Dataset Information

Overcoming steric restrictions of VRC01 HIV-1 neutralizing antibodies through immunization

ABSTRACT: Broadly HIV-1 neutralizing VRC01-class antibodies target the CD4-binding site of Env. They are derived from VH1-2*02 antibody heavy chains paired with rare light chains expressing five amino acid long CDRL3s. They have been isolated from infected subjects but have not yet been elicited by immunization. Env-derived immunogens capable of binding the germline forms of VRC01 B cell receptors on naïve B cells have been designed and evaluated in knock-in mice. However, the elicited antibodies cannot bypass glycans present on the conserved position N276 of Env, which restricts access to the CD4-binding site. Efforts to guide the appropriate maturation of these antibodies by sequential immunization have not yet been successful. Here, we report on a two-step immunization scheme that led to the maturation of VRC01-like antibodies capable of accommodating the N276 glycan and displaying autologous tier 2 neutralizing activities. Our results are relevant to clinical trials aiming to elicit VRC01 antibodies.

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Homo Sapiens Human Immunodeficiency Virus 1

SUBMITTER: Andrew Borst

LAB HEAD: David Veesler

PROVIDER: PXD015168 | Pride | 2020-05-26

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	20190303_426c_P1B5_DSxtal_IgG_lysCdigest.raw	Raw
	20190303_426c_P1B5_DSxtal_IgG_lysCdigest.raw_20190409_Byonic.byparms	Raw
	20190303_426c_P1B5_DSxtal_IgG_lysCdigest.raw_20190409_Byonic.byrslt	Raw
	20190303_426c_P1B5_DSxtal_IgG_lysCdigest.raw_20190409_Byonic.mgf	Mgf
	20190303_426c_P1B5_DSxtal_IgG_lysCdigest.raw_20190409_Byonic.mzid.gz	Mzid

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Publications

Overcoming Steric Restrictions of VRC01 HIV-1 Neutralizing Antibodies through Immunization.

Parks K Rachael KR MacCamy Anna J AJ Trichka Josephine J Gray Matthew M Weidle Connor C Borst Andrew J AJ Khechaduri Arineh A Takushi Brittany B Agrawal Parul P Guenaga Javier J Wyatt Richard T RT Coler Rhea R Seaman Michael M LaBranche Celia C Montefiori David C DC Veesler David D Pancera Marie M McGuire Andrew A Stamatatos Leonidas L

Cell reports 20191201 10

Broadly HIV-1 neutralizing VRC01 class antibodies target the CD4-binding site of Env. They are derived from VH1-2<sup>∗</sup>02 antibody heavy chains paired with rare light chains expressing 5-amino acid-long CDRL3s. They have been isolated from infected subjects but have not yet been elicited by immunization. Env-derived immunogens capable of binding the germline forms of VRC01 B cell receptors on naive B cells have been designed and evaluated in knockin mice. However, the elicited antibodies c ...[more]

PMID: 31801073

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Project description:The HIV-1 envelope glycoprotein (Env) is the sole neutralizing determinant on the surface of the virus. The Env gp120 and gp41 subunits mediate receptor binding and membrane fusion and are generated from the gp160 precursor by cellular furins. This cleavage event is required for viral entry. One approach to generate HIV-1 neutralizing antibodies following immunization is to express membrane-bound Env anchored on the cell-surface by genetic means using the natural HIV gp41 transmembrane (TM) spanning domain. To simplify the process of Env trimer membrane expression we sought to remove the need for Env precursor cleavage while maintaining native-like conformation following genetic expression. To accomplish these objectives, we selected our previously developed 'native flexibly linked' (NFL) stabilized soluble trimers that are both near native in conformation and cleavage-independent. We genetically fused the NFL construct to the HIV TM domain by using a short linker or by restoring the native membrane external proximal region, absent in soluble trimers, to express the full HIV Env ectodomain on the plasma membrane. Both forms of cell-surface NFL trimers, without and with the MPER, displayed favorable antigenic profiles by flow cytometry when expressed from plasmid DNA or mRNA. These results were consistent with the presence of well-ordered cell surface native-like trimeric Env, a necessary requirement to generate neutralizing antibodies by vaccination. Inoculation of rabbits with mRNA lipid nanoparticles (LNP) expressing membrane-bound stabilized HIV Env NFL trimers generated tier 2 neutralizing antibody serum titers in immunized animals. Multiple inoculations of mRNA LNPs generated similar neutralizing antibody titers compared to immunizations of matched NFL soluble proteins in adjuvant. Given the recent success of mRNA vaccines to prevent severe COVID, these are important developments for genetic expression of native-like HIV Env trimers in animals and potentially in humans.