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TitleVaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability.
Journal, issue, pagesImmunity, Vol. 51, Issue 5, Page 915-929.e7, Year 2019
Publish dateNov 19, 2019
AuthorsViktoriya Dubrovskaya / Karen Tran / Gabriel Ozorowski / Javier Guenaga / Richard Wilson / Shridhar Bale / Christopher A Cottrell / Hannah L Turner / Gemma Seabright / Sijy O'Dell / Jonathan L Torres / Lifei Yang / Yu Feng / Daniel P Leaman / Néstor Vázquez Bernat / Tyler Liban / Mark Louder / Krisha McKee / Robert T Bailer / Arlette Movsesyan / Nicole A Doria-Rose / Marie Pancera / Gunilla B Karlsson Hedestam / Michael B Zwick / Max Crispin / John R Mascola / Andrew B Ward / Richard T Wyatt /
PubMed AbstractThe 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 ...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.
External linksImmunity / PubMed:31732167 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.296 - 30.0 Å
Structure data

20259

6p62

EMDB-20259, PDB-6p62:
HIV Env BG505 NFL TD+ in complex with antibody E70 fragment antigen binding
Method: EM (single particle) / Resolution: 3.57 Å

20260

6p65

EMDB-20260, PDB-6p65:
HIV Env 16055 NFL TD 2CC+ in complex with antibody 1C2 fragment antigen binding
Method: EM (single particle) / Resolution: 3.94 Å

EMDB-20273:
Negative-stain reconstruction of HIV-1 Env BG505 NFL CC+ trimer in complex with rabbit antibody E70 fragment antigen binding
Method: EM (single particle) / Resolution: 21.0 Å

EMDB-20274:
Negative stain reconstruction of HIV-1 Env 16055 NFL TD 2CC+ trimer in complex with rabbit antibody 1C2 fragment antigen binding
Method: EM (single particle) / Resolution: 21.0 Å

EMDB-20279:
Polyclonal Fabs from rabbit C3 post 5th immunization in complex with heterologous Env trimer 45_01dH5
Method: EM (single particle) / Resolution: 30.0 Å

EMDB-20280:
Polyclonal Fabs from rabbit C3 post 5th immunization in complex with heterologous Env trimer 45_01dH5
Method: EM (single particle) / Resolution: 30.0 Å

EMDB-20342:
Polyclonal serum of rabbit C3 boost 5 in complex with heterologous Env trimer SC422 NFL TD CC+
Method: EM (single particle) / Resolution: 18.0 Å

EMDB-20343:
Polyclonal serum from rabbit C3 post 4th immunization in complex with heterologous Env trimer 45_01dG5 NFL TD 2CC+
Method: EM (single particle) / Resolution: 19.0 Å

EMDB-20344:
Polyclonal serum of rabbit C3 post 5th immunization in complex with heterologous Env trimer 45_01dG5 NFL TD 2CC+
Method: EM (single particle) / Resolution: 21.0 Å

EMDB-20345:
Polyclonal serum of rabbit A1 post 6th immunization in complex with homologous Env trimer 16055 NFL TD CC+
Method: EM (single particle) / Resolution: 18.0 Å

EMDB-20346:
Polyclonal serum of rabbit A1 post 6th immunization in complex with heterologous Env trimer 45_01dG5 NFL TD 2CC+, class 1
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-20347:
Polyclonal serum of rabbit A1 post 6th immunization in complex with heterologous Env trimer 45_01dG5 NFL TD 2CC+, class 2
Method: EM (single particle) / Resolution: 24.0 Å

PDB-6peh:
Crystal structure of rabbit monoclonal anti-HIV antibody 1C2
Method: X-RAY DIFFRACTION / Resolution: 2.296 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-SO4:
SULFATE ION / Sulfate

ChemComp-HOH:
WATER / Water

Source
  • human immunodeficiency virus 1
  • oryctolagus cuniculus (rabbit)
  • homo sapiens (human)
KeywordsVIRAL PROTEIN/immune system / HIV-1 / CD4 binding site / neutralizing antibody / rabbit antibody / VIRAL PROTEIN / VIRAL PROTEIN-immune system complex / IMMUNE SYSTEM / Antibody / bnAb / HIV

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