Co-administration of plasmid-encoded granulocyte-macrophage colony-stimulating factor increases human immunodeficiency virus-1 DNA vaccine-induced polyfunctional CD4+ T-cell responses.

Vinicius Canato Santana,Rafael Ribeiro Almeida,Daniela Santoro Rosa,Susan Pereira Ribeiro,Edecio Cunha Neto,Jorge Kalil,Luís Carlos De Souza Ferreira

doi:10.1590/0074-02760150283

Abstract

T-cell based vaccines against human immunodeficiency virus (HIV) generate specific responses that may limit both transmission and disease progression by controlling viral load. Broad, polyfunctional, and cytotoxic CD4+T-cell responses have been associated with control of simian immunodeficiency virus/HIV-1 replication, supporting the inclusion of CD4+ T-cell epitopes in vaccine formulations. Plasmid-encoded granulocyte-macrophage colony-stimulating factor (pGM-CSF) co-administration has been shown to induce potent CD4+ T-cell responses and to promote accelerated priming and increased migration of antigen-specific CD4+ T-cells. However, no study has shown whether co-immunisation with pGM-CSF enhances the number of vaccine-induced polyfunctional CD4+ T-cells. Our group has previously developed a DNA vaccine encoding conserved, multiple human leukocyte antigen (HLA)-DR binding HIV-1 subtype B peptides, which elicited broad, polyfunctional and long-lived CD4+ T-cell responses. Here, we show that pGM-CSF co-immunisation improved both magnitude and quality of vaccine-induced T-cell responses, particularly by increasing proliferating CD4+ T-cells that produce simultaneously interferon-γ, tumour necrosis factor-α and interleukin-2. Thus, we believe that the use of pGM-CSF may be helpful for vaccine strategies focused on the activation of anti-HIV CD4+ T-cell immunity.

Highlights

A safe and effective human immunodeficiency virus (HIV) vaccine is still the most promising strategy for controlling the acquired immune deficiency syndrome pandemic
To evaluate the impact of GMCSF on the breadth of T-cell responses we measured the frequency of IFN-γ-secreting T-cells against individual HIVBr18-encoded peptides and observed that co-administration of Plasmid-encoded granulocyte-macrophage colony-stimulating factor (pGM-CSF) enhanced the magnitude of T-cell responses, no difference was observed in the number of recognised peptides (Fig. 1B)
Co-administration of pGM-CSF increases the frequency of HIVBr18-induced polyfunctional CD4+ Tcells - We addressed the question whether GM-CSF would improve the quality of HIVBr18-induced immune responses by measuring the frequency of antigenspecific polyfunctional CD4+ T-cells

Summary

Introduction

A safe and effective human immunodeficiency virus (HIV) vaccine is still the most promising strategy for controlling the acquired immune deficiency syndrome pandemic. While the clinical associations of CD4+ T-cell responses and HIV-1 control face a cause-effect issue, the finding that CD4+ T-cell depletion contributes to reducing vaccine-mediated protection against SIV (Vaccari et al 2008) supports a direct role of such cells in antiviral immunity. In order to induce HIV-specific CD4+ T-cell responses, our group developed a DNA vaccine encoding multiple human leukocyte antigen (HLA)-DR binding HIV1 subtype B conserved peptides (HIVBr18). DNA vaccine immunisation leads to direct transfection of antigen presenting cells (APCs) and tissue-resident-cells, providing local and systemic expression of target antigens and subsequent induction of cellular and humoral immunity. Professional APCs are not typically found in muscle tissue and they need to migrate to the inoculation site in response to inflammatory or chemotactic signals before an efficient immune response is mounted (Kutzler & Weiner 2008)

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Conclusion