Browsing by Subject "Binding Sites, Antibody"

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    A Prevalent Focused Human Antibody Response to the Influenza Virus Hemagglutinin Head Interface.
    (mBio, 2021-06) McCarthy, Kevin R; Lee, Jiwon; Watanabe, Akiko; Kuraoka, Masayuki; Robinson-McCarthy, Lindsey R; Georgiou, George; Kelsoe, Garnett; Harrison, Stephen C
    Novel animal influenza viruses emerge, initiate pandemics, and become endemic seasonal variants that have evolved to escape from prevalent herd immunity. These processes often outpace vaccine-elicited protection. Focusing immune responses on conserved epitopes may impart durable immunity. We describe a focused, protective antibody response, abundant in memory and serum repertoires, to a conserved region at the influenza virus hemagglutinin (HA) head interface. Structures of 11 examples, 8 reported here, from seven human donors demonstrate the convergence of responses on a single epitope. The 11 are genetically diverse, with one class having a common, IGκV1-39, light chain. All of the antibodies bind HAs from multiple serotypes. The lack of apparent genetic restriction and potential for elicitation by more than one serotype may explain their abundance. We define the head interface as a major target of broadly protective antibodies with the potential to influence the outcomes of influenza virus infection. IMPORTANCE The rapid appearance of mutations in circulating human influenza viruses and selection for escape from herd immunity require prediction of likely variants for an annual updating of influenza vaccines. The identification of human antibodies that recognize conserved surfaces on the influenza virus hemagglutinin (HA) has prompted efforts to design immunogens that might selectively elicit such antibodies. The recent discovery of a widely prevalent antibody response to the conserved interface between two HA "heads" (the globular, receptor-binding domains at the apex of the spike-like trimer) has added a new target for these efforts. We report structures of eight such antibodies, bound with HA heads, and compare them with each other and with three others previously described. Although genetically diverse, they all converge on a common binding site. The analysis here can guide immunogen design for preclinical trials.
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    Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals.
    (PLoS One, 2010-01-20) Corti, Davide; Langedijk, Johannes PM; Hinz, Andreas; Seaman, Michael S; Vanzetta, Fabrizia; Fernandez-Rodriguez, Blanca M; Silacci, Chiara; Pinna, Debora; Jarrossay, David; Balla-Jhagjhoorsingh, Sunita; Willems, Betty; Zekveld, Maria J; Dreja, Hanna; O'Sullivan, Eithne; Pade, Corinna; Orkin, Chloe; Jeffs, Simon A; Montefiori, David C; Davis, David; Weissenhorn, Winfried; McKnight, Aine; Heeney, Jonathan L; Sallusto, Federica; Sattentau, Quentin J; Weiss, Robin A; Lanzavecchia, Antonio
    BACKGROUND: The isolation of human monoclonal antibodies (mAbs) that neutralize a broad spectrum of primary HIV-1 isolates and the characterization of the human neutralizing antibody B cell response to HIV-1 infection are important goals that are central to the design of an effective antibody-based vaccine. METHODS AND FINDINGS: We immortalized IgG(+) memory B cells from individuals infected with diverse clades of HIV-1 and selected on the basis of plasma neutralization profiles that were cross-clade and relatively potent. Culture supernatants were screened using various recombinant forms of the envelope glycoproteins (Env) in multiple parallel assays. We isolated 58 mAbs that were mapped to different Env surfaces, most of which showed neutralizing activity. One mAb in particular (HJ16) specific for a novel epitope proximal to the CD4 binding site on gp120 selectively neutralized a multi-clade panel of Tier-2 HIV-1 pseudoviruses, and demonstrated reactivity that was comparable in breadth, but distinct in neutralization specificity, to that of the other CD4 binding site-specific neutralizing mAb b12. A second mAb (HGN194) bound a conserved epitope in the V3 crown and neutralized all Tier-1 and a proportion of Tier-2 pseudoviruses tested, irrespective of clade. A third mAb (HK20) with broad neutralizing activity, particularly as a Fab fragment, recognized a highly conserved epitope in the HR-1 region of gp41, but showed striking assay-dependent selectivity in its activity. CONCLUSIONS: This study reveals that by using appropriate screening methods, a large proportion of memory B cells can be isolated that produce mAbs with HIV-1 neutralizing activity. Three of these mAbs show unusual breadth of neutralization and therefore add to the current panel of HIV-1 neutralizing antibodies with potential for passive protection and template-based vaccine design.
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    Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9.
    (Nature, 2011-11-23) McLellan, JS; Pancera, M; Carrico, C; Gorman, J; Julien, JP; Khayat, R; Louder, R; Pejchal, R; Sastry, M; Dai, K; O'Dell, S; Patel, N; Shahzad ul Hussan, S; Yang, Y; Zhang, B; Zhou, T; Zhu, J; Boyington, JC; Chuang, GY; Diwanji, D; Georgiev, I; Kwon, YD; Lee, D; Louder, MK; Moquin, S; Schmidt, SD; Yang, ZY; Bonsignori, M; Crump, JA; Kapiga, SH; Sam, NE; Haynes, BF; Burton, DR; Koff, WC; Walker, LM; Phogat, S; Wyatt, R; Orwenyo, J; Wang, LX; Arthos, J; Bewley, CA; Mascola, JR; Nabel, GJ; Schief, WR; Ward, AB; Wilson, IA; Kwong, PD
    Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence diversity and N-linked glycosylation. Human antibodies such as PG9 nonetheless engage V1/V2 and neutralize 80% of HIV-1 isolates. Here we report the structure of V1/V2 in complex with PG9. V1/V2 forms a four-stranded β-sheet domain, in which sequence diversity and glycosylation are largely segregated to strand-connecting loops. PG9 recognition involves electrostatic, sequence-independent and glycan interactions: the latter account for over half the interactive surface but are of sufficiently weak affinity to avoid autoreactivity. The structures of V1/V2-directed antibodies CH04 and PGT145 indicate that they share a common mode of glycan penetration by extended anionic loops. In addition to structurally defining V1/V2, the results thus identify a paradigm of antibody recognition for highly glycosylated antigens, which-with PG9-involves a site of vulnerability comprising just two glycans and a strand.