Novel mucosal DNA-MVA HIV vaccination in which DNA-IL-12 plus cholera toxin B subunit (CTB) cooperates to enhance cellular systemic and mucosal genital tract immunity.

Cynthia Maeto,Ana María Rodríguez,María Magdalena Gherardi,María Pía Holgado,Juliana Falivene,Clive M Gray

doi:10.1371/journal.pone.0107524

Abstract

Induction of local antiviral immune responses at the mucosal portal surfaces where HIV-1 and other viral pathogens are usually first encountered remains a primary goal for most vaccines against mucosally acquired viral infections. Exploring mucosal immunization regimes in order to find optimal vector combinations and also appropriate mucosal adjuvants in the HIV vaccine development is decisive. In this study we analyzed the interaction of DNA-IL-12 and cholera toxin B subunit (CTB) after their mucosal administration in DNA prime/MVA boost intranasal regimes, defining the cooperation of both adjuvants to enhance immune responses against the HIV-1 Env antigen. Our results demonstrated that nasal mucosal DNA/MVA immunization schemes can be effectively improved by the co-delivery of DNA-IL-12 plus CTB inducing elevated HIV-specific CD8 responses in spleen and more importantly in genital tract and genito-rectal draining lymph nodes. Remarkably, these CTL responses were of superior quality showing higher avidity, polyfunctionality and a broader cytokine profile. After IL-12+CTB co-delivery, the cellular responses induced showed an enhanced breadth recognizing with higher efficiency Env peptides from different subtypes. Even more, an in vivo CTL cytolytic assay demonstrated the higher specific CD8 T-cell performance after the IL-12+CTB immunization showing in an indirect manner its potential protective capacity. Improvements observed were maintained during the memory phase where we found higher proportions of specific central memory and T memory stem-like cells T-cell subpopulations. Together, our data show that DNA-IL-12 plus CTB can be effectively employed acting as mucosal adjuvants during DNA prime/MVA boost intranasal vaccinations, enhancing magnitude and quality of HIV-specific systemic and mucosal immune responses.

Highlights

Natural transmission of HIV and SIV occurs predominantly via mucosal surfaces, which are the major entry points of these viruses and concomitantly are the first line of host defense to combat the infection
With the aim to evaluate the IL-12 plus cholera toxin B subunit (CTB) action on DNA/MVA regimes administered by intranasal route, different immunization schemes were designed in order to delineate the best DNA-IL-12 dose and to discern the benefits of IL-12 and CTB codelivery
All groups were boosted with 107 PFU/animal of MVAEnvB, but in those groups which had previously received cholera toxin (CT) or CTB during priming, the viral boost had the incorporation of CT or CTB respectively

Summary

Introduction

Natural transmission of HIV and SIV occurs predominantly via mucosal surfaces, which are the major entry points of these viruses and concomitantly are the first line of host defense to combat the infection. Once the mucosal epithelial barrier is crossed, a small founder population of infected cells is rapidly established. Local viral expansion occurs during the first week and later, a selfpropagating systemic infection throughout the secondary lymphoid organs is established [1,2]. The small infected founder populations implied during HIV-1 mucosal transmission clearly indicate that the greatest opportunities for prevention may be strategies that target these initially small and genetically homogeneous foci of mucosal infection in the first week of infection [2]. Despite evidences related to the kinetic characteristics of the infection and the mucosal natural transmission of the virus, mucosal surfaces are not targeted by most HIV vaccines currently under trial (http://www.iavi.org). Most of the research emphasis is focused on the analysis of systemic routes of inoculation, mainly the intramuscular one

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Conclusion