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Vaccine Details
Notes
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2 notes.
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DH570: The authors used nuclear magnetic resonance (NMR) to define the structure of the HIV-1 MPER when linked to the transmembrane domain (MPER-TMD) in the context of a lipid bilayer. In particular, they looked at the accessibility of the MPER-TMD to 2F5, 4E10, 10E8 and DH570. The MPER appears to be accessible up to ∼10% of the time to the 2F5, 4E10, and 10E8 Fabs but ∼40% of time to the DH570 Fab. To assess possible functional roles for the MPER in membrane fusion, they generated 17 Env mutants using the sequence of a clade A isolate, 92UG037.8, mutating each of the three structural elements: hydrophobic core, turn, and kink. Mutants W670A (hydrophobic core), F673A (turn), and W680A (kink), while still sensitive to VRC01, became much more resistant to the trimer-specific bNAbs and also gained sensitivity to b6, 3791, and 17b. All mutants with changes at W666 in the hydrophobic core and K683 at the kink lost infectivity almost completely. For the rest of the mutants, infectivity ranged from 4.3 to 50.8% of that of the wild type, showing that key residues important for stabilizing the MPER structure are also critical for Env-induced membrane fusion activity, especially in the context of viral infection.
Fu2018
(antibody binding site, antibody interactions, neutralization, variant cross-reactivity, binding affinity, structure)
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DH570: HIV gp41 bNAbs have characteristics that predispose them to be controlled by immunological tolerance. The study explored whether the germline unmutated ancestors (UA) of MPER bNAbs are also controlled by tolerance, and, if so, whether any remaining B cells can be activated to clonally expand. Germline knock-in mice expressing precursors of bNAb 2F5 showed B cell deletion in the bone marrow prevaccination, and the anergic bnAb precursors that survived in the periphery could be partially rescued, become activated, and clonally expand by immunization with MPER peptide-liposomes. Immunized macaques made B cell clonal lineages targeted to the 2F5 bnAb epitope, but 2F5-like antibodies were either deleted or did not attain sufficient affinity for MPER in gp41-lipid complexes to achieve the neutralization potency of 2F5. Structural analysis of members of a vaccine-induced antibody lineage DH570 revealed that heavy chain complementarity-determining region 3 (HCDR3) hydrophobicity was important for neutralization but unlike 2F5 DH570 light chain did not interact with the gp41660-670 peptide. DH570 lineage antibodies include many DH570 Abs (1-32) and IA47.
Zhang2016
(antibody generation, neutralization, structure, antibody lineage)
References
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2 references.
Isolation Paper
Zhang2016
Ruijun Zhang, Laurent Verkoczy, Kevin Wiehe, S. Munir Alam, Nathan I. Nicely, Sampa Santra, Todd Bradley, Charles W. Pemble, 4th, Jinsong Zhang, Feng Gao, David C. Montefiori, Hilary Bouton-Verville, Garnett Kelsoe, Kevin Larimore, Phillip D. Greenberg, Robert Parks, Andrew Foulger, Jessica N. Peel, Kan Luo, Xiaozhi Lu, Ashley M. Trama, Nathan Vandergrift, Georgia D. Tomaras, Thomas B. Kepler, M. Anthony Moody, Hua-Xin Liao, and Barton F. Haynes. Initiation of Immune Tolerance-Controlled HIV gp41 Neutralizing B Cell Lineages. Sci. Transl. Med., 8(336):336ra62, 27 Apr 2016. PubMed ID: 27122615.
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Fu2018
Qingshan Fu, Md Munan Shaik, Yongfei Cai, Fadi Ghantous, Alessandro Piai, Hanqin Peng, Sophia Rits-Volloch, Zhijun Liu, Stephen C. Harrison, Michael S. Seaman, Bing Chen, and James J. Chou. Structure of the Membrane Proximal External Region of HIV-1 Envelope Glycoprotein. Proc. Natl. Acad. Sci. U.S.A., 115(38):E8892-E8899, 18 Sep 2018. PubMed ID: 30185554.
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