadly neutralizing antibody.

ABSTRACT: Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV broadly neutralizing antibody.

PROVIDER: PRJNA564087 | ENA |

REPOSITORIES: ENA

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Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV broadly neutralizing antibody.

Project description:Treatment of HIV infection with either anti-retroviral therapy (ART) or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ART and NAbs prevent new rounds of viral infection but NAbs may have the additional capacity to accelerate the loss of virus-infected cells through Fc gamma receptor (FcgR) mediated effector functions, which should affect the kinetics of plasma virus decline. Here we formally test this premise in vivo by comparing the plasma virus response to a single dose treatment with either unmodified NAb or those with either reduced or augmented Fc function. When infused into viremic SHIV-infected rhesus macaques, there was a 21% difference in slope of plasma virus decline between wt NAb and NAb with reduced Fc function. NAb engineered to increase FcgRIII binding and improve ADCC in vitro resulted in arming of effector cells in vivo yet led to viral decay kinetics similar to NAbs with reduced Fc function. These studies show that the predominant mechanism of antiviral activity of HIV NAbs is through inhibition of viral entry, but that Fc function does contribute to the overall antiviral activity, making them unique from standard ART. However, these data also show that increased FcgRIII engagement is insufficient to improve in vivo virus clearance.

2020-07-20 | GSE136938 | GEO

Neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions and monocytes for optimal therapeutic activity

Project description:SARS-CoV-2 has spread globally and caused the COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 are in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected mice. Whereas Fc effector functions are fully dispensable when mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact but not LALA-PG loss of Fc effector function variant mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and enhanced tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes for therapeutic efficacy. Our study demonstrates that therapeutic neutralizing mAbs require Fc effector functions to reduce SARS-CoV-2 infection and modulate protective immune responses.

2021-03-01 | GSE161615 | GEO

Human Immunoglobulin Repertoire-Guided Immunogen Design Targeting HIV V2-Apex Broadly Neutralizing Antibody Precursors

Project description:Broadly neutralizing antibodies (bnAbs) to the HIV envelope (Env) V2-apex region are important leads for HIV vaccine design. Most V2-apex bnAbs engage Env with an uncommonly long heavy chain complementarity-determining region 3 (HCDR3), suggesting that rarity of bnAb precursors poses a challenge for vaccine priming. We created precursor sequence definitions for V2-apex HCDR3-dependent bnAbs and searched for related precursors in human antibody heavy chain ultradeep sequencing data from 14 HIV-unexposed donors. We found potential precursors in a majority of donors for only two long-HCDR3 V2-apex bnAbs, PCT64 and PG9, identifying these bnAbs as priority vaccine targets. We then engineered ApexGT Env trimers that bind inferred germlines for PCT64 and PG9 and have higher affinities for bnAbs; determined cryo-EM structures of ApexGT trimers bound to inferred germline and bnAb forms of PCT64 and PG9; and developed an mRNA-encoded cell-surface trimer for our lead ApexGT candidate. The methods and immunogens developed here have promise to assist the development of an HIV vaccine.

2023-03-11 | PXD033766 | Pride

IgG3 enhances neutralization potency and Fc effector function of an HIV V2-specific broadly neutralizing antibody.

Project description: Not available

| S-EPMC6936867 | biostudies-literature

Smart-seq2 data from memory B cells from an individual living with HIV with broadly neutralizing plasma and an individual living with HIV who is aviremic without treatment

Project description:Tissue-like memory, activated memory and resting memory B cells were sorted by FACS from the individual living with HIV (EC17) who was aviremic and transcriptomes generated using the SmartSeq2 protocol. This was to provide a reference set for each memory B cell subset in the context of HIV. Next, HIV-specific memory B cells from the individual with broadly neutralizing plasma were then also sorted by FACS and single cell transcriptomes generated using the SmartSeq2 protocol. The phenotypes of memory B cells from the individual with broadly neutralizing plasma (T125) were then inferred from the reference set using Glmnet and Celltypist packages.

2023-12-24 | E-MTAB-13592 | biostudies-arrayexpress

Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody.

Project description: Not available

| S-EPMC7414046 | biostudies-literature

Vaccine priming of rare HIV broadly neutralizing antibody precursors in nonhuman primates

Project description:Germline-targeting immunogens hold promise for initiating the induction of broadly neutralizing antibodies (bnAbs) to human immunodeficiency virus (HIV) and other pathogens. However, antibody-antigen recognition is typically dominated by heavy chain complementarity determining region 3 (HCDR3) interactions, and vaccine priming of HCDR3-dominant bnAbs by germline-targeting immunogens has not been demonstrated in humans or outbred animals. We found that immunization with N332-GT5, an HIV envelope trimer designed to target precursors of the HCDR3-dominant bnAb BG18, primed bnAb-precursor B cells in 8 of 8 rhesus macaques to substantial frequencies, and with diverse lineages, in germinal center and memory B cells. We confirmed bnAb-mimicking, HCDR3-dominant, trimer-binding interactions with cryo-electron microscopy. The results demonstrate proof of principle for priming of HCDR3-dominant bnAb precursors in outbred animals, suggest that N332-GT5 has promise to induce similar responses in humans, and encourage application of HCDR3-dominant germline-targeting for other bnAbs to HIV and additional pathogens.

2024-02-26 | MSV000094174 | MassIVE

Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies

Project description:Many human monoclonal antibodies that neutralize multiple clades of HIV-1 are polyreactive and bind avidly to mammalian autoantigens. Indeed, the generation of neutralizing antibodies to the 2F5 and 4E10 epitopes of HIV-1 gp41 in man may be proscribed by immune tolerance since mice expressing the VH and VL regions of 2F5 have a block in B-cell development characteristic of central tolerance. This developmental blockade implies the presence of tolerizing autoantigens that are mimicked by the membrane-proximal external region of HIV-1 gp41. Here we identify human kynureninase (KYNU) and splicing factor 3b subunit 3 (SF3B3) as the primary conserved, vertebrate self-antigens recognized by the 2F5 and 4E10 antibodies, respectively. 2F5 binds the H4 domain of KYNU which contains the complete 2F5 linear epitope (ELDKWA). 4E10 recognizes a conformational epitope of SF3B3 that is strongly dependent on hydrophobic interactions. Opossums carry a rare KYNU H4 domain that abolishes 2F5 binding, but retain all SF3B3 4E10 epitopes. Immunization of opossums with HIV-1 gp140 induced extraordinary titers of serum antibody to the 2F5 ELDKWA epitope but little or nothing to the 4E10 determinant. Identification of structural motif shared by vertebrates and HIV-1 provides direct evidence that immunological tolerance can impair humoral responses to HIV-1. The invitrogen protoarray that contains >9,400 recombinant human proteins was used to identify self-ligands that are recognized by broadly neutralizing HIV-1 antibodies 2F5 and 4E10. An isotype-matched human myeloma protein (151K, Southern Biotech) was used as control.

2012-12-03 | E-GEOD-42673 | biostudies-arrayexpress

Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity.

Project description: Not available

| S-EPMC4167398 | biostudies-literature

Neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions and monocytes for optimal therapeutic activity

Project description:Neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions and monocytes for optimal therapeutic activity

| PRJNA678953 | ENA

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