Abstract
It is widely anticipated that a prophylactic vaccine may be needed to control the HIV/AIDS epidemic worldwide. Despite over two decades of research, a vaccine against HIV-1 remains elusive, although a recent clinical trial has shown promising results. Recent studies have focused on highly conserved domains within HIV-1 such as the membrane proximal external region (MPER) of the envelope glycoprotein, gp41. MPER has been shown to play critical roles in mucosal transmission of HIV-1, though this peptide is poorly immunogenic on its own. Here we provide evidence that plant-produced HIV-1 enveloped virus-like particles (VLPs) consisting of Gag and a deconstructed form of gp41 comprising the MPER, transmembrane, and cytoplasmic domains (Dgp41) provides an effective platform to display MPER for use as an HIV vaccine candidate. Prime-boost strategies combining systemic and mucosal priming with systemic boosting using two different vaccine candidates (VLPs and CTB-MPR—a fusion of MPER and the B-subunit of cholera toxin) were investigated in BALB/c mice. Serum antibody responses against both the Gag and gp41 antigens were elicited when systemically primed with VLPs. These responses could be recalled following systemic boosting with VLPs. In addition, mucosal priming with VLPs allowed for a boosting response against Gag and gp41 when boosted with either candidate. Importantly, the VLPs also induced Gag-specific CD4 and CD8 T-cell responses. This report on the immunogenicity of plant-based Gag/Dgp41 VLPs may represent an important milestone on the road towards a broadly efficacious and inexpensive subunit vaccine against HIV-1.
Highlights
The HIV-1 transmembrane subunit of the envelope protein (Env), gp41, contains the highly conserved membrane proximal external region, located just outside the lipid viral envelope (MPER, amino acids 661–683, [1])
The gp41 domain that encompasses the MPER and extends toward the C-terminal heptad repeat functions as a galactosyl-ceramide-binding lectin and is critical for mediating viral transcytosis across mucosal membranes [3] and other mucosal transmission routes [4, 5]. Both mucosal and systemic antibodies (Abs) raised against immunogens containing the MPER can block the transcytosis of HIV across the epithelial barrier [6, 7], similar to naturally occurring polyclonal mucosal IgAs found in the mucosal secretions of some highly exposed persistently seronegative (HEPS) individuals [8,9,10,11]
We previously reported that Gag virus-like particles (VLPs) displaying a deconstructed form of gp41 (Dgp41, comprising MPER, transmembrane, and cytoplasmic domains) could be produced in Nicotiana benthamiana plants (Fig 1) [40]
Summary
The HIV-1 transmembrane subunit of the envelope protein (Env), gp, contains the highly conserved membrane proximal external region, located just outside the lipid viral envelope (MPER, amino acids 661–683, [1]). The proximity of the MPER to the viral envelope is increasingly recognized as a major factor in the antigenicity and immunogenicity of the domain [23,24,25], suggesting that the presentation of the MPER in the context of a membrane, e.g. in virus-like particles (VLPs) may be of value This notion and the recent success of prophylactic VLP-based vaccines such as those aimed at human papillomaviruses [26] provide the motivation for VLP-based vaccines against HIV-1. Gag VLPs can display HIV Env proteins on their surface in their native conformation [32], and these VLPs have been shown to induce both Env- and Gag-specific Abs and CTLs [33], making Gag VLPs attractive candidates as an HIV vaccine platform [34]
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