IDLV-HIV-1 Env vaccination in non-human primates induces affinity maturation of antigen-specific memory B cells

Blasi, Maria Di; Negri, Donatella; LaBranche, Celia C.; Alam, S. Munir; Baker, Erich J.; Brunner, E.; Gladden, Morgan A.; Michelini, Zuleika; Vandergrift, Nathan; Wiehe, Kevin; Parks, Robert; Shen, Xiaoying; Bonsignori, Mattia; Tomaras, Georgia D.; Ferrari, Guido; Montefiori, David C.; Santra, Sampa; Haynes, Barton F.; Moody, M. Anthony; Cara, Andrea; Klotman, Mary E.

doi:10.1038/s42003-018-0131-6

Cited by 29 publications

(38 citation statements)

References 64 publications

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“…Rhesus B cell staining and sorting of strain-specific mAbs. CH505 gp120 T/F CD4bs-specific antibodies were isolated from memory B cells in PBMCs, lymph node or bone marrow collected at weeks 20, 24, 32 and 52 using two approaches: direct single-cell sorting into PCR plates (weeks 20, 32 and 52) (26,90), and memory B cell cultures (week 24) (91,92). For direct sorting, we performed singlecell isolation of memory B cells decorated with AlexaFluor® 647 (AF647) or Brilliant Violet 421 (BV421)tagged HIV-1 CH505 TF gp120 using a BD FACSAria™ or a BD FACSAria™ II (BD Biosciences, San Jose, CA), as previously described (26).…”

Section: Shiv Construction and Characterizationmentioning

confidence: 99%

Recapitulation of HIV-1 Env-Antibody Coevolution in Macaques Leading to Neutralization Breadth

Roark

Williams

et al. 2020

Preprint

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Neutralizing antibodies elicited by HIV-1 coevolve with viral Envs in distinctive patterns, in some cases acquiring substantial breadth. Here we show that primary HIV-1 Envs, 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-amino 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/PCT64-35M. 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.One sentence summaryVirus-antibody coevolution in rhesus macaques recapitulates developmental features of human antibodies.

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Section: Shiv Construction and Characterizationmentioning

confidence: 99%

Recapitulation of HIV-1 Env-Antibody Coevolution in Macaques Leading to Neutralization Breadth

Roark

Williams

et al. 2020

Preprint

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“…Integrase-defective lentiviral vectors (IDLV) are also very safe and have several advantages, such as induction of strong and long-lasting antigen-specific responses related to long DNA persistence in tissues [270]. A single dose of IDLV encoding for HIV-1 transmitter/founder (T/F) 1086c Env induced specific Ab titres that waned by less than four-fold in a one-year period [271].…”

Section: Viral-vectored Vaccinesmentioning

confidence: 99%

Strategies for inducing effective neutralizing antibody responses against HIV-1

Moral-Sánchez

Sliepen

2019

Expert Review of Vaccines

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Introduction: Despite intensive research efforts, there is still no effective prophylactic vaccine available against HIV-1. Currently, substantial efforts are devoted to the development of vaccines aimed at inducing broadly neutralizing antibodies (bNAbs), which are capable of neutralizing most HIV-1 strains. All bNAbs target the HIV-1 envelope glycoprotein (Env), but Env immunizations usually only induce neutralizing antibodies (NAbs) against the sequence-matched virus and not against other strains. Areas covered: We describe the different strategies that have been explored to improve the breadth and potency of anti-HIV-1 NAb responses. The discussed strategies include the application of engineered Env immunogens, optimization of (bNAb) epitopes, different cocktail and sequential vaccination strategies, nanoparticles and nucleic acid-based vaccines. Expert opinion: A combination of the strategies described in this review and future approaches are probably needed to develop an effective HIV-1 vaccine that can induce broad, potent and long-lasting NAb responses.

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Section: Introductionmentioning

confidence: 99%

“…We have shown, in both mice and macaque studies, that integrase defective lentiviral vectors (IDLV) provide prolonged antigen expression and can induce potent and durable antigenspecific immune responses [9][10][11][12][13] . We demonstrated that immunization with an SIV-based IDLV expressing an HIV-1 Env induces continued antibody affinity maturation up to three months postprime, which is further improved upon additional IDLV-Env immunizations 12 . Furthermore we demonstrated persistent antigen expression at the site of injection up to three months post intramuscular immunization 12,14 , suggesting a direct correlation between continuous antigen expression by IDLV and durability of antigen-specific immune responses 14 .…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity, safety, and efficacy of sequential immunizations with an SIV-based IDLV expressing CH505 Envs

et al. 2020

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A preventative HIV-1 vaccine is an essential intervention needed to halt the HIV-1 pandemic. Neutralizing antibodies protect against HIV-1 infection in animal models, and thus an approach toward a protective HIV-1 vaccine is to induce broadly cross-reactive neutralizing antibodies (bnAbs). One strategy to achieve this goal is to define envelope (Env) evolution that drives bnAb development in infection and to recreate those events by vaccination. In this study, we report the immunogenicity, safety, and efficacy in rhesus macaques of an SIV-based integrase defective lentiviral vector (IDLV) expressing sequential gp140 Env immunogens derived from the CH505 HIV-1-infected individual who made the CH103 and CH235 bnAb lineages. Immunization with IDLV expressing sequential CH505 Envs induced higher magnitude and more durable binding and neutralizing antibody responses compared to protein or DNA +/− protein immunizations using the same sequential envelopes. Compared to monkeys immunized with a vector expressing Envs alone, those immunized with the combination of IDLV expressing Env and CH505 Env protein demonstrated improved durability of antibody responses at six months after the last immunization as well as lower peak viremia and better virus control following autologous SHIV-CH505 challenge. There was no evidence of vector mobilization or recombination in the immunized and challenged monkeys. Although the tested vaccines failed to induce bnAbs and to mediate significant protection following SHIV-challenge, our results show that IDLV proved safe and successful at inducing higher titer and more durable immune responses compared to other vaccine platforms.

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IDLV-HIV-1 Env vaccination in non-human primates induces affinity maturation of antigen-specific memory B cells

Cited by 29 publications

References 64 publications

Recapitulation of HIV-1 Env-Antibody Coevolution in Macaques Leading to Neutralization Breadth

Recapitulation of HIV-1 Env-Antibody Coevolution in Macaques Leading to Neutralization Breadth

Strategies for inducing effective neutralizing antibody responses against HIV-1

Immunogenicity, safety, and efficacy of sequential immunizations with an SIV-based IDLV expressing CH505 Envs

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