Sublingual Immunization with Chimeric C1q/CD40 Ligand/HIV Virus-like Particles Induces Strong Mucosal Immune Responses against HIV.

Dongliang Liu,Christian Marin-Muller,Qizhi Yao,Changyi Chen,Sheng Zhang,Ethan Poteet

doi:10.3390/vaccines9111236

Dongliang Liu, Christian Marin-Muller + Show 4 more

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https://doi.org/10.3390/vaccines9111236

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Abstract

Development of a vaccine that can elicit robust HIV specific antibody responses in the mucosal compartments is desired for effective prevention of HIV via sexual transmission. However, the current mucosal vaccines have either poor immunogenicity when administered orally or invite safety concerns when administered intranasally. Sublingual immunization has received more attention in recent years based on its efficiency in inducing systemic and mucosal immune responses in both mucosal and extra-mucosal tissues. To facilitate the transport of the immunogen across the sub-mucosal epithelial barrier, we found that CD91, the receptor of C1q, is prevalently expressed in the sublingual mucosal lining, and thus, a modified chimeric C1q surface conjugated CD40L/HIV VLP was generated. The ability of this chimeric C1q/CD40L/HIV VLP to bind, cross the epithelial layer, access and activate the sub-mucosal layer dendritic cells (DCs), and ultimately induce enhanced mucosal and systemic immune responses against HIV is evaluated in this study. We found that C1q/CD40L/HIV VLPs have enhanced binding, increased transport across the epithelial layer, and upregulate DC activation markers as compared to CD40L/HIV VLPs alone. Mice immunized with C1q/CD40L/HIV VLPs by sublingual administration showed higher levels of IgA salivary antibodies against both HIV Gag and Env than mice immunized with CD40L/HIV VLPs. Moreover, sublingual immunization with C1q/CD40L/HIV VLPs induced more Env- and Gag-specific IFN-γ producing T cells than the CD40L/HIV VLPs group. Interestingly, C1q/CD40L/HIV VLP immunization can also induce more mucosal homing T cells than that in CD40L/HIV VLP group. Our data suggest that incorporation of C1q to CD40L/HIV VLPs is a promising novel strategy and that the sublingual immunization can be a favorite immunization route for HIV mucosal vaccines.

Highlights

Gastrointestinal and reproductive mucosal tissues are primary sites for HIV transmission and the draining lymph nodes are susceptible to HIV infection and viral replication which can result in systemic CD4+ T cell deficiency [1,2]
To characterize C1q conjugation to HIV Gag, Bal envelope gp160, CD40 ligand (CD40L) virus-like particles (VLPs) (CD40L/HIV VLPs), we performed C1q specific immunogold staining on VLPs alone and C1q conjugated CD40L/HIV VLPs
To quantify the amount of C1q conjugated to the CD40L/HIV VLP surface, we conjugated C1q to AF488 and determined the ratio of C1q to AF488 to be 1:6.7 (C1q to AF488 respectively), in reference to an AF488 standard curve

Summary

Introduction

Gastrointestinal and reproductive mucosal tissues are primary sites for HIV transmission and the draining lymph nodes are susceptible to HIV infection and viral replication which can result in systemic CD4+ T cell deficiency [1,2]. It is believed that the generation of an HIV specific antibody and cytotoxic T-lymphocyte (CTL) response in the mucosal compartment may preserve CD4+ T-cell populations and provide protection against viral replication, viremia, and/or result in lower viral loads in HIV infected individuals [3]. In HIV vaccine development, sublingual vaccination with an HIV subunit vaccine can induce strong mucosal immune responses evidenced by high levels of antibodies and CTLs detected in the mouse female genital tract [6]. By using adenoviral vector encoding HIV-Gag or HIV-envelope gp120 (Env), sublingual immunization can elicit both mucosal and systemic immunity against HIV [7,8]. These data indicate the sublingual immunization route is a promising route for mucosal vaccine development

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