NFκB activation by modified vaccinia virus as a novel strategy to enhance neutrophil migration and HIV-specific T-cell responses

Pilato, Mauro Di; Mejías-Pérez, Ernesto; Zonca, Manuela; Perdiguero, Beatriz; Gómez, Carmen Elena; Trakala, Marianna; Nieto, Jacobo; Nájera, José Luis; Sorzano, Carlos Óscar S.; Combadière, Christophe; Pantaleo, Giuseppe; Planelles, Lourdes; Esteban, Mariano

doi:10.1073/pnas.1424341112

Cited by 29 publications

(61 citation statements)

References 55 publications

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“…Neutrophils cross-prime naive T cells and induce adaptive immune responses (40,41). A52R, B15R, and K7R gene deletion enhances chemokines that can directly induce neutrophil migration, and thus HIV-specific CD8 T cell and IgG responses, which supports neutrophil mediation of HIV immune responses (18). NK cells also mediate adaptive immune responses (42), and A52, B15, and K7 together are needed to reduce NK cell migration Attenuated VACV vectors (NYVAC and MVA) are used as vaccine candidates for emerging infectious diseases and cancer in humans (43).…”

Section: Discussionmentioning

confidence: 89%

“…To study the ability of NYVAC-C deletion mutants to induce HIV-specific adaptive cellular responses, we tested a heterologous DNA prime/poxvirus boost immunization regimen in BALB/c mice, a protocol widely used to enhance immune responses to HIV antigens (18,25). At 11 days after the last immunization, splenocytes from NYVAC-C-or NYVAC-C deletion mutant-infected mice were stimulated with HIV-1 Pol-1, Pol-2, or Gag-Pool (representing 60 peptides of Gag-1 plus 61 peptides of Gag-2) to study HIV-1-specific CD8 T cell responses (32).…”

Section: Resultsmentioning

confidence: 99%

“…A52, K7, and B15 vaccinia virus proteins, members of the B cell lymphoma-2 family (Bcl-2) (33,34), have an important NF-B inhibitory role (18) and thus induce suppression and evasion of host immune responses (14). During infection, A52 and K7 interact with TRAF6 and inhibit its kinase activity (15,16), whereas B15 binds the IKK complex to inhibit IB␣ phosphorylation and degradation (17).…”

Section: Discussionmentioning

confidence: 99%

“…A52 and K7 block IRAK2 and TRAF6 activation (15,16), and B15 inhibits IB␣ phosphorylation and proteasome degradation (17), thus avoiding release of the NF-B complex into the cell nucleus. NYVAC infection limits NF-B binding to the B site and transcription of proinflammatory cytokine and chemokine genes (18).…”

mentioning

confidence: 99%

“…The effect of their concomitant ablation on increased neutrophil migration and HIV-specific CD8 T cell responses has been studied (18). Here we used NYVAC-C (18) to define the specific role of single, double, and triple deletion of these genes in innate and adaptive HIV-specific cell-mediated and humoral responses.…”

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confidence: 99%

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Distinct Roles of Vaccinia Virus NF-κB Inhibitor Proteins A52, B15, and K7 in the Immune Response

Pilato

Mejías-Pérez

Sorzano

et al. 2017

J Virol

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Poxviruses use a complex strategy to escape immune control, by expressing immunomodulatory proteins that could limit their use as vaccine vectors. To test the role of poxvirus NF-B pathway inhibitors A52, B15, and K7 in immunity, we deleted their genes in an NYVAC (New York vaccinia virus) strain that expresses HIV-1 clade C antigens. After infection of mice, ablation of the A52R, B15R, and K7R genes increased dendritic cell, natural killer cell, and neutrophil migration as well as chemokine/cytokine expression. Revertant viruses with these genes confirmed their role in inhibiting the innate immune system. To different extents, enhanced innate immune responses correlated with increased HIV Pol-and Gag-specific polyfunctional CD8 T cell and HIV Env-specific IgG responses induced by single-, double-, and triple-deletion mutants. These poxvirus proteins thus influence innate and adaptive cell-mediated and humoral immunity, and their ablation offers alternatives for design of vaccine vectors that regulate immune responses distinctly.IMPORTANCE Poxvirus vectors are used in clinical trials as candidate vaccines for several pathogens, yet how these vectors influence the immune system is unknown. We developed distinct poxvirus vectors that express heterologous antigens but lack different inhibitors of the central host-cell signaling pathway. Using mice, we studied the capacity of these viruses to induce innate and adaptive immune responses and showed that these vectors can distinctly regulate the magnitude and quality of these responses. These findings provide important insights into the mechanism of poxvirus-induced immune response and alternative strategies for vaccine vector design.KEYWORDS NF-B, NYVAC, T cell immunity, adaptive immunity, human immunodeficiency virus, immunomodulation, innate immunity, poxvirus, vaccines, vaccinia virus S everal vaccine strategies have been developed to improve immune responses to heterologous antigens expressed by attenuated poxvirus vectors (1). Given the limited effectiveness of the ALVAC poxvirus vector in the RV144 phase III HIV/AIDS clinical trial (2), the need remains to improve poxvirus vector capacity as an immunogen, to increase protection levels, and to understand how innate and adaptive immune responses can be regulated.The attenuated poxvirus strain NYVAC (New York vaccinia virus) has been used as a vaccine vector in HIV clinical trials (3,4). Studies in nonhuman primates showed that NYVAC expressing Env and/or the Gag-Pol-Nef (GPN) clade C HIV antigens elicited a balanced CD4/CD8 T cell response (5) or robust T cell immunity (6). In clinical trials in healthy volunteers and in chronically HIV-infected patients, NYVAC showed clear immunogenic potential to induce expansion of preexisting T cell responses as well as the appearance of newly detected polyfunctional CD8 T cell responses (7).

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Section: Discussionmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Distinct Roles of Vaccinia Virus NF-κB Inhibitor Proteins A52, B15, and K7 in the Immune Response

Pilato

Mejías-Pérez

Sorzano

et al. 2017

J Virol

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Engineering Gene Therapy: Advances and Barriers

Shahryari

Burtscher

Nazari

et al. 2021

Advanced Therapeutics

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Currently, 33 gene‐therapy drugs/products have been approved in the clinic. Over 3000 completed and ongoing clinical gene therapy trials have been reported worldwide. The development/maturation of tools for gene manipulation and gene delivery, as well as molecular advances in the diagnosis of genetic diseases, have played a central role in gene therapy, which have greatly revolutionized the field. Versatile and diverse genetic tools for gene manipulations and deliveries, with the possibility of short and long‐term effects, are vital advantages of gene therapy tools, paving the road for the development of new therapies. However, efficacy and safety concerns, immune system responses, laborious approaches for developing and manufacturing, unknown gene‐therapy drug interactions with the host and the high cost of drugs/products, are significant barriers in gene therapy. Here, the authors review the attempts for engineering of the gene manipulations that have been undertaken in the last three decades and used in clinical trials focusing on 1) gene‐editing platforms, 2) viral gene delivery systems, and 3) nonviral gene tools. In this comprehensive review, the principles of these gene manipulation tools as well as advances and barriers for their application in modern therapies are discussed. Furthermore, trends and future directions in gene therapy are discussed.

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Inflammatory transcription factors as activation markers and functional readouts in immune-to-brain communication

Rummel

2016

Brain, Behavior, and Immunity

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NFκB activation by modified vaccinia virus as a novel strategy to enhance neutrophil migration and HIV-specific T-cell responses

Cited by 29 publications

References 55 publications

Distinct Roles of Vaccinia Virus NF-κB Inhibitor Proteins A52, B15, and K7 in the Immune Response

Distinct Roles of Vaccinia Virus NF-κB Inhibitor Proteins A52, B15, and K7 in the Immune Response

Engineering Gene Therapy: Advances and Barriers

Inflammatory transcription factors as activation markers and functional readouts in immune-to-brain communication

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