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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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			Action	DRS
	SRR10072806_1.fastq.gz	Fastqsanger.gz
	SRR10072806_2.fastq.gz	Fastqsanger.gz
	SRR10072807_1.fastq.gz	Fastqsanger.gz
	SRR10072807_2.fastq.gz	Fastqsanger.gz
	SRR10072808_1.fastq.gz	Fastqsanger.gz

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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.

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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.

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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:Treatment of HIV infection with either antiretroviral (ARV) therapy or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ARVs 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 (FcγR)-mediated effector functions, which should affect the kinetics of plasma-virus decline. Here, we formally test the role of effector function in vivo by comparing the rate and timing of plasma-virus clearance in response to a single-dose treatment with either unmodified NAb or those with either reduced or augmented Fc function. When infused into viremic simian HIV (SHIV)-infected rhesus macaques, there was a 21% difference in slope of plasma-virus decline between NAb and NAb with reduced Fc function. NAb engineered to increase FcγRIII binding and improve antibody-dependent cellular cytotoxicity (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 can contribute to the overall antiviral activity, making them distinct from standard ARVs.

| S-EPMC7414046 | biostudies-literature

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