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  1. Article ; Online: HIV mRNA Vaccines—Progress and Future Paths

    Zekun Mu / Barton F. Haynes / Derek W. Cain

    Vaccines, Vol 9, Iss 2, p

    2021  Volume 134

    Abstract: The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host’s cells to manufacture protein ... ...

    Abstract The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host’s cells to manufacture protein immunogens which, in turn, are targets for antibody and cytotoxic T cell responses. mRNA-based vaccines have been the subject of research for over three decades as a platform to protect against or treat a variety of cancers, amyloidosis and infectious diseases. In this review, we discuss mRNA-based approaches for the generation of prophylactic and therapeutic vaccines to HIV. We examine the special immunological hurdles for a vaccine to elicit broadly neutralizing antibodies and effective T cell responses to HIV. Lastly, we outline an mRNA-based HIV vaccination strategy based on the immunobiology of broadly neutralizing antibody development.
    Keywords HIV ; vaccine ; messenger RNA ; Medicine ; R
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Neonatal SHIV infection in rhesus macaques elicited heterologous HIV-1-neutralizing antibodies

    Bhavna Hora / Hui Li / Xiaoying Shen / Mitchell Martin / Yue Chen / Madison Berry / Tyler Evangelous / Andrew N. Macintyre / Aria Arus-Altuz / Shuyi Wang / Ajay Singh / Chengyan Zhao / Nicole De Naeyer / Todd DeMarco / Cindy Kuykendall / Thaddeus Gurley / Kevin O. Saunders / Thomas Denny / M. Anthony Moody /
    John Misamore / Mark G. Lewis / Kevin Wiehe / Derek W. Cain / David C. Montefiori / George M. Shaw / Wilton B. Williams

    Cell Reports, Vol 42, Iss 3, Pp 112255- (2023)

    2023  

    Abstract: Summary: Infants and children infected with human immunodeficiency virus (HIV)-1 have been shown to develop neutralizing antibodies (nAbs) against heterologous HIV-1 strains, characteristic of broadly nAbs (bnAbs). Thus, having a neonatal model for the ... ...

    Abstract Summary: Infants and children infected with human immunodeficiency virus (HIV)-1 have been shown to develop neutralizing antibodies (nAbs) against heterologous HIV-1 strains, characteristic of broadly nAbs (bnAbs). Thus, having a neonatal model for the induction of heterologous HIV-1 nAbs may provide insights into the mechanisms of neonatal bnAb development. Here, we describe a neonatal model for heterologous HIV-1 nAb induction in pathogenic simian-HIV (SHIV)-infected rhesus macaques (RMs). Viral envelope (env) evolution showed mutations at multiple sites, including nAb epitopes. All 13 RMs generated plasma autologous HIV-1 nAbs. However, 8/13 (62%) RMs generated heterologous HIV-1 nAbs with increasing potency over time, albeit with limited breadth, and mapped to multiple nAb epitopes, suggestive of a polyclonal response. Moreover, plasma heterologous HIV-1 nAb development was associated with antigen-specific, lymph-node-derived germinal center activity. We define a neonatal model for heterologous HIV-1 nAb induction that may inform future pediatric HIV-1 vaccines for bnAb induction in infants and children.
    Keywords CP: Immunology ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: HIV envelope antigen valency on peptide nanofibers modulates antibody magnitude and binding breadth

    Chelsea N. Fries / Jui-Lin Chen / Maria L. Dennis / Nicole L. Votaw / Joshua Eudailey / Brian E. Watts / Kelly M. Hainline / Derek W. Cain / Richard Barfield / Cliburn Chan / M. Anthony Moody / Barton F. Haynes / Kevin O. Saunders / Sallie R. Permar / Genevieve G. Fouda / Joel H. Collier

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 15

    Abstract: Abstract A major challenge in developing an effective vaccine against HIV-1 is the genetic diversity of its viral envelope. Because of the broad range of sequences exhibited by HIV-1 strains, protective antibodies must be able to bind and neutralize a ... ...

    Abstract Abstract A major challenge in developing an effective vaccine against HIV-1 is the genetic diversity of its viral envelope. Because of the broad range of sequences exhibited by HIV-1 strains, protective antibodies must be able to bind and neutralize a widely mutated viral envelope protein. No vaccine has yet been designed which induces broadly neutralizing or protective immune responses against HIV in humans. Nanomaterial-based vaccines have shown the ability to generate antibody and cellular immune responses of increased breadth and neutralization potency. Thus, we have developed supramolecular nanofiber-based immunogens bearing the HIV gp120 envelope glycoprotein. These immunogens generated antibody responses that had increased magnitude and binding breadth compared to soluble gp120. By varying gp120 density on nanofibers, we determined that increased antigen valency was associated with increased antibody magnitude and germinal center responses. This study presents a proof-of-concept for a nanofiber vaccine platform generating broad, high binding antibody responses against the HIV-1 envelope glycoprotein.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Mouse and human antibodies bind HLA-E-leader peptide complexes and enhance NK cell cytotoxicity

    Dapeng Li / Simon Brackenridge / Lucy C. Walters / Olivia Swanson / Karl Harlos / Daniel Rozbesky / Derek W. Cain / Kevin Wiehe / Richard M. Scearce / Maggie Barr / Zekun Mu / Robert Parks / Max Quastel / Robert J. Edwards / Yunfei Wang / Wes Rountree / Kevin O. Saunders / Guido Ferrari / Persephone Borrow /
    E. Yvonne Jones / S. Munir Alam / Mihai L. Azoitei / Geraldine M. Gillespie / Andrew J. McMichael / Barton F. Haynes

    Communications Biology, Vol 5, Iss 1, Pp 1-

    2022  Volume 17

    Abstract: The identification and structural analysis of HLA-E-VL9-targeting antibodies that block a natural killer (NK) cell receptor pathway and regulate NK function in vitro. ...

    Abstract The identification and structural analysis of HLA-E-VL9-targeting antibodies that block a natural killer (NK) cell receptor pathway and regulate NK function in vitro.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Inflammation triggers emergency granulopoiesis through a density-dependent feedback mechanism.

    Derek W Cain / Pilar B Snowden / Gregory D Sempowski / Garnett Kelsoe

    PLoS ONE, Vol 6, Iss 5, p e

    2011  Volume 19957

    Abstract: Normally, neutrophil pools are maintained by homeostatic mechanisms that require the transcription factor C/EBPα. Inflammation, however, induces neutrophilia through a distinct pathway of "emergency" granulopoiesis that is dependent on C/EBPβ. Here, we ... ...

    Abstract Normally, neutrophil pools are maintained by homeostatic mechanisms that require the transcription factor C/EBPα. Inflammation, however, induces neutrophilia through a distinct pathway of "emergency" granulopoiesis that is dependent on C/EBPβ. Here, we show in mice that alum triggers emergency granulopoiesis through the IL-1RI-dependent induction of G-CSF. G-CSF/G-CSF-R neutralization impairs proliferative responses of hematopoietic stem and progenitor cells (HSPC) to alum, but also abrogates the acute mobilization of BM neutrophils, raising the possibility that HSPC responses to inflammation are an indirect result of the exhaustion of BM neutrophil stores. The induction of neutropenia, via depletion with Gr-1 mAb or myeloid-specific ablation of Mcl-1, elicits G-CSF via an IL-1RI-independent pathway, stimulating granulopoietic responses indistinguishable from those induced by adjuvant. Notably, C/EBPβ, thought to be necessary for enhanced generative capacity of BM, is dispensable for increased proliferation of HSPC to alum or neutropenia, but plays a role in terminal neutrophil differentiation during granulopoietic recovery. We conclude that alum elicits a transient increase in G-CSF production via IL-1RI for the mobilization of BM neutrophils, but density-dependent feedback sustains G-CSF for accelerated granulopoiesis.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2011-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Engineered immunogens to elicit antibodies against conserved coronavirus epitopes

    A. Brenda Kapingidza / Daniel J. Marston / Caitlin Harris / Daniel Wrapp / Kaitlyn Winters / Dieter Mielke / Lu Xiaozhi / Qi Yin / Andrew Foulger / Rob Parks / Maggie Barr / Amanda Newman / Alexandra Schäfer / Amanda Eaton / Justine Mae Flores / Austin Harner / Nicholas J. Catanzaro / Michael L. Mallory / Melissa D. Mattocks /
    Christopher Beverly / Brianna Rhodes / Katayoun Mansouri / Elizabeth Van Itallie / Pranay Vure / Brooke Dunn / Taylor Keyes / Sherry Stanfield-Oakley / Christopher W. Woods / Elizabeth A. Petzold / Emmanuel B. Walter / Kevin Wiehe / Robert J. Edwards / David C. Montefiori / Guido Ferrari / Ralph Baric / Derek W. Cain / Kevin O. Saunders / Barton F. Haynes / Mihai L. Azoitei

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 18

    Abstract: Abstract Immune responses to SARS-CoV-2 primarily target the receptor binding domain of the spike protein, which continually mutates to escape acquired immunity. Other regions in the spike S2 subunit, such as the stem helix and the segment encompassing ... ...

    Abstract Abstract Immune responses to SARS-CoV-2 primarily target the receptor binding domain of the spike protein, which continually mutates to escape acquired immunity. Other regions in the spike S2 subunit, such as the stem helix and the segment encompassing residues 815-823 adjacent to the fusion peptide, are highly conserved across sarbecoviruses and are recognized by broadly reactive antibodies, providing hope that vaccines targeting these epitopes could offer protection against both current and emergent viruses. Here we employ computational modeling to design scaffolded immunogens that display the spike 815-823 peptide and the stem helix epitopes without the distracting and immunodominant receptor binding domain. These engineered proteins bind with high affinity and specificity to the mature and germline versions of previously identified broadly protective human antibodies. Epitope scaffolds interact with both sera and isolated monoclonal antibodies with broadly reactivity from individuals with pre-existing SARS-CoV-2 immunity. When used as immunogens, epitope scaffolds elicit sera with broad betacoronavirus reactivity and protect as “boosts” against live virus challenge in mice, illustrating their potential as components of a future pancoronavirus vaccine.
    Keywords Science ; Q
    Subject code 570
    Language English
    Publishing date 2023-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Immune checkpoint modulation enhances HIV-1 antibody induction

    Todd Bradley / Masayuki Kuraoka / Chen-Hao Yeh / Ming Tian / Huan Chen / Derek W. Cain / Xuejun Chen / Cheng Cheng / Ali H. Ellebedy / Robert Parks / Maggie Barr / Laura L. Sutherland / Richard M. Scearce / Cindy M. Bowman / Hilary Bouton-Verville / Sampa Santra / Kevin Wiehe / Mark G. Lewis / Ane Ogbe /
    Persephone Borrow / David Montefiori / Mattia Bonsignori / M. Anthony Moody / Laurent Verkoczy / Kevin O. Saunders / Rafi Ahmed / John R. Mascola / Garnett Kelsoe / Frederick W. Alt / Barton F. Haynes

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 16

    Abstract: Elucidation of broadly neutralizing antibodies (bnAb) is a goal in HIV vaccine development. Here, Bradley et al. show that administration of CTLA-4 blocking antibody with vaccine antigens increases HIV-1 envelope antibody responses in macaques and a bnAb ...

    Abstract Elucidation of broadly neutralizing antibodies (bnAb) is a goal in HIV vaccine development. Here, Bradley et al. show that administration of CTLA-4 blocking antibody with vaccine antigens increases HIV-1 envelope antibody responses in macaques and a bnAb precursor mouse model.
    Keywords Science ; Q
    Language English
    Publishing date 2020-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Neonatal Rhesus Macaques Have Distinct Immune Cell Transcriptional Profiles following HIV Envelope Immunization

    Qifeng Han / Todd Bradley / Wilton B. Williams / Derek W. Cain / David C. Montefiori / Kevin O. Saunders / Robert J. Parks / Regina W. Edwards / Guido Ferrari / Olaf Mueller / Xiaoying Shen / Kevin J. Wiehe / Steven Reed / Christopher B. Fox / Wes Rountree / Nathan A. Vandergrift / Yunfei Wang / Laura L. Sutherland / Sampa Santra /
    M. Anthony Moody / Sallie R. Permar / Georgia D. Tomaras / Mark G. Lewis / Koen K.A. Van Rompay / Barton F. Haynes

    Cell Reports, Vol 30, Iss 5, Pp 1553-1569.e

    2020  Volume 6

    Abstract: Summary: 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 ... ...

    Abstract Summary: 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. : Han et al. demonstrate that infant macaques are capable of responding to HIV vaccines currently studied in human clinical trials. The nature of the neonatal immune system following immunization also suggests a state permissive for generating HIV-1 antibodies. Thus, infant HIV-1 immunization remains a viable strategy to end this pandemic. Keywords: neonates, HIV-1 envelope, immunization, transcriptome, rhesus macaques, single-cell RNA sequencing
    Keywords Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2020-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models

    Kevin O. Saunders / Laurent K. Verkoczy / Chuancang Jiang / Jinsong Zhang / Robert Parks / Haiyan Chen / Max Housman / Hilary Bouton-Verville / Xiaoying Shen / Ashley M. Trama / Richard Scearce / Laura Sutherland / Sampa Santra / Amanda Newman / Amanda Eaton / Kai Xu / Ivelin S. Georgiev / M. Gordon Joyce / Georgia D. Tomaras /
    Mattia Bonsignori / Steven G. Reed / Andres Salazar / John R. Mascola / M. Anthony Moody / Derek W. Cain / Mireille Centlivre / Sandra Zurawski / Gerard Zurawski / Harold P. Erickson / Peter D. Kwong / S. Munir Alam / Yves Levy / David C. Montefiori / Barton F. Haynes

    Cell Reports, Vol 21, Iss 13, Pp 3681-

    2017  Volume 3690

    Abstract: The events required for the induction of broad neutralizing antibodies (bnAbs) following HIV-1 envelope (Env) vaccination are unknown, and their induction in animal models as proof of concept would be critical. Here, we describe the induction of plasma ... ...

    Abstract The events required for the induction of broad neutralizing antibodies (bnAbs) following HIV-1 envelope (Env) vaccination are unknown, and their induction in animal models as proof of concept would be critical. Here, we describe the induction of plasma antibodies capable of neutralizing heterologous primary (tier 2) HIV-1 strains in one macaque and two rabbits. Env immunogens were designed to induce CD4 binding site (CD4bs) bnAbs, but surprisingly, the macaque developed V1V2-glycan bnAbs. Env immunization of CD4bs bnAb heavy chain rearrangement (VHDJH) knockin mice similarly induced V1V2-glycan neutralizing antibodies (nAbs), wherein the human CD4bs VH chains were replaced with mouse rearrangements bearing diversity region (D)-D fusions, creating antibodies with long, tyrosine-rich HCDR3s. Our results show that Env vaccination can elicit broad neutralization of tier 2 HIV-1, demonstrate that V1V2-glycan bnAbs are more readily induced than CD4bs bnAbs, and define VH replacement and diversity region fusion as potential mechanisms for generating V1V2-glycan bnAb site antibodies.
    Keywords HIV vaccine ; broadly neutralizing antibodies ; knockin mice ; CH103 ; CH505 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2017-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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