Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability

Dubrovskaya, Viktoriya; Tran, Karen; Ozorowski, Gabriel; Guenaga, Javier; Wilson, Richard; Bale, Shridhar; Cottrell, Christopher A.; Turner, Hannah L.; Seabright, Gemma; O’Dell, Sijy; Torres, Jonathan L.; Yang, Lifei; Feng, Yu; Leaman, Daniel P.; Vázquez Bernat, Néstor; Liban, Tyler; Louder, Mark; McKee, Krisha; Bailer, Robert T.; Movsesyan, Arlette; Doria-Rose, Nicole A.; Pancera, Marie; Karlsson Hedestam, Gunilla B.; Zwick, Michael B.; Crispin, Max; Mascola, John R.; Ward, Andrew B.; Wyatt, Richard T.

doi:10.1016/j.immuni.2019.10.008

Title: Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability

Journal Article · Tue Nov 12 00:00:00 EST 2019 · Immunity

DOI:https://doi.org/10.1016/j.immuni.2019.10.008· OSTI ID:1577147

Dubrovskaya, Viktoriya ^[1]; Tran, Karen ^[1]; Ozorowski, Gabriel ^[1]; Guenaga, Javier ^[1]; Wilson, Richard ^[1]; Bale, Shridhar ^[1]; Cottrell, Christopher A. ^[1]; Turner, Hannah L. ^[1]; Seabright, Gemma ^[2]; O’Dell, Sijy ^[3]; Torres, Jonathan L. ^[1]; Yang, Lifei ^[1]; Feng, Yu ^[1]; Leaman, Daniel P. ^[1]; Vázquez Bernat, Néstor ^[4]; Liban, Tyler ^[5]; Louder, Mark ^[3]; McKee, Krisha ^[3]; Bailer, Robert T. ^[3]; Movsesyan, Arlette ^[1] more »

The Scripps Research Inst., La Jolla, CA (United States)
Univ. of Southampton (United Kingdom)
National Inst. of Health (NIH), Bethesda, MD (United States)
Karolinska Inst., Stockholm (Sweden)
Fred Hutchinson Cancer Research Center, Seattle, WA (United States)

The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); Scripps CHAVI-ID; Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery

Grant/Contract Number:: AC02-06CH11357; P01 AI104722; R01 AI136621; UM1 AI100663; OPP1115782; OPP1084519; OPP1196345

OSTI ID:: 1577147

Journal Information:: Immunity, Vol. 51, Issue 5; ISSN 1074-7613

Publisher:: Cell PressCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 68 works

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Title: Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability

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