Myomedin replicas of gp120 V3 loop glycan epitopes recognized by PGT121 and PGT126 antibodies as non-cognate antigens for stimulation of HIV-1 broadly neutralizing antibodies

0569555 - BTÚ 2023 RIV CH eng J - Článek v odborném periodiku
Lišková, Veronika - Kosztyu, P. - Kuchař, Milan - Černý, Jiří - Bharadwaj, Shiv - Petroková, Hana - Vroblova, E. - Křupka, M. - Malý, Michal - Zosincuková, Tereza - Sulc, Josef - Kafkova, L. R. - Raška, M. - Malý, Petr
Myomedin replicas of gp120 V3 loop glycan epitopes recognized by PGT121 and PGT126 antibodies as non-cognate antigens for stimulation of HIV-1 broadly neutralizing antibodies.
Frontiers in Immunology. Roč. 13, DEC 8 2022 (2022), č. článku 1066361. ISSN 1664-3224. E-ISSN 1664-3224
Grant CEP: GA MŠMT(CZ) EF16_025/0007397
Institucionální podpora: RVO:86652036
Klíčová slova: hiv-1 * glycoprotein 120 * protein scaffold * protein engineering * broadly neutralizing antibody * vaccine
Obor OECD: Immunology
Impakt faktor: 7.3, rok: 2022
Způsob publikování: Open access
https://www.frontiersin.org/articles/10.3389/fimmu.2022.1066361/full

IntroductionImprinting broadly neutralizing antibody (bNAb) paratopes by shape complementary protein mimotopes represents a potential alternative for developing vaccine immunogens. This approach, designated as a Non-Cognate Ligand Strategy (NCLS), has recently been used for the identification of protein variants mimicking CD4 binding region epitope or membrane proximal external region (MPER) epitope of HIV-1 envelope (Env) glycoprotein. However, the potential of small binding proteins to mimic viral glycan-containing epitopes has not yet been verified. MethodsIn this work, we employed a highly complex combinatorial Myomedin scaffold library to identify variants recognizing paratopes of super candidate bNAbs, PGT121 and PGT126, specific for HIV-1 V3 loop epitopes. ResultsIn the collection of Myomedins called MLD variants targeted to PGT121, three candidates competed with gp120 for binding to this bNAb in ELISA, thus suggesting an overlapping binding site and epitope-mimicking potential. Myomedins targeted to PGT126 designated MLB also provided variants that competed with gp120. Immunization of mice with MLB or MLD binders resulted in the production of anti-gp120 andEnv serum antibodies. Mouse hyper-immune sera elicited with MLB036, MLB041, MLB049, and MLD108 moderately neutralized 8-to-10 of 22 tested HIV-1-pseudotyped viruses of A, B, and C clades in vitro. DiscussionOur data demonstrate that Myomedin-derived variants can mimic particular V3 glycan epitopes of prominent anti-HIV-1 bNAbs, ascertain the potential of particular glycans controlling neutralizing sensitivity of individual HIV-1 pseudoviruses, and represent promising prophylactic candidates for HIV-1 vaccine development.
Trvalý link: https://hdl.handle.net/11104/0341007