Browsing by Author "Harrison, Stephen C"

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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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    Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations.
    (Nature communications, 2017-11-23) Williams, Wilton B; Zhang, Jinsong; Jiang, Chuancang; Nicely, Nathan I; Fera, Daniela; Luo, Kan; Moody, M Anthony; Liao, Hua-Xin; Alam, S Munir; Kepler, Thomas B; Ramesh, Akshaya; Wiehe, Kevin; Holland, James A; Bradley, Todd; Vandergrift, Nathan; Saunders, Kevin O; Parks, Robert; Foulger, Andrew; Xia, Shi-Mao; Bonsignori, Mattia; Montefiori, David C; Louder, Mark; Eaton, Amanda; Santra, Sampa; Scearce, Richard; Sutherland, Laura; Newman, Amanda; Bouton-Verville, Hilary; Bowman, Cindy; Bomze, Howard; Gao, Feng; Marshall, Dawn J; Whitesides, John F; Nie, Xiaoyan; Kelsoe, Garnett; Reed, Steven G; Fox, Christopher B; Clary, Kim; Koutsoukos, Marguerite; Franco, David; Mascola, John R; Harrison, Stephen C; Haynes, Barton F; Verkoczy, Laurent
    A strategy for HIV-1 vaccine development is to define envelope (Env) evolution of broadly neutralizing antibodies (bnAbs) in infection and to recreate those events by vaccination. Here, we report host tolerance mechanisms that limit the development of CD4-binding site (CD4bs), HCDR3-binder bnAbs via sequential HIV-1 Env vaccination. Vaccine-induced macaque CD4bs antibodies neutralize 7% of HIV-1 strains, recognize open Env trimers, and accumulate relatively modest somatic mutations. In naive CD4bs, unmutated common ancestor knock-in mice Env+B cell clones develop anergy and partial deletion at the transitional to mature B cell stage, but become Env- upon receptor editing. In comparison with repetitive Env immunizations, sequential Env administration rescue anergic Env+ (non-edited) precursor B cells. Thus, stepwise immunization initiates CD4bs-bnAb responses, but immune tolerance mechanisms restrict their development, suggesting that sequential immunogen-based vaccine regimens will likely need to incorporate strategies to expand bnAb precursor pools.
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    Recapitulation of HIV-1 Env-antibody coevolution in macaques leading to neutralization breadth.
    (Science (New York, N.Y.), 2020-11-19) Roark, Ryan S; Li, Hui; Williams, Wilton B; Chug, Hema; Mason, Rosemarie D; Gorman, Jason; Wang, Shuyi; Lee, Fang-Hua; Rando, Juliette; Bonsignori, Mattia; Hwang, Kwan-Ki; Saunders, Kevin O; Wiehe, Kevin; Moody, M Anthony; Hraber, Peter T; Wagh, Kshitij; Giorgi, Elena E; Russell, Ronnie M; Bibollet-Ruche, Frederic; Liu, Weimin; Connell, Jesse; Smith, Andrew G; DeVoto, Julia; Murphy, Alexander I; Smith, Jessica; Ding, Wenge; Zhao, Chengyan; Chohan, Neha; Okumura, Maho; Rosario, Christina; Ding, Yu; Lindemuth, Emily; Bauer, Anya M; Bar, Katharine J; Ambrozak, David; Chao, Cara W; Chuang, Gwo-Yu; Geng, Hui; Lin, Bob C; Louder, Mark K; Nguyen, Richard; Zhang, Baoshan; Lewis, Mark G; Raymond, Donald D; Doria-Rose, Nicole A; Schramm, Chaim A; Douek, Daniel C; Roederer, Mario; Kepler, Thomas B; Kelsoe, Garnett; Mascola, John R; Kwong, Peter D; Korber, Bette T; Harrison, Stephen C; Haynes, Barton F; Hahn, Beatrice H; Shaw, George M
    Neutralizing antibodies elicited by HIV-1 coevolve with viral envelope proteins (Env) in distinctive patterns, in some cases acquiring substantial breadth. We report that primary HIV-1 envelope proteins-when expressed by simian-human immunodeficiency viruses in rhesus macaques-elicited patterns of Env-antibody coevolution strikingly similar to those in humans. This included conserved immunogenetic, structural and chemical solutions to epitope recognition and precise Env-am ino acid substitutions, insertions and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2-apex mode of recognition like that of human bNAbs PGT145/PCT64-35S. Another rhesus antibody bound the CD4-binding site by CD4 mimicry mirroring human bNAbs 8ANC131/CH235/VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.