Browsing by Author "Williams, Wilton B"

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    Correction: Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies.
    (PLoS pathogens, 2019-12-02) LaBranche, Celia C; Henderson, Rory; Hsu, Allen; Behrens, Shay; Chen, Xuejun; Zhou, Tongqing; Wiehe, Kevin; Saunders, Kevin O; Alam, S Munir; Bonsignori, Mattia; Borgnia, Mario J; Sattentau, Quentin J; Eaton, Amanda; Greene, Kelli; Gao, Hongmei; Liao, Hua-Xin; Williams, Wilton B; Peacock, James; Tang, Haili; Perez, Lautaro G; Edwards, Robert J; Kepler, Thomas B; Korber, Bette T; Kwong, Peter D; Mascola, John R; Acharya, Priyamvada; Haynes, Barton F; Montefiori, David C
    [This corrects the article DOI: 10.1371/journal.ppat.1008026.].
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    Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies.
    (Cell, 2021-05-18) Williams, Wilton B; Meyerhoff, R Ryan; Edwards, RJ; Li, Hui; Manne, Kartik; Nicely, Nathan I; Henderson, Rory; Zhou, Ye; Janowska, Katarzyna; Mansouri, Katayoun; Gobeil, Sophie; Evangelous, Tyler; Hora, Bhavna; Berry, Madison; Abuahmad, A Yousef; Sprenz, Jordan; Deyton, Margaret; Stalls, Victoria; Kopp, Megan; Hsu, Allen L; Borgnia, Mario J; Stewart-Jones, Guillaume BE; Lee, Matthew S; Bronkema, Naomi; Moody, M Anthony; Wiehe, Kevin; Bradley, Todd; Alam, S Munir; Parks, Robert J; Foulger, Andrew; Oguin, Thomas; Sempowski, Gregory D; Bonsignori, Mattia; LaBranche, Celia C; Montefiori, David C; Seaman, Michael; Santra, Sampa; Perfect, John; Francica, Joseph R; Lynn, Geoffrey M; Aussedat, Baptiste; Walkowicz, William E; Laga, Richard; Kelsoe, Garnett; Saunders, Kevin O; Fera, Daniela; Kwong, Peter D; Seder, Robert A; Bartesaghi, Alberto; Shaw, George M; Acharya, Priyamvada; Haynes, Barton F
    Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.
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    Functional Relevance of Improbable Antibody Mutations for HIV Broadly Neutralizing Antibody Development.
    (Cell host & microbe, 2018-06) Wiehe, Kevin; Bradley, Todd; Meyerhoff, R Ryan; Hart, Connor; Williams, Wilton B; Easterhoff, David; Faison, William J; Kepler, Thomas B; Saunders, Kevin O; Alam, S Munir; Bonsignori, Mattia; Haynes, Barton F
    HIV-1 broadly neutralizing antibodies (bnAbs) require high levels of activation-induced cytidine deaminase (AID)-catalyzed somatic mutations for optimal neutralization potency. Probable mutations occur at sites of frequent AID activity, while improbable mutations occur where AID activity is infrequent. One bottleneck for induction of bnAbs is the evolution of viral envelopes (Envs) that can select bnAb B cell receptors (BCR) with improbable mutations. Here we define the probability of bnAb mutations and demonstrate the functional significance of key improbable mutations in three bnAb B cell lineages. We show that bnAbs are enriched for improbable mutations, which implies that their elicitation will be critical for successful vaccine induction of potent bnAb B cell lineages. We discuss a mutation-guided vaccine strategy for identification of Envs that can select B cells with BCRs that have key improbable mutations required for bnAb development.
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    Host immunity associated with spontaneous suppression of viremia in therapy-naïve young rhesus macaques following neonatal SHIV infection.
    (Journal of virology, 2023-10) Evangelous, Tyler D; Berry, Madison; Venkatayogi, Sravani; LeMaster, Cas; Geanes, Eric S; De Naeyer, Nicole; DeMarco, Todd; Shen, Xiaoying; Li, Hui; Hora, Bhavna; Solomonis, Nicholas; Misamore, Johnathan; Lewis, Mark G; Denny, Thomas N; Montefiori, David; Shaw, George M; Wiehe, Kevin; Bradley, Todd; Williams, Wilton B
    We recently found that a new pathogenic chimeric simian-human immunodeficiency virus (SHIV) elicited heterologous human immunodeficiency virus type-1 (HIV-1) neutralizing antibodies (nAbs) in therapy-naïve young rhesus macaques (RMs) following neonatal SHIV infection. Moreover, a subset of the SHIV-infected young RMs spontaneously controlled viremia. Here we evaluated humoral and cellular immunity and plasma biomarkers associated with spontaneous viremia suppression in a new model of young SHIV-infected RMs that generated heterologous HIV-1 nAbs independent of viremia control to gain insights into pediatric immunity that may be harnessed by appropriate therapies in HIV-1-infected infants and children. We determined the levels of 31 plasma analytes (cytokines, chemokines, and growth factors) in SHIV-infected RMs over the course of infection and found that six analytes with chemoattractant or pro-inflammatory activities had significantly lower levels in plasma of RMs that controlled viremia compared to non-controllers. Single-cell transcriptomics of blood-derived immune cells demonstrated that RMs with viremia control had upregulated genes associated with immune activation and cytotoxic functions, whereas non-controllers had upregulated genes associated with immune cell exhaustion and dysfunction. In addition to CD8 T and natural killer cells, monocytes with upregulation of inhibitory genes previously reported only in cytotoxic cells constituted the immunologic environment associated with viremia suppression. These data implicated a complex immunologic milieu of viremia suppression that is not fully defined in pediatric subjects. Understanding immune cell subsets that may be harnessed to control viremia will provide insights into future designs of HIV-1 therapeutic strategies. IMPORTANCE Despite the advent of highly active anti-retroviral therapy, people are still dying from HIV-related causes, many of whom are children, and a protective vaccine or cure is needed to end the HIV pandemic. Understanding the nature and activation states of immune cell subsets during infection will provide insights into the immunologic milieu associated with viremia suppression that can be harnessed via therapeutic strategies to achieve a functional cure, but these are understudied in pediatric subjects. We evaluated humoral and adaptive host immunity associated with suppression of viremia in rhesus macaques infected soon after birth with a pathogenic SHIV. The results from our study provide insights into the immune cell subsets and functions associated with viremia control in young macaques that may translate to pediatric subjects for the design of future anti-viral strategies in HIV-1-infected infants and children and contribute to an understudied area of HIV-1 pathogenesis in pediatric subjects.
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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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    Neonatal Rhesus Macaques Have Distinct Immune Cell Transcriptional Profiles following HIV Envelope Immunization.
    (Cell reports, 2020-02) Han, Qifeng; Bradley, Todd; Williams, Wilton B; Cain, Derek W; Montefiori, David C; Saunders, Kevin O; Parks, Robert J; Edwards, Regina W; Ferrari, Guido; Mueller, Olaf; Shen, Xiaoying; Wiehe, Kevin J; Reed, Steven; Fox, Christopher B; Rountree, Wes; Vandergrift, Nathan A; Wang, Yunfei; Sutherland, Laura L; Santra, Sampa; Moody, M Anthony; Permar, Sallie R; Tomaras, Georgia D; Lewis, Mark G; Van Rompay, Koen KA; Haynes, Barton F
    HIV-1-infected infants develop broadly neutralizing antibodies (bnAbs) more rapidly than adults, suggesting differences in the neonatal versus adult responses to the HIV-1 envelope (Env). Here, trimeric forms of HIV-1 Env immunogens elicit increased gp120- and gp41-specific antibodies more rapidly in neonatal macaques than adult macaques. Transcriptome analyses of neonatal versus adult immune cells after Env vaccination reveal that neonatal macaques have higher levels of the apoptosis regulator BCL2 in T cells and lower levels of the immunosuppressive interleukin-10 (IL-10) receptor alpha (IL10RA) mRNA transcripts in T cells, B cells, natural killer (NK) cells, and monocytes. In addition, immunized neonatal macaques exhibit increased frequencies of activated blood T follicular helper-like (Tfh) cells compared to adults. Thus, neonatal macaques have transcriptome signatures of decreased immunosuppression and apoptosis compared with adult macaques, providing an immune landscape conducive to early-life immunization prior to sexual debut.
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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.
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    Stabilized HIV-1 envelope immunization induces neutralizing antibodies to the CD4bs and protects macaques against mucosal infection.
    (Science translational medicine, 2022-09) Saunders, Kevin O; Edwards, Robert J; Tilahun, Kedamawit; Manne, Kartik; Lu, Xiaozhi; Cain, Derek W; Wiehe, Kevin; Williams, Wilton B; Mansouri, Katayoun; Hernandez, Giovanna E; Sutherland, Laura; Scearce, Richard; Parks, Robert; Barr, Maggie; DeMarco, Todd; Eater, Chloe M; Eaton, Amanda; Morton, Georgeanna; Mildenberg, Benjamin; Wang, Yunfei; Rountree, R Wes; Tomai, Mark A; Fox, Christopher B; Moody, M Anthony; Alam, S Munir; Santra, Sampa; Lewis, Mark G; Denny, Thomas N; Shaw, George M; Montefiori, David C; Acharya, Priyamvada; Haynes, Barton F
    A successful HIV-1 vaccine will require induction of a polyclonal neutralizing antibody (nAb) response, yet vaccine-mediated induction of such a response in primates remains a challenge. We found that a stabilized HIV-1 CH505 envelope (Env) trimer formulated with a Toll-like receptor 7/8 agonist induced potent HIV-1 polyclonal nAbs that correlated with protection from homologous simian-human immunodeficiency virus (SHIV) infection. The serum dilution that neutralized 50% of virus replication (ID50 titer) required to protect 90% of macaques was 1:364 against the challenge virus grown in primary rhesus CD4+ T cells. Structural analyses of vaccine-induced nAbs demonstrated targeting of the Env CD4 binding site or the N156 glycan and the third variable loop base. Autologous nAb specificities similar to those elicited in macaques by vaccination were isolated from the human living with HIV from which the CH505 Env immunogen was derived. CH505 viral isolates were isolated that mutated the V1 to escape both the infection-induced and vaccine-induced antibodies. These results define the specificities of a vaccine-induced nAb response and the protective titers of HIV-1 vaccine-induced nAbs required to protect nonhuman primates from low-dose mucosal challenge by SHIVs bearing a primary transmitted/founder Env.