Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells

Bonsmann, Michael Storcksdieck genannt; Niezold, Thomas; Temchura, Vladimir; Pissani, Franco; Ehrhardt, Katrin; Brown, Eric N.; Osei-Owusu, Nana Yaw; Hannaman, Drew; Hengel, Hartmut; Ackerman, Margaret E.; Streeck, Hendrik; Nabi, Ghulam; Tenbusch, Matthias; Überla, Klaus

doi:10.4049/jimmunol.1501377

Cited by 34 publications

(54 citation statements)

References 81 publications

(108 reference statements)

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“…Immediately following the DNA injection, in vivo electroporation was performed using the BTX AgilePulse system (BTX Molecular Delivery Systems, Holliston, MA) or the Ichor electroporation system (Ichor Medical Systems, San Diego, CA) using electroporation protocols described before [56, 57]. Electroporation with both devices gave similar results.…”

Section: Methodsmentioning

confidence: 99%

Interference of retroviral envelope with vaccine-induced CD8+ T cell responses is relieved by co-administration of cytokine-encoding vectors

Bongard¹,

Lapuente

Windmann³

et al. 2017

Retrovirology

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BackgroundRetroviral envelope (Env) proteins are known to exhibit immunosuppressive properties, which become apparent not only in retroviral infections, but also in gene-based immunizations using retroviral immunogens, where envelope interferes with the induction of CD8+ T cell responses towards another, simultaneously or subsequently delivered, immunogen.ResultsIn the Friend retrovirus mouse model, immunization with a plasmid encoding the Friend murine leukemia virus (F-MuLV) Leader-Gag protein resulted in induction of a strong GagL85–93-specific CD8+ T cell response, while the response was completely abrogated by co-immunization with an F-MuLV Env-encoding plasmid. In order to overcome this interference of retroviral envelope, we employed plasmids encoding the cytokines interleukin (IL) 1β, IL2, IL12, IL15, IL21, IL28A or granulocyte–macrophage colony-stimulating factor (GM-CSF) as genetic adjuvants. Co-application of plasmids encoding IL2, IL12, IL21, IL28A and especially GM-CSF rescued the induction of GagL85–93-specific CD8+ T cells in mice vaccinated with FV Leader-Gag and Env. Mice that were immunized with plasmids encoding Leader-Gag and Env and the cytokines IL1β, IL12, IL15, IL28A or GM-CSF, but not Leader-Gag and Env without any cytokine, showed significantly reduced viral loads upon a high-dose Friend virus challenge infection.ConclusionsOur data demonstrate the potency of cytokine-encoding vectors as adjuvants and immune modulators in composite vaccines for anti-retroviral immunization.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-017-0352-7) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Interference of retroviral envelope with vaccine-induced CD8+ T cell responses is relieved by co-administration of cytokine-encoding vectors

Bongard¹,

Lapuente

Windmann³

et al. 2017

Retrovirology

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“…HIV-1 Env-specific T cell responses in the spleens were detected by intracellular cytokine staining (ICS) as previously described [12]. Briefly, mice were sacrificed, spleens removed, and single-cell suspensions prepared by homogenization through a 70 µm cell strainer (Corning Inc., Corning, Harrodsburg, KY, USA).…”

Section: Analysis Of Cellular Immune Responsesmentioning

confidence: 99%

“…However, in contrast to the surface proteins of RSV and Influenza A, i.m. EP of plasmids encoding for HIV-1 Env elicits an antibody response strongly biased towards the T H 2-associated IgG1 subclass in mice [11,12].…”

Section: Introductionmentioning

confidence: 99%

Modulation of Vaccine-Induced HIV-1-Specific Immune Responses by Co-Electroporation of PD-L1 Encoding DNA

et al. 2020

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The importance of a balanced TH1/TH2 humoral immune response against the HIV-1 envelope protein (Env) for antibody-mediated HIV-1 control is increasingly recognized. However, there is no defined vaccination strategy to raise it. Since immune checkpoints are involved in the induction of adoptive immunity and their inhibitors (monoclonal antibodies) are licensed for cancer therapy, we investigated the effect of checkpoint blockade after HIV-1 genetic vaccination on enhancement and modulation of antiviral antibody responses. By intraperitoneal administration of checkpoint antibodies in mice we observed an induction of anti-drug antibodies which may interfere with immunomodulation by checkpoint inhibitors. Therefore, we blocked immune checkpoints locally by co-electroporation of DNA vaccines encoding the active soluble ectodomains of programmed cell death protein-1 (PD-1) or its ligand (PD-L1), respectively. Plasmid-encoded immune checkpoints did not elicit a detectable antibody response, suggesting no interference with their immunomodulatory effects. Co-electroporation of a HIV-1 DNA vaccine formulation with soluble PD-L1 ectodomain increased HIV-1 Env-specific TH1 CD4 T cell and IgG2a antibody responses. The overall antibody response was hereby shifted towards a more TH1/TH2 balanced subtype pattern. These findings indicate that co-electroporation of soluble checkpoint ectodomains together with DNA-based vaccines has modulatory effects on vaccine-induced immune responses that could improve vaccine efficacies.

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“…Using these high-throughput biophysical and functional profiling, "Systems Serology" approaches, we have begun to define protective humoral immune response signatures among vaccinees and naturally infected cohorts. 11,[21][22][23][24][25][26][27][28][29][30][31][32][33][34] In parallel, diverse vaccine regimens with varying levels of protective efficacy have been tested in nonhuman primates. 32,33,64,67,68 Application of these Systems Serology approaches has begun to identify novel correlates of vaccine-mediated protection 32,33 and provides a strong rationale for their continued use and further expansion in support of future clinical vaccine development.…”

Section: Systems Serology 20mentioning

confidence: 99%

“…Techniques capable of parsing this milieu into components that can be associated with other relevant clinical, genetic, or functional characteristics are beginning to demonstrate utility in affording enabling insights into humoral immunity via statistically principled analysis of humoral response profiles and relationships between antibody features, antibody functions, and clinical outcomes. 11,[21][22][23][24][25][26][27][28][29][30][31][32][33][34] The resulting integrated analytical approach to objectively and broadly characterize diverse aspects of the humoral immune response in vaccine efficacy studies or by evaluation of natural disease resistance offers an enhanced ability to identify unanticipated correlates of protection, direct the selection of promising vaccines/immunogens, and define mechanisms of protective immunity. 21…”

Section: Introductionmentioning

confidence: 99%

Systems serology for evaluation of HIV vaccine trials

Ackerman

Barouch

Alter

2017

Immunological Reviews

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Summary The scale and scope of the global epidemic, coupled to challenges with traditional vaccine development approaches, point towards a need for novel methodologies for HIV vaccine research. While the development of vaccines able to induce broadly neutralizing antibodies remains the ultimate goal, to date vaccines continue to fail to induce these rare humoral immune responses. Conversely, growing evidence across vaccine platforms in both non-human primates and humans, point to a role for polyclonal vaccine-induced antibody responses in protection from infection. These candidate vaccines, despite employing disparate viral vectors and immunization strategies, consistently point to a role for functional or non-traditional antibody activities as correlates of immunity. However, the precise mechanism(s) of action of these “binding” antibodies, their specific characteristics, and ability to be selectively induced and/or potentiated to induce complete protection merits parallel investigation to neutralizing antibody-based vaccine design approaches. Ultimately while neutralizing and functional antibody-based vaccine strategies need not be mutually exclusive, defining the specific characteristics of “protective” functional antibodies may provide a target immune profile to potentially induce more robust immunity against HIV. Specifically, one approach to guide the development of functional antibody based vaccine strategies, termed “systems serology”, offers an unbiased and comprehensive approach to systematically survey humoral immune responses, capturing the array of functions and humoral response characteristics that may be induced following vaccination with high resolution. Coupled to machine learning tools, large datasets that explore the “antibody-ome” offer a means to step back from anticipated correlates and mechanisms of protection and toward a more fundamental understanding of coordinated aspects of humoral immune responses, their ability to more globally differentiate among vaccine candidates, and most critically, to identify the features of humoral immunity that distinguish protective from non-protective responses. Overall, the systematic serological approach described here aimed at broadly capturing the enormous biodiversity in antibody profiles that may emerge following vaccination complements existing cutting edge tools in the cellular immunology space that capture vaccine-induced polyfunctional cellular activity by flow cytometry, transcriptional profiling, epigenetic, and metabolomic analysis to offer a means to develop both a more nuanced and more complete understanding of correlates of protection to support the design of functional vaccine strategies.

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Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells

Cited by 34 publications

References 81 publications

Interference of retroviral envelope with vaccine-induced CD8+ T cell responses is relieved by co-administration of cytokine-encoding vectors

Interference of retroviral envelope with vaccine-induced CD8+ T cell responses is relieved by co-administration of cytokine-encoding vectors

Modulation of Vaccine-Induced HIV-1-Specific Immune Responses by Co-Electroporation of PD-L1 Encoding DNA

Systems serology for evaluation of HIV vaccine trials

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